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Vaidyanathan, Ganesan

Overview:

Dr. Vaidyanathan is a professor in the Department of Radiology.  He is a member of the Nuclear Medicine track of the Medical Physics Graduate Program.  His research involves development of radiopharmaceuticals especially for oncologic applications.  Some of the projects he is involved in are given below.


I.          New methods of radiohalogenating antibodies and its variants 

a) Development of newer residualizing agents for the radiohalogenation of internalizing monoclonal antibodies.


b)  Development of fluorine-18 labeled residualizing agents for labeling nanobodies.


c) Pre-targeting approach via bioorthogonal chemistry for in vivo labeling of antibodies and nanobodies with 18F and 211At.


d)  Methods to label antibodies pre-conjugated with a prosthetic group of the tin precursor of residualizing agents.


e) Multimodal prosthetic groups for labeling antibodies and peptides with multiple radioisotopes.


II.         MIBG Analogs for PET imaging

Radioiodinated MIBG is used in the diagnosis of the pathophysiology of the heart as well as neuroendocrine tumors such as neuroblastoma (NB).  Design and development of newer fluorine-18 labeled MIBG analogues useful in the PET imaging of NB as well as that of myocardial diseases.

III. Noninvasive Imaging of Alkylguanine-DNA alkyltransferase (AGT) 

AGT is a DNA repair protein and is primarily responsible for drug resistance in alkylator chemotherapy. An inverse correlation has been established between the tumor AGT content and the therapeutic outcome. The amount of AGT varies from tumor to tumor and within a group of patients of similar cancer. Thus, it is important to quantify tumor AGT of individual patients before administering alkylator chemotherapy. Our goal is to develop radiolabeled agents with which AGT can be quantified in a noninvasive manner by PET or SPECT imaging. 

IV. PSMA targeting for prostate cancer therapy 

Development of At-211 labeled urea-based inhibitor of Prostate-specific membrane antigen.

Positions:

Professor in Radiology

Radiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1987

Ph.D. — University of Kentucky at Lexington

Grants:

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 1985
End Date
December 31, 2020

Human EGFRvIII-specific BiTE for the treatment of Glioblastoma

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
July 01, 2015
End Date
June 30, 2020

Labeling nanobodies with 18F residualizing labels for HER2 specific PET imaging

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2015
End Date
April 30, 2020

Development of Tethered Hsp90 Inhibitors Carrying Radioiodinated Probes to Specifically Discriminate and Kill Malignant

Administered By
Radiology
AwardedBy
Department of Defense
Role
Investigator
Start Date
May 01, 2015
End Date
April 30, 2018

Novel Radiohalogenation Strategies for Enhancing Imaging and Targeted Radiotherapy

Administered By
Radiology
AwardedBy
Memorial Sloan Kettering Cancer Center
Role
Co-Principal Investigator
Start Date
August 01, 2016
End Date
July 31, 2017

Development of a Targeted Radionuclide Therapy for Triple Negative Breast Cancer

Administered By
Radiology
AwardedBy
OncoTAb, Inc.
Role
Principal Investigator
Start Date
September 19, 2016
End Date
June 18, 2017

Small Molecule PSMA-Targeted Alpha Therapy

Administered By
Radiology
AwardedBy
Johns Hopkins University
Role
Co Investigator
Start Date
May 01, 2014
End Date
April 30, 2017

Enhancing the efficacy of targeted radiotherapy for neuroblastoma

Administered By
Radiology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
September 30, 2013
End Date
September 29, 2014

Cross-disciplinary Training in Medical Physics

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2007
End Date
June 30, 2013

Brain Tumors - Immunological and Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
April 20, 2001
End Date
March 31, 2013

Small Animal PET / CT Molecular Imaging

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Major User
Start Date
April 01, 2011
End Date
March 31, 2012

Radionuclide-based Molecular Imaging of the DNA Repair Protein AGT

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2009
End Date
February 28, 2011

Astatine-211 Radiochemistry: The Development of Methodologies for High Activity Level Radio-Synthesis

Administered By
Radiology
AwardedBy
Department of Energy
Role
Co Investigator
Start Date
September 15, 2008
End Date
December 14, 2010

Imaging of O6-Alkylguianine-DNA Alkyltransferase

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2002
End Date
August 31, 2007

Targeted Radiotherapeutics: Chemical and Biological Aspects

Administered By
Radiology
AwardedBy
Department of Energy
Role
Investigator
Start Date
December 01, 2004
End Date
November 30, 2006

Astatine-211 & Radioiodine Labeled Octreotide Conjugates

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Associate in Research
Start Date
July 01, 2001
End Date
June 30, 2006

Anti-Tenascin Antibody Constructs

Administered By
Radiology
AwardedBy
Department of Energy
Role
Co Investigator
Start Date
May 01, 1995
End Date
November 30, 2005

Molecular Imaging Center Planning Grant

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Project Leader
Start Date
August 01, 2000
End Date
July 31, 2004

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1999
End Date
January 31, 2004

MIBG Analogue Radiopharmaceuticals

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1997
End Date
June 30, 2003

Brain Tumors--Immunological and Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
December 01, 1976
End Date
March 31, 2001

Brain Tumors - Immunological And Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1997
End Date
March 31, 1999

Src On Primary And Matastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1994
End Date
March 31, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1994
End Date
March 31, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1993
End Date
January 31, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1985
End Date
January 31, 1999

Positron Emission Imaging Of Tumors Using Monoclonal Antib

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Co-Principal Investigator
Start Date
November 01, 1995
End Date
October 31, 1998

Migb And Analogs For Diagnosis And Therapy

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1994
End Date
March 31, 1998

Mibg And Analogs For Diagnosis And Therapy

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1998

Mibg And Analogs For Diagnosis And Therapy

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1998

Migb And Analogs For Diagnosis And Therapy

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1998

Cancer And Leukemia Group B Statistical Center

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1992
End Date
March 31, 1993
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Publications:

Synthesis and preliminary evaluation of 5-[18F] fluoroleucine.

Amino acid transporters, such as LAT1, are overexpressed in aggressive prostate and breast carcinomas, directly influencing pathways of growth and proliferation.The purpose of this study is to synthesize and characterize a novel 18F labeled leucine analog, 5-[18F]fluoroleucine, as a potential imaging agent for aggressive tumors which may not be amenable to imaging by FDG PET.5-fluoroleucine was synthesized and characterized, and its 18F-labeled analog was synthesized from a mesylate precursor. First, breast cancer cell line assays were performed to evaluate uptake of L-leucine and other essential amino acids. Both L-leucine and 5-[18F]fluoroleucine were tested for uptake and accumulation over time, and for uptake via LAT1. Biodistribution studies were performed to estimate radiation dosimetry for human studies. Small animal PET / CT studies of a breast cancer were performed to evaluate in vivo 5-[18F]fluoroleucine tumor uptake.Breast cancer cell lines showed increasing high net accumulation of L-leucine. Both L-leucine and 5-[18F]fluoroleucine showed increasing uptake over time in in vitro tumor cell assays, and uptake was also shown to occur via LAT1. The biodistribution study of 5-[18F]fluoroleucine showed rapid renal excretion, no significant in vivo metabolism, and acceptable dosimetry for use in humans. In vivo small animal PET / CT imaging of a breast cancer xenograft showed uptake of 5-[18F]fluoroleucine in the tumor, which progressively increased over time.5-[18F]fluoroleucine is a leucine analog which may be useful in identifying tumors with high or upregulated expression of amino acid transporters, providing additional information that may not be provided by FDG PET.

Authors
Chin, BB; McDougald, D; Weitzel, D; Hawk, T; Reiman, RE; Zalutsky, MR; Vaidyanathan, G
MLA Citation
Chin, BB, McDougald, D, Weitzel, D, Hawk, T, Reiman, RE, Zalutsky, MR, and Vaidyanathan, G. "Synthesis and preliminary evaluation of 5-[18F] fluoroleucine." Current radiopharmaceuticals (December 30, 2016).
Website
http://hdl.handle.net/10161/13590
PMID
28034351
Source
epmc
Published In
Current Radiopharmaceuticals
Publish Date
2016

(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy.

Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, 211At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC).PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid (211At- 6: ) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human PC cells after 211At- 6: treatment. The antitumor efficacy of 211At- 6: was evaluated in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA+, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts. Suborgan distribution was evaluated using α-camera images, and microscale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo.211At- 6: treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA+ PC3 PIP cells and caused significant tumor growth delay in PSMA+ PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of 211At- 6: in PSMA+ PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on α-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy.PSMA-targeted 211At- 6: α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. 211At- 6: also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry.

Authors
Kiess, AP; Minn, I; Vaidyanathan, G; Hobbs, RF; Josefsson, A; Shen, C; Brummet, M; Chen, Y; Choi, J; Koumarianou, E; Baidoo, K; Brechbiel, MW; Mease, RC; Sgouros, G; Zalutsky, MR; Pomper, MG
MLA Citation
Kiess, AP, Minn, I, Vaidyanathan, G, Hobbs, RF, Josefsson, A, Shen, C, Brummet, M, Chen, Y, Choi, J, Koumarianou, E, Baidoo, K, Brechbiel, MW, Mease, RC, Sgouros, G, Zalutsky, MR, and Pomper, MG. "(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57.10 (October 2016): 1569-1575.
PMID
27230930
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
57
Issue
10
Publish Date
2016
Start Page
1569
End Page
1575

Anti-HER2 Single Domain Antibody 2Rs15d Labeled with F-18 Using a Residualizing Label: Preliminary Evaluation

Authors
Vaidyanathan, GV; Zhou, Z; McDougald, D; Lahoutte, T; Zalutsky, MR
MLA Citation
Vaidyanathan, GV, Zhou, Z, McDougald, D, Lahoutte, T, and Zalutsky, MR. "Anti-HER2 Single Domain Antibody 2Rs15d Labeled with F-18 Using a Residualizing Label: Preliminary Evaluation." October 2016.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
43
Publish Date
2016
Start Page
S179
End Page
S179

Preclinical Evaluation of 18F-Labeled Anti-HER2 Nanobody Conjugates for Imaging HER2 Receptor Expression by Immuno-PET.

The human growth factor receptor type 2 (HER2) is overexpressed in breast as well as other types of cancer. Immuno-PET, a noninvasive imaging procedure that could assess HER2 status in both primary and metastatic lesions simultaneously, could be a valuable tool for optimizing application of HER2-targeted therapies in individual patients. Herein, we have evaluated the tumor-targeting potential of the 5F7 anti-HER2 Nanobody (single-domain antibody fragment; ∼13 kDa) after (18)F labeling by 2 methods.The 5F7 Nanobody was labeled with (18)F using the novel residualizing label N-succinimidyl 3-((4-(4-(18)F-fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ((18)F-SFBTMGMB; (18)F-RL-I) and also via the most commonly used (18)F protein-labeling prosthetic agent N-succinimidyl 3-(18)F-fluorobenzoate ((18)F-SFB). For comparison, 5F7 Nanobody was also labeled using the residualizing radioiodination agent N-succinimidyl 4-guanidinomethyl-3-(125)I-iodobenzoate ((125)I-SGMIB). Paired-label ((18)F/(125)I) internalization assays and biodistribution studies were performed on HER2-expressing BT474M1 breast carcinoma cells and in mice with BT474M1 subcutaneous xenografts, respectively. Small-animal PET/CT imaging of 5F7 Nanobody labeled using (18)F-RL-I also was performed.Internalization assays indicated that intracellularly retained radioactivity for (18)F-RL-I-5F7 was similar to that for coincubated (125)I-SGMIB-5F7, whereas that for (18)F-SFB-5F7 was lower than coincubated (125)I-SGMIB-5F7 and decreased with time. BT474M1 tumor uptake of (18)F-RL-I-5F7 was 28.97 ± 3.88 percentage injected dose per gram of tissue (%ID/g) at 1 h and 36.28 ± 14.10 %ID/g at 2 h, reduced by more than 90% on blocking with trastuzumab, indicating HER2 specificity of uptake, and was also 26%-28% higher (P < 0.05) than that of (18)F-SFB-5F7. At 2 h, the tumor-to-blood ratio for (18)F-RL-I-5F7 (47.4 ± 13.1) was significantly higher (P < 0.05) than for (18)F-SFB-5F7 (25.4 ± 10.3); however, kidney uptake was 28-36-fold higher for (18)F-RL-I-5F7.(18)F-RL-I-5F7 is a promising tracer for evaluating HER2 status by immuno-PET; however, in settings in which renal background is problematic, strategies for reducing its kidney uptake may be needed.

Authors
Vaidyanathan, G; McDougald, D; Choi, J; Koumarianou, E; Weitzel, D; Osada, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Choi, J, Koumarianou, E, Weitzel, D, Osada, T, Lyerly, HK, and Zalutsky, MR. "Preclinical Evaluation of 18F-Labeled Anti-HER2 Nanobody Conjugates for Imaging HER2 Receptor Expression by Immuno-PET." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57.6 (June 2016): 967-973.
PMID
26912425
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
57
Issue
6
Publish Date
2016
Start Page
967
End Page
973
DOI
10.2967/jnumed.115.171306

N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([(18)F]SFBTMGMB): a residualizing label for (18)F-labeling of internalizing biomolecules.

Residualizing labeling methods for internalizing peptides and proteins are designed to trap the radionuclide inside the cell after intracellular degradation of the biomolecule. The goal of this work was to develop a residualizing label for the (18)F-labeling of internalizing biomolecules based on a template used successfully for radioiodination. N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(bis-Boc-guanidinomethyl)benzoate ([(18)F]SFBTMGMB-Boc2) was synthesized by a click reaction of an azide precursor and [(18)F]fluorohexyne in 8.5 ± 2.8% average decay-corrected radiochemical yield (n = 15). An anti-HER2 nanobody 5F7 was labeled with (18)F using [(18)F]SFBTMGMB ([(18)F]RL-I), obtained by the deprotection of [(18)F]SFBTMGMB-Boc2, in 31.2 ± 6.7% (n = 5) conjugation efficiency. The labeled nanobody had a radiochemical purity of >95%, bound to HER2-expressing BT474M1 breast cancer cells with an affinity of 4.7 ± 0.9 nM, and had an immunoreactive fraction of 62-80%. In summary, a novel residualizing prosthetic agent for labeling biomolecules with (18)F has been developed. An anti-HER2 nanobody was labeled using this prosthetic group with retention of affinity and immunoreactivity to HER2.

Authors
Vaidyanathan, G; McDougald, D; Choi, J; Pruszynski, M; Koumarianou, E; Zhou, Z; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Choi, J, Pruszynski, M, Koumarianou, E, Zhou, Z, and Zalutsky, MR. "N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([(18)F]SFBTMGMB): a residualizing label for (18)F-labeling of internalizing biomolecules." Organic & biomolecular chemistry 14.4 (January 2016): 1261-1271.
PMID
26645790
Source
epmc
Published In
Organic & Biomolecular Chemistry
Volume
14
Issue
4
Publish Date
2016
Start Page
1261
End Page
1271
DOI
10.1039/c5ob02258d

An Anti-HER2 Nanobody Labeled with 18F Using a Residualizing Label for Assessing HER2 Status

Authors
Vaidyanathan, G; McDougald, D; Choi, J; Koumarianou, E; Pruszynski, M; Osada, T; Lyerly, H; Lahoutte, T; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Choi, J, Koumarianou, E, Pruszynski, M, Osada, T, Lyerly, H, Lahoutte, T, and Zalutsky, MR. "An Anti-HER2 Nanobody Labeled with 18F Using a Residualizing Label for Assessing HER2 Status." October 2015.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
42
Publish Date
2015
Start Page
S102
End Page
S102

Abstract 1610: Development of meta-[211At]astatobenzylguanidine ([211At]MABG) as an alpha particle emitting systemic targeted radiotherapeutic for neuroblastoma

Authors
Batra, V; Ranieri, P; Makvandi, M; Tsang, M; Hou, C; Li, Y; Vaidyanathan, G; Pryma, DA; Maris, JM
MLA Citation
Batra, V, Ranieri, P, Makvandi, M, Tsang, M, Hou, C, Li, Y, Vaidyanathan, G, Pryma, DA, and Maris, JM. "Abstract 1610: Development of meta-[211At]astatobenzylguanidine ([211At]MABG) as an alpha particle emitting systemic targeted radiotherapeutic for neuroblastoma." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
1610
End Page
1610
DOI
10.1158/1538-7445.AM2015-1610

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG.

Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an (18)F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG).Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with (18)F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [(125)I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values.[(18)F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [(18)F]FPOIBG at 2h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [(125)I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The (125)I-labeled congener of FPOIBG gave similar results. On the other hand, [(18)F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [(125)I]MIBG. IC50 values for FPOIBG were higher than those obtained for MIBG and FPOBBG. Unlike the case with [(18)F]FPOBBG, the heart uptake [(18)F]FPOIBG in normal mice was significantly lower than that of MIBG.Although [(18)F]FPOIBG does not appear to warrant further consideration as an (18)F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing.An (18)F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although (18)F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.

Authors
Vaidyanathan, G; McDougald, D; Koumarianou, E; Choi, J; Hens, M; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Koumarianou, E, Choi, J, Hens, M, and Zalutsky, MR. "Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG." Nuclear medicine and biology 42.8 (August 2015): 673-684.
PMID
25956997
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
42
Issue
8
Publish Date
2015
Start Page
673
End Page
684
DOI
10.1016/j.nucmedbio.2015.04.005

Preclinical development of Meta-[At-211]astatobenzylguanidine ([At-211]MABG) as an alpha particle emitting systemic targeted radiotherapeutic for neuroblastoma (NB).

Authors
Batra, V; Makvandi, M; Ranieri, P; Tsang, M; Hou, C; Li, Y; Vaidyanathan, G; Maris, J; Pryma, D
MLA Citation
Batra, V, Makvandi, M, Ranieri, P, Tsang, M, Hou, C, Li, Y, Vaidyanathan, G, Maris, J, and Pryma, D. "Preclinical development of Meta-[At-211]astatobenzylguanidine ([At-211]MABG) as an alpha particle emitting systemic targeted radiotherapeutic for neuroblastoma (NB)." May 1, 2015.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
56
Issue
3
Publish Date
2015

A At-211-labeled nanobody for alpha-particle therapy of HER2-expressing cancers

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; Lahoutte, T; Zalutsky, M
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, Lahoutte, T, and Zalutsky, M. "A At-211-labeled nanobody for alpha-particle therapy of HER2-expressing cancers." May 1, 2015.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
56
Issue
3
Publish Date
2015

D-Amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination.

Proteins that undergo receptor-mediated endocytosis are subject to lysosomal degradation, requiring radioiodination methods that minimize loss of radioactivity from tumor cells after this process occurs. To accomplish this, we developed the residualizing radioiodination agent N(ϵ)-(3-[(*)I]iodobenzoyl)-Lys(5)-N(α)-maleimido-Gly(1)-D-GEEEK (Mal-D-GEEEK-[(*)I]IB), which enhanced tumor uptake but also increased kidney activity and necessitates generation of sulfhydryl moieties on the protein. The purpose of the current study was to synthesize and evaluate a new D-amino acid based agent that might avoid these potential problems.N(α)-(3-iodobenzoyl)-(5-succinimidyloxycarbonyl)-D-EEEG (NHS-IB-D-EEEG), which contains 3 D-glutamates to provide negative charge and a N-hydroxysuccinimide function to permit conjugation to unmodified proteins, and the corresponding tin precursor were produced by solid phase peptide synthesis and subsequent conjugation with appropriate reagents. Radioiodination of the anti-HER2 antibody trastuzumab using NHS-IB-D-EEEG and Mal-D-GEEEK-IB was compared. Paired-label internalization assays on BT474 breast carcinoma cells and biodistribution studies in athymic mice bearing BT474M1 xenografts were performed to evaluate the two radioiodinated D-peptide trastuzumab conjugates.NHS-[(131)I]IB-D-EEEG was produced in 53.8%±13.4% and conjugated to trastuzumab in 39.5%±7.6% yield. Paired-label internalization assays with trastuzumab-NHS-[(131)I]IB-D-EEEG and trastuzumab-Mal-D-GEEEK-[(125)I]IB demonstrated similar intracellular trapping for both conjugates at 1h ((131)I, 84.4%±6.1%; (125)I, 88.6%±5.2%) through 24h ((131)I, 60.7%±6.8%; (125)I, 64.9%±6.9%). In the biodistribution experiment, tumor uptake peaked at 48 h (trastuzumab-NHS-[(131)I]IB-D-EEEG, 29.8%±3.6%ID/g; trastuzumab-Mal-D-GEEEK-[(125)I]IB, 45.3%±5.3%ID/g) and was significantly higher for (125)I at all time points. In general, normal tissue levels were lower for trastuzumab-NHS-[(131)I]IB-D-EEEG, with the differences being greatest in kidneys ((131)I, 2.2%±0.4%ID/g; (125)I, 16.9%±2.8%ID/g at 144 h).NHS-[(131)I]IB-D-EEEG warrants further evaluation as a residualizing radioiodination agent for labeling internalizing antibodies/fragments, particularly for applications where excessive renal accumulation could be problematic.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Chitneni, S; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Chitneni, S, and Zalutsky, MR. "D-Amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination." Nuclear medicine and biology 42.1 (January 2015): 19-27.
Website
http://hdl.handle.net/10161/10679
PMID
25240914
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
42
Issue
1
Publish Date
2015
Start Page
19
End Page
27
DOI
10.1016/j.nucmedbio.2014.08.007

A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy.

Nanomedicine has attracted increasing attention in recent years, because it offers great promise to provide personalized diagnostics and therapy with improved treatment efficacy and specificity. In this study, we developed a gold nanostar (GNS) probe for multi-modality theranostics including surface-enhanced Raman scattering (SERS) detection, x-ray computed tomography (CT), two-photon luminescence (TPL) imaging, and photothermal therapy (PTT). We performed radiolabeling, as well as CT and optical imaging, to investigate the GNS probe's biodistribution and intratumoral uptake at both macroscopic and microscopic scales. We also characterized the performance of the GNS nanoprobe for in vitro photothermal heating and in vivo photothermal ablation of primary sarcomas in mice. The results showed that 30-nm GNS have higher tumor uptake, as well as deeper penetration into tumor interstitial space compared to 60-nm GNS. In addition, we found that a higher injection dose of GNS can increase the percentage of tumor uptake. We also demonstrated the GNS probe's superior photothermal conversion efficiency with a highly concentrated heating effect due to a tip-enhanced plasmonic effect. In vivo photothermal therapy with a near-infrared (NIR) laser under the maximum permissible exposure (MPE) led to ablation of aggressive tumors containing GNS, but had no effect in the absence of GNS. This multifunctional GNS probe has the potential to be used for in vivo biosensing, preoperative CT imaging, intraoperative detection with optical methods (SERS and TPL), as well as image-guided photothermal therapy.

Authors
Liu, Y; Ashton, JR; Moding, EJ; Yuan, H; Register, JK; Fales, AM; Choi, J; Whitley, MJ; Zhao, X; Qi, Y; Ma, Y; Vaidyanathan, G; Zalutsky, MR; Kirsch, DG; Badea, CT; Vo-Dinh, T
MLA Citation
Liu, Y, Ashton, JR, Moding, EJ, Yuan, H, Register, JK, Fales, AM, Choi, J, Whitley, MJ, Zhao, X, Qi, Y, Ma, Y, Vaidyanathan, G, Zalutsky, MR, Kirsch, DG, Badea, CT, and Vo-Dinh, T. "A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy." Theranostics 5.9 (January 2015): 946-960.
Website
http://hdl.handle.net/10161/11045
PMID
26155311
Source
epmc
Published In
Theranostics
Volume
5
Issue
9
Publish Date
2015
Start Page
946
End Page
960
DOI
10.7150/thno.11974

N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: influence of isomeric substitution on radiolabeling and target cell residualization.

N-succinimidyl 4-guanidinomethyl-3-[(*)I]iodobenzoate ([(*)I]SGMIB) has shown promise for the radioiodination of monoclonal antibodies (mAbs) and other proteins that undergo extensive internalization after receptor binding, enhancing tumor targeting compared to direct electrophilic radioiodination. However, radiochemical yields for [(131)I]SGMIB synthesis are low, which we hypothesize is due to steric hindrance from the Boc-protected guanidinomethyl group ortho to the tin moiety. To overcome this, we developed the isomeric compound, N-succinimidyl 3-guanidinomethyl-5-[(131)I]iodobenzoate (iso-[(131)I]SGMIB) wherein this bulky group was moved from ortho to meta position.Boc2-iso-SGMIB standard and its tin precursor, N-succinimidyl 3-((1,2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-(trimethylstannyl)benzoate (Boc2-iso-SGMTB), were synthesized using two disparate routes, and iso-[*I]SGMIB synthesized from the tin precursor. Two HER2-targeted vectors - trastuzumab (Tras) and a nanobody 5F7 (Nb) - were labeled using iso-[(*)I]SGMIB and [(*)I]SGMIB. Paired-label internalization assays in vitro with both proteins, and biodistribution in vivo with trastuzumab, labeled using the two isomeric prosthetic agents were performed.When the reactions were performed under identical conditions, radioiodination yields for the synthesis of Boc2-iso-[(131)I]SGMIB were significantly higher than those for Boc2-[(131)I]SGMIB (70.7±2.0% vs 56.5±5.5%). With both Nb and trastuzumab, conjugation efficiency also was higher with iso-[(131)I]SGMIB than with [(131)I]SGMIB (Nb, 33.1±7.1% vs 28.9±13.0%; Tras, 45.1±4.5% vs 34.8±10.3%); however, the differences were not statistically significant. Internalization assays performed on BT474 cells with 5F7 Nb indicated similar residualizing capacity over 6h; however, at 24h, radioactivity retained intracellularly for iso-[(131)I]SGMIB-Nb was lower than for [(125)I]SGMIB-Nb (46.4±1.3% vs 56.5±2.5%); similar results were obtained using Tras. Likewise, a paired-label biodistribution of Tras labeled using iso-[(125)I]SGMIB and [(131)I]SGMIB indicated an up to 22% tumor uptake advantage at later time points for [(131)I]SGMIB-Tras.Given the higher labeling efficiency obtained with iso-SGMIB, this residualizing agent might be of value for use with shorter half-life radiohalogens.

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; McDougald, D; Pruszynski, M; Osada, T; Lahoutte, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, McDougald, D, Pruszynski, M, Osada, T, Lahoutte, T, Lyerly, HK, and Zalutsky, MR. "N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: influence of isomeric substitution on radiolabeling and target cell residualization." Nuclear medicine and biology 41.10 (November 2014): 802-812.
PMID
25156548
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
41
Issue
10
Publish Date
2014
Start Page
802
End Page
812
DOI
10.1016/j.nucmedbio.2014.07.005

Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic.

Modular nanotransporters (MNTs) are vehicles designed to transport drugs from the cell surface via receptor-mediated endocytosis and endosomal escape to nucleus. Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with (67)Ga.EGF was the targeting ligand on the MNT, and NOTA was selected for its radiolabeling with (67)Ga. In the radiolabeling study we dealt with the precipitation of MNT (pI 5.7) at the labeling pH (4.5-5.5) of (67)Ga. Cellular and nuclei uptake of (67)Ga-NOTA-MNT by the A431 cell line was determined. Its specific cytotoxicity was compared to that of (67)Ga-EDTA, (67)Ga-NOTA-BSA and (67)Ga-NOTA-hEGF, in A431 and U87MGWTT, cell lines, by clonogenic assay. Dosimetry studies were also performed.(67)Ga-NOTA-MNT was produced with 90% yield and specific activity of 25.6mCi/mg. The in vitro kinetics revealed an increased uptake over 24h. 55% of the internalized radioactivity was detected in the nuclei at 1h. The cytotoxicity of (67)Ga-NOTA-MNT on A431 cell line was 17 and 385-fold higher when compared to non-specific (67)Ga-NOTA-BSA and (67)Ga-EDTA. While its cytotoxic potency was 13 and 72-fold higher when compared to (67)Ga-NOTA-hEGF in the A431 and the U87MGWTT cell lines, respectively, validating its nuclear localization. The absorbed dose, for 63% cell killing, was 8Gy, confirming the high specific index of (67)Ga.These results demonstrate the feasibility of using MNT as a platform for single cell kill targeted radiotherapy by Auger electron emitters.

Authors
Koumarianou, E; Slastnikova, TA; Pruszynski, M; Rosenkranz, AA; Vaidyanathan, G; Sobolev, AS; Zalutsky, MR
MLA Citation
Koumarianou, E, Slastnikova, TA, Pruszynski, M, Rosenkranz, AA, Vaidyanathan, G, Sobolev, AS, and Zalutsky, MR. "Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic." Nuclear medicine and biology 41.6 (July 2014): 441-449.
PMID
24776093
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
41
Issue
6
Publish Date
2014
Start Page
441
End Page
449
DOI
10.1016/j.nucmedbio.2014.03.026

PRE-CLINICAL EFFICACY STUDY OF INTRA-THECAL (IT) (LU)-L-177-DOTA-TATE (SOMATOSTATIN ANALOGUE) IN ATHYMIC RATS WITH LEPTOMENINGEAL DISEASE (LMD) FROM MEDULLOBLASTOMA (MBL)

Authors
Vaidyanathan, G; Gururangan, S; Bigner, D; Zalutsky, M
MLA Citation
Vaidyanathan, G, Gururangan, S, Bigner, D, and Zalutsky, M. "PRE-CLINICAL EFFICACY STUDY OF INTRA-THECAL (IT) (LU)-L-177-DOTA-TATE (SOMATOSTATIN ANALOGUE) IN ATHYMIC RATS WITH LEPTOMENINGEAL DISEASE (LMD) FROM MEDULLOBLASTOMA (MBL)." June 2014.
Source
wos-lite
Published In
Neuro-Oncology
Volume
16
Publish Date
2014
Start Page
71
End Page
71

Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling.

Nanobodies are approximately 15-kDa proteins based on the smallest functional fragments of naturally occurring heavy chain-only antibodies and represent an attractive platform for the development of molecularly targeted agents for cancer diagnosis and therapy. Because the human epidermal growth factor receptor type 2 (HER2) is overexpressed in breast and ovarian carcinoma, as well as in other malignancies, HER2-specific Nanobodies may be valuable radiodiagnostics and therapeutics for these diseases. The aim of the present study was to evaluate the tumor-targeting potential of anti-HER2 5F7GGC Nanobody after radioiodination with the residualizing agent N-succinimidyl 4-guanidinomethyl 3-(125/131)I-iodobenzoate (*I-SGMIB).The 5F7GGC Nanobody was radiolabeled using *I-SGMIB and, for comparison, with N(ε)-(3-*I-iodobenzoyl)-Lys(5)-N(α)-maleimido-Gly(1)-GEEEK (*I-IB-Mal-d-GEEEK), another residualizing agent, and by direct radioiodination using IODO-GEN ((125)I-Nanobody). The 3 labeled Nanobodies were evaluated in affinity measurements, and paired-label internalization assays were performed on HER2-expressing BT474M1 breast carcinoma cells and in paired-label tissue distribution measurements in mice bearing subcutaneous BT474M1 xenografts.*I-SGMIB-Nanobody was produced in 50.4% ± 3.6% radiochemical yield and exhibited a dissociation constant of 1.5 ± 0.5 nM. Internalization assays demonstrated that intracellular retention of radioactivity was up to 1.5-fold higher for *I-SGMIB-Nanobody than for coincubated (125)I-Nanobody or *I-IB-Mal-d-GEEEK-Nanobody. Peak tumor uptake for *I-SGMIB-Nanobody was 24.50% ± 9.89% injected dose/g at 2 h, 2- to 4-fold higher than observed with other labeling methods, and was reduced by 90% with trastuzumab blocking, confirming the HER2 specificity of localization. Moreover, normal-organ clearance was fastest for *I-SGMIB-Nanobody, such that tumor-to-normal-organ ratios greater than 50:1 were reached by 24 h in all tissues except lungs and kidneys, for which the values were 10.4 ± 4.5 and 5.2 ± 1.5, respectively.Labeling anti-HER2 Nanobody 5F7GGC with *I-SGMIB yields a promising new conjugate for targeting HER2-expressing malignancies. Further research is needed to determine the potential utility of *I-SGMIB-5F7GGC labeled with (124)I, (123)I, and (131)I for PET and SPECT imaging and for targeted radiotherapy, respectively.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Revets, H; Devoogdt, N; Lahoutte, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Revets, H, Devoogdt, N, Lahoutte, T, Lyerly, HK, and Zalutsky, MR. "Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 55.4 (April 2014): 650-656.
PMID
24578241
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
55
Issue
4
Publish Date
2014
Start Page
650
End Page
656
DOI
10.2967/jnumed.113.127100

Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter.

PURPOSE: Both (131)I- and (123)I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with (124)I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). (18)F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [(18)F]MFBG and [(18)F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts. METHODS: [(18)F]MFBG and [(18)F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the (18)F-labeled analogs with [(123)I]/[(124)I]MIBG. RESULTS: The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75 ± 7%) than meta-isomer (21 ± 5%). The reaction of [(18)F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11 ± 2% (n = 12) for [(18)F]MFBG and 41 ± 12% (n = 5) for [(18)F]PFBG, respectively. The specific uptakes of [(18)F]MFBG and [(18)F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [(123)I]/[(124)I]MIBG. However, in vivo [(18)F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [(18)F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [(18)F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [(123)I]/[(124)I]MIBG, PET imaging demonstrated that [(18)F]MFBG was able to visualize C6-hNET xenografts better than [(124)I]MIBG. Biodistribution studies showed [(18)F]MFBG and (123)I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [(124)I]MIBG, but [(18)F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs. CONCLUSION: [(18)F]MFBG and [(18)F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [(18)F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [(18)F]PFBG and [(123)I]/[(124)I]MIBG.

Authors
Zhang, H; Huang, R; Pillarsetty, N; Thorek, DLJ; Vaidyanathan, G; Serganova, I; Blasberg, RG; Lewis, JS
MLA Citation
Zhang, H, Huang, R, Pillarsetty, N, Thorek, DLJ, Vaidyanathan, G, Serganova, I, Blasberg, RG, and Lewis, JS. "Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter." Eur J Nucl Med Mol Imaging 41.2 (February 2014): 322-332.
PMID
24173571
Source
pubmed
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
41
Issue
2
Publish Date
2014
Start Page
322
End Page
332
DOI
10.1007/s00259-013-2558-9

Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter

Purpose: Both 131I- and 123I-labeled meta-iodobenzyl-guanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with 124I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). 18F-labeled MIBG analogs may be ideal to image hNETexpression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [18F]MFBG and [18F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts. Methods: [18F]MFBG and [18F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the 18F-labeled analogs with [123I]/[124I]MIBG. Results: The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75±7 %) than meta-isomer (21±5 %). The reaction of [ 18F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11±2 % (n =12) for [18F]MFBG and 41±12 % (n =5) for [18F]PFBG, respectively. The specific uptakes of [18F]MFBG and [18F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [123I]/[124I]MIBG. However, in vivo [18F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [18F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [18F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [123I]/[124I]MIBG, PET imaging demonstrated that [18F]MFBG was able to visualize C6-hNET xenografts better than [124I]MIBG. Biodistribution studies showed [18F]MFBG and 123I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [124I]MIBG, but [18F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs. Conclusion: [18F]MFBG and [18F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [ 18F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [18F]PFBG and [123I]/[ 124I]MIBG. © Springer-Verlag Berlin Heidelberg 2013.

Authors
Zhang, H; Huang, R; Pillarsetty, NVK; Thorek, DLJ; Vaidyanathan, G; Serganova, I; Blasberg, RG; Lewis, JS
MLA Citation
Zhang, H, Huang, R, Pillarsetty, NVK, Thorek, DLJ, Vaidyanathan, G, Serganova, I, Blasberg, RG, and Lewis, JS. "Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter." European Journal of Nuclear Medicine and Molecular Imaging 41.2 (January 1, 2014): 322-332.
Source
scopus
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
41
Issue
2
Publish Date
2014
Start Page
322
End Page
332
DOI
10.1007/s00259-013-2558-9

Radiolabeling and in vitro evaluation of 67Ga-NOTA-modular nanotransporter - A potential Auger electron emitting EGFR-targeted radiotherapeutic

Introduction: Modular nanotransporters (MNTs) are vehicles designed to transport drugs from the cell surface via receptor-mediated endocytosis and endosomal escape to nucleus. Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with 67Ga. Methods: EGF was the targeting ligand on the MNT, and NOTA was selected for its radiolabeling with 67Ga. In the radiolabeling study we dealt with the precipitation of MNT (pI 5.7) at the labeling pH (4.5-5.5) of 67Ga. Cellular and nuclei uptake of 67Ga-NOTA-MNT by the A431 cell line was determined. Its specific cytotoxicity was compared to that of 67Ga-EDTA, 67Ga-NOTA-BSA and 67Ga-NOTA-hEGF, in A431 and U87MGWTT, cell lines, by clonogenic assay. Dosimetry studies were also performed. Results: 67Ga-NOTA-MNT was produced with 90% yield and specific activity of 25.6mCi/mg. The in vitro kinetics revealed an increased uptake over 24h. 55% of the internalized radioactivity was detected in the nuclei at 1h. The cytotoxicity of 67Ga-NOTA-MNT on A431 cell line was 17 and 385-fold higher when compared to non-specific 67Ga-NOTA-BSA and 67Ga-EDTA. While its cytotoxic potency was 13 and 72-fold higher when compared to 67Ga-NOTA-hEGF in the A431 and the U87MGWTT cell lines, respectively, validating its nuclear localization. The absorbed dose, for 63% cell killing, was 8Gy, confirming the high specific index of 67Ga. Conclusion: These results demonstrate the feasibility of using MNT as a platform for single cell kill targeted radiotherapy by Auger electron emitters. © 2014 Elsevier Inc.

Authors
Koumarianou, E; Slastnikova, TA; Pruszynski, M; Rosenkranz, AA; Vaidyanathan, G; Sobolev, AS; Zalutsky, MR
MLA Citation
Koumarianou, E, Slastnikova, TA, Pruszynski, M, Rosenkranz, AA, Vaidyanathan, G, Sobolev, AS, and Zalutsky, MR. "Radiolabeling and in vitro evaluation of 67Ga-NOTA-modular nanotransporter - A potential Auger electron emitting EGFR-targeted radiotherapeutic." Nuclear Medicine and Biology 41.6 (January 1, 2014): 441-449.
Source
scopus
Published In
Nuclear Medicine and Biology
Volume
41
Issue
6
Publish Date
2014
Start Page
441
End Page
449
DOI
10.1016/j.nucmedbio.2014.03.026

N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: Influence of isomeric substitution on radiolabeling and target cell residualization

© 2014 Elsevier Inc.Introduction: N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB) has shown promise for the radioiodination of monoclonal antibodies (mAbs) and other proteins that undergo extensive internalization after receptor binding, enhancing tumor targeting compared to direct electrophilic radioiodination. However, radiochemical yields for [131I]SGMIB synthesis are low, which we hypothesize is due to steric hindrance from the Boc-protected guanidinomethyl group ortho to the tin moiety. To overcome this, we developed the isomeric compound, N-succinimidyl 3-guanidinomethyl-5-[131I]iodobenzoate (iso-[131I]SGMIB) wherein this bulky group was moved from ortho to meta position. Methods: Boc2-iso-SGMIB standard and its tin precursor, N-succinimidyl 3-((1,2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-(trimethylstannyl)benzoate (Boc2-iso-SGMTB), were synthesized using two disparate routes, and iso-[*I]SGMIB synthesized from the tin precursor. Two HER2-targeted vectors - trastuzumab (Tras) and a nanobody 5F7 (Nb) - were labeled using iso-[*I]SGMIB and [*I]SGMIB. Paired-label internalization assays in vitro with both proteins, and biodistribution in vivo with trastuzumab, labeled using the two isomeric prosthetic agents were performed. Results: When the reactions were performed under identical conditions, radioiodination yields for the synthesis of Boc2-iso-[131I]SGMIB were significantly higher than those for Boc2-[131I]SGMIB (70.7±2.0% vs 56.5±5.5%). With both Nb and trastuzumab, conjugation efficiency also was higher with iso-[131I]SGMIB than with [131I]SGMIB (Nb, 33.1±7.1% vs 28.9±13.0%; Tras, 45.1±4.5% vs 34.8±10.3%); however, the differences were not statistically significant. Internalization assays performed on BT474 cells with 5F7 Nb indicated similar residualizing capacity over 6h; however, at 24h, radioactivity retained intracellularly for iso-[131I]SGMIB-Nb was lower than for [125I]SGMIB-Nb (46.4±1.3% vs 56.5±2.5%); similar results were obtained using Tras. Likewise, a paired-label biodistribution of Tras labeled using iso-[125I]SGMIB and [131I]SGMIB indicated an up to 22% tumor uptake advantage at later time points for [131I]SGMIB-Tras. Conclusion: Given the higher labeling efficiency obtained with iso-SGMIB, this residualizing agent might be of value for use with shorter half-life radiohalogens.

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; McDougald, D; Pruszynski, M; Osada, T; Lahoutte, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, McDougald, D, Pruszynski, M, Osada, T, Lahoutte, T, Lyerly, HK, and Zalutsky, MR. "N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: Influence of isomeric substitution on radiolabeling and target cell residualization." Nuclear Medicine and Biology 41.10 (January 1, 2014): 802-812.
Source
scopus
Published In
Nuclear Medicine and Biology
Volume
41
Issue
10
Publish Date
2014
Start Page
802
End Page
812
DOI
10.1016/j.nucmedbio.2014.07.005

Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

Inhibitors of heat-shock protein 90 (Hsp90) have demonstrated an unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained, but could be influenced by ectopically expressed Hsp90 in tumors. In this work, we synthesized Hsp90 inhibitors that can carry optical or radioiodinated probes via a polyethyleneglycol tether. We show that these tethered inhibitors selectively recognize cells expressing ectopic Hsp90 and become internalized. The internalization process is blocked by Hsp90 antibodies, suggesting that active cycling of the protein occurs at the plasma membrane. In mice, we observed exquisite accumulation of the fluor-tethered versions within breast tumors at very sensitive levels. Cell-based assays with the radiolabeled version showed picomolar detection in cells that express ectopic Hsp90. Our findings show that fluor-tethered or radiolabeled inhibitors that target ectopic Hsp90 can be used to detect breast cancer malignancies through noninvasive imaging.

Authors
Barrott, JJ; Hughes, PF; Osada, T; Yang, X-Y; Hartman, ZC; Loiselle, DR; Spector, NL; Neckers, L; Rajaram, N; Hu, F; Ramanujam, N; Vaidyanathan, G; Zalutsky, MR; Lyerly, HK; Haystead, TA
MLA Citation
Barrott, JJ, Hughes, PF, Osada, T, Yang, X-Y, Hartman, ZC, Loiselle, DR, Spector, NL, Neckers, L, Rajaram, N, Hu, F, Ramanujam, N, Vaidyanathan, G, Zalutsky, MR, Lyerly, HK, and Haystead, TA. "Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells." Chem Biol 20.9 (September 19, 2013): 1187-1197.
PMID
24035283
Source
pubmed
Published In
Chemistry and Biology
Volume
20
Issue
9
Publish Date
2013
Start Page
1187
End Page
1197
DOI
10.1016/j.chembiol.2013.08.004

Modular nanotransporters efficiently deliver Auger electron emitters into nuclei of cancer cells

Authors
Slastnikova, T; Koumarianou, E; Rosenkranz, A; Vaidyanathan, G; Zalutsky, M; Sobolev, A
MLA Citation
Slastnikova, T, Koumarianou, E, Rosenkranz, A, Vaidyanathan, G, Zalutsky, M, and Sobolev, A. "Modular nanotransporters efficiently deliver Auger electron emitters into nuclei of cancer cells." July 2013.
Source
wos-lite
Published In
FEBS Journal
Volume
280
Publish Date
2013
Start Page
315
End Page
316

Isomeric N-succinimidyl 3-guanidinomethyl-5-[I-131]iodobenzoate (iso-[I-131]SGMIB): A guanidine-containing residualizing agent for radiohalogenation of internalizing biomolecules

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; Pruszynski, M; Lahoutte, T; Zalutsky, MR
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, Pruszynski, M, Lahoutte, T, and Zalutsky, MR. "Isomeric N-succinimidyl 3-guanidinomethyl-5-[I-131]iodobenzoate (iso-[I-131]SGMIB): A guanidine-containing residualizing agent for radiohalogenation of internalizing biomolecules." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 56 (May 2013): S39-S39.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
56
Publish Date
2013
Start Page
S39
End Page
S39

SFBTMGMB (N-succinimidyl 3-((4-(4-fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate): An SGMIB analogue for labeling internalizing biomolecules with F-18

Authors
Vaidyanathan, G; McDougald, D; Pruszynski, M; Koumarianou, E; Hens, MA; Lahoutte, T; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Pruszynski, M, Koumarianou, E, Hens, MA, Lahoutte, T, and Zalutsky, MR. "SFBTMGMB (N-succinimidyl 3-((4-(4-fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate): An SGMIB analogue for labeling internalizing biomolecules with F-18." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 56 (May 2013): S127-S127.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
56
Publish Date
2013
Start Page
S127
End Page
S127

A radioisotope based methodology for plant-fungal interactions in the rhizosphere

In plant ecophysiology research there is interest in studying the biology of the rhizosphere because of its importance in plant nutrient-interactions. The rhizosphere is the zone of soil surrounding a plant's root system where microbes (such as fungi) are influenced by the root and the roots by the microbes. We are investigating a methodology for imaging the distribution of molecular compounds of interest in the rhizosphere without disturbing the root or soil habitat. Our intention is to develop a single photon emission computed tomography (SPECT) system (PhytoSPECT) to image the bio-distribution of fungi in association with a host plant's roots. The technique we are exploring makes use of radioactive isotopes as tracers to label molecules that bind to fungal-specific compounds of interest and to image the fungi distribution in the plant and/or soil. We report on initial experiments designed to test the ability of fungal-specific compounds labeled with an iodine radioisotope that binds to chitin monomers (N-acetylglucosamine). Chitin is a compound not found in roots but in fungal cell walls. We will test the ability to label the compound with radioactive isotopes of iodine (125I, and 123I). © 2013 IEEE.

Authors
Weisenberger, AG; Bonito, G; Lee, S; McKisson, JE; Gryganskyi, A; Reid, CD; Smith, MF; Vaidyanathan, G; Welch, B
MLA Citation
Weisenberger, AG, Bonito, G, Lee, S, McKisson, JE, Gryganskyi, A, Reid, CD, Smith, MF, Vaidyanathan, G, and Welch, B. "A radioisotope based methodology for plant-fungal interactions in the rhizosphere." IEEE Nuclear Science Symposium Conference Record (January 1, 2013).
Source
scopus
Published In
IEEE Nuclear Science Symposium Conference Record
Publish Date
2013
DOI
10.1109/NSSMIC.2013.6829457

Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody.

INTRODUCTION: With a molecular weight an order of magnitude lower than antibodies but possessing comparable affinities, Nanobodies (Nbs) are attractive as targeting agents for cancer diagnosis and therapy. An anti-HER2 Nb could be utilized to determine HER2 status in breast cancer patients prior to trastuzumab treatment. This provided motivation for the generation of HER2-specific 5F7GGC Nb, its radioiodination and evaluation for targeting HER2 expressing tumors. METHODS: 5F7GGC Nb was radioiodinated with ¹²⁵I using Iodogen and with ¹³¹I using the residualizing agent N(ɛ)-(3-[¹³¹I]iodobenzoyl)-Lys⁵-N(α)-maleimido-Gly¹-GEEEK ([¹³¹I]IB-Mal-D-GEEEK) used previously successfully with intact antibodies. Paired-label internalization assays using BT474M1 cells and tissue distribution experiments in athymic mice bearing BT474M1 xenografts were performed to compare the two labeled Nb preparations. RESULTS: The radiochemical yields for Iodogen and [¹³¹I]IB-Mal-D-GEEEK labeling were 83.6±5.0% (n=10) and 59.6±9.4% (n=15), respectively. The immunoreactivity of labeled proteins was preserved as confirmed by in vitro and in vivo binding to tumor cells. Biodistribution studies showed that Nb radiolabeled using [¹³¹I]IB-Mal-D-GEEEK, compared with the directly labeled Nb, had a higher tumor uptake (4.65±0.61% ID/g vs. 2.92±0.24% ID/g at 8h), faster blood clearance, lower accumulation in non-target organs except kidneys, and as a result, higher concomitant tumor-to-blood and tumor-to-tissue ratios. CONCLUSIONS: Taken together, these results demonstrate that 5F7GGC anti-HER2 Nb labeled with residualizing [¹³¹I]IB-Mal-D-GEEEK had better tumor targeting properties compared to the directly labeled Nb suggesting the potential utility of this Nb conjugate for SPECT (¹²⁹I) and PET imaging (¹²⁴I) of patients with HER2-expressing tumors.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Revets, H; Devoogdt, N; Lahoutte, T; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Revets, H, Devoogdt, N, Lahoutte, T, and Zalutsky, MR. "Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody." Nucl Med Biol 40.1 (January 2013): 52-59.
PMID
23159171
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
40
Issue
1
Publish Date
2013
Start Page
52
End Page
59
DOI
10.1016/j.nucmedbio.2012.08.008

Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody

Introduction: With a molecular weight an order of magnitude lower than antibodies but possessing comparable affinities, Nanobodies (Nbs) are attractive as targeting agents for cancer diagnosis and therapy. An anti-HER2 Nb could be utilized to determine HER2 status in breast cancer patients prior to trastuzumab treatment. This provided motivation for the generation of HER2-specific 5F7GGC Nb, its radioiodination and evaluation for targeting HER2 expressing tumors. Methods: 5F7GGC Nb was radioiodinated with 125I using Iodogen and with 131I using the residualizing agent Ne-(3-[131I]iodobenzoyl)-Lys5-Nα -maleimido-Gly1-GEEEK ([131I]IB-Mal-d-GEEEK) used previously successfully with intact antibodies. Paired-label internalization assays using BT474M1 cells and tissue distribution experiments in athymic mice bearing BT474M1 xenografts were performed to compare the two labeled Nb preparations. Results: The radiochemical yields for Iodogen and [131I]IB-Mal-d-GEEEK labeling were 83.6±5.0% (n=10) and 59.6±9.4% (n=15), respectively. The immunoreactivity of labeled proteins was preserved as confirmed by in vitro and in vivo binding to tumor cells. Biodistribution studies showed that Nb radiolabeled using [131I]IB-Mal-d-GEEEK, compared with the directly labeled Nb, had a higher tumor uptake (4.65±0.61% ID/g vs. 2.92±0.24% ID/g at 8h), faster blood clearance, lower accumulation in non-target organs except kidneys, and as a result, higher concomitant tumor-to-blood and tumor-to-tissue ratios. Conclusions: Taken together, these results demonstrate that 5F7GGC anti-HER2 Nb labeled with residualizing [131I]IB-Mal-d-GEEEK had better tumor targeting properties compared to the directly labeled Nb suggesting the potential utility of this Nb conjugate for SPECT (129I) and PET imaging (124I) of patients with HER2-expressing tumors. © 2013 Elsevier Inc.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Revets, H; Devoogdt, N; Lahoutte, T; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Revets, H, Devoogdt, N, Lahoutte, T, and Zalutsky, MR. "Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody." Nuclear Medicine and Biology 40.1 (2013): 52-59.
Source
scival
Published In
Nuclear Medicine and Biology
Volume
40
Issue
1
Publish Date
2013
Start Page
52
End Page
59
DOI
10.1016/j.nucmedbio.2012.08.008

SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies.

A major drawback of internalizing monoclonal antibodies (mAbs) radioiodinated with direct electrophilic approaches is that tumor retention of radioactivity is compromised by the rapid washout of iodo-tyrosine, the primary labeled catabolite for mAbs labeled via this strategy. In our continuing efforts to develop more versatile residualizing labels that could overcome this problem, we have designed SIB-DOTA, a prosthetic labeling template that combines the features of the prototypical, dehalogenation-resistant N-succinimidyl 3-iodobenzoate (SIB) with DOTA, a useful macrocyclic chelator for labeling with radiometals. Herein we describe the synthesis of the unlabeled standard of this prosthetic moiety, its protected tin precursor, and radioiodinated SIB-DOTA. An anti-EGFRvIII-reactive mAb, L8A4 was radiolabeled with [(131)I]SIB-DOTA in 27.1±6.2% (n=2) conjugation yields and its targeting properties to the same mAb labeled with [(125)I]SGMIB both in vitro and in vivo using U87MG·ΔEGFR cells and xenografts were compared. In vitro paired-label internalization assays showed that the intracellular radioactivity from [(131)I]SIB-DOTA-L8A4 was 21.4±0.5% and 26.2±1.1% of initially bound radioactivity at 16 and 24h, respectively. In comparison, these values for [(125)I]SGMIB-L8A4 were 16.7±0.5% and 14.9±1.1%. Similarly, the SIB-DOTA prosthetic group provided better tumor targeting in vivo than SGMIB over 8 d period. These results suggest that SIB-DOTA warrants further evaluation as a residualizing agent for labeling internalizing mAbs including those targeted to EGFRvIII.

Authors
Vaidyanathan, G; White, BJ; Affleck, DJ; Zhao, XG; Welsh, PC; McDougald, D; Choi, J; Zalutsky, MR
MLA Citation
Vaidyanathan, G, White, BJ, Affleck, DJ, Zhao, XG, Welsh, PC, McDougald, D, Choi, J, and Zalutsky, MR. "SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies." Bioorg Med Chem 20.24 (December 15, 2012): 6929-6939.
PMID
23159039
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
20
Issue
24
Publish Date
2012
Start Page
6929
End Page
6939
DOI
10.1016/j.bmc.2012.10.025

Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I.

UNLABELLED: BACKGROUND: This study evaluates the potential utility of a modular nanotransporter (MNT) for enhancing the nuclear delivery and cytotoxicity of the Auger electron emitter 125I in cancer cells that overexpress the epidermal growth factor receptor (EGFR). METHODS: MNTs are recombinant multifunctional polypeptides that we have developed for achieving selective delivery of short-range therapeutics into cancer cells. MNTs contain functional modules for receptor binding, internalization, endosomal escape and nuclear translocation, thereby facilitating the transport of drugs from the cell surface to the nucleus. The MNT described herein utilized EGF as the targeting ligand and was labeled with 125I using N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate (SGMIB). Membrane binding, intracellular and nuclear accumulation kinetics, and clonogenic survival assays were performed using the EGFR-expressing A431 epidermoid carcinoma and D247 MG glioma cell lines. RESULTS: [125I]SGMIB-MNT bound to A431 and D247 MG cells with an affinity comparable to that of native EGF. More than 60% of internalized [125I]SGMIB-MNT radioactivity accumulated in the cell nuclei after a 1-h incubation. The cytotoxic effectiveness of [125I]SGMIB-MNT compared with 125I-labeled bovine serum albumin control was enhanced by a factor of 60 for D247 MG cells and more than 1,000-fold for A431 cells, which express higher levels of EGFR. CONCLUSIONS: MNT can be utilized to deliver 125I into the nuclei of cancer cells overexpressing EGFR, significantly enhancing cytotoxicity. Further evaluation of [125I]SGMIB-MNT as a targeted radiotherapeutic for EGFR-expressing cancer cells appears warranted.

Authors
Slastnikova, TA; Koumarianou, E; Rosenkranz, AA; Vaidyanathan, G; Lupanova, TN; Sobolev, AS; Zalutsky, MR
MLA Citation
Slastnikova, TA, Koumarianou, E, Rosenkranz, AA, Vaidyanathan, G, Lupanova, TN, Sobolev, AS, and Zalutsky, MR. "Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I. (Published online)" EJNMMI Res 2.1 (October 29, 2012): 59-.
Website
http://hdl.handle.net/10161/11046
PMID
23107475
Source
pubmed
Published In
EJNMMI Research
Volume
2
Issue
1
Publish Date
2012
Start Page
59
DOI
10.1186/2191-219X-2-59

Synthesis and preliminary evaluation of n.c.a. iodoquine: a novel radiotracer with high uptake in cells with high ALDH1 expression.

PURPOSE: Chloroquine has demonstrated high affinity for aldehyde dehydrogenase 1A1 (ALDH1), an enzyme expressed in the highly tumorigenic CD133+ brain tumor initiating subpopulation. The purpose of this study is to report the novel synthesis of a chloroquine analogue, n.c.a. iodoquine, and the in vitro and in vivo uptake in cells with high ALDH1 content. METHODS AND MATERIALS: Iodoquine was synthesized in novel no-carrier-added forms (n.c.a.) for both 125I and 123I. I25I IQ and 18F FDG cell uptake assays were performed in the L1210 and L1210cpa (cyclophosphamide resistant), A549, and MG456 glioblastoma cell lines. Uptake was expressed as a percent of the administered activity. 125I IQ biodistribution studies assessed organ uptake at 1, 4, and 24 hours after IV administration (n= 15 total; 5 mice/timepoint). Radiation dosimetry estimates were calculated using standard OLINDA/EXM software. In vivo imaging of 123I IQ uptake in MG456 glioblastoma mouse model (n=10) was performed with small animal high resolution micro-SPECT. Autoradiography and histology co-localized radiotracer and tumor biodistribution. Uptake in MG456 glioblastoma tumors was quantified with gamma counting. RESULTS: L1210 cpa (high ALDH1) showed significantly higher 125I IQ uptake compared to the parental L1210 (low ALDH1) for all time points through 4 hours (20.7% ± 1.4% versus 11.0% ± 0.5%; 21.3% ± 0.9% versus 11.0% ± 0.4%; 20.6% ± 0.7% versus 9.4% ± 0.3%; and 15.7% ± 0.7% versus 7.5% + 0.4% at 30 minutes, and 1, 2 and 4 hours, respectively; p < 0.001 for all time points). In the CD133+ fraction of MG456 glioblastoma cell line, IQ uptake was significantly higher compared to FDG at all time points through 4 hours (81.5% ± 0.9% versus 1.3% ± 0.1%; 88.8% ± 0.4% versus 1.3% ± 0.1%; 87.8% ± 2.1% versus 1.7% ± 0.2%; and 87.0% ± 2.4% versus 1.8% ± 0.1 at 30 minutes, and 1, 2 and 4 hours, respectively; p > 0.001 for all time points). The A549 lung cancer cell line also showed high IQ uptake through 4 hours. IQ normal biodistribution studies showed rapid renal excretion and very low normal background brain activity after IV administration. In vivo micro-SPECT images showed mild uptake in larger MG456 glioblastomas (n=6) as verified with autoradiography and histology. Gamma well counter uptake in large tumors was 2.3% ± 0.48% ID/g (n=5). CONCLUSION: Iodoquine localizes to cells with high ALDH1 content. Cell assays show high 125I IQ uptake in the MG456 cell line, and in vivo micro-SPECT imaging showed mild 123I IQ uptake in MG456 glioblastomas. Further studies are necessary to investigate 131I IQ as a potential therapeutic agent targeting the highly tumorigenic CD133+ brain tumor stem cell subpopulation.

Authors
Chin, BB; Hjelemand, A; Rich, J; Song, H; Lascola, C; Storms, R; McLendon, R; Reiman, R; Greer, KL; Metzler, SD; McDougald, D; Dai, D; Vaidyanathan, G
MLA Citation
Chin, BB, Hjelemand, A, Rich, J, Song, H, Lascola, C, Storms, R, McLendon, R, Reiman, R, Greer, KL, Metzler, SD, McDougald, D, Dai, D, and Vaidyanathan, G. "Synthesis and preliminary evaluation of n.c.a. iodoquine: a novel radiotracer with high uptake in cells with high ALDH1 expression." Curr Radiopharm 5.1 (January 2012): 47-58.
PMID
21864242
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
5
Issue
1
Publish Date
2012
Start Page
47
End Page
58

Virus hunters: catching bugs in the field.

Densely populated areas in rural China require constant vigilance and state-of-the-art technology to stop new pandemics in their tracks. Hurdles are not only scientific in some parts of the developing world.

Authors
Vaidyanathan, G
MLA Citation
Vaidyanathan, G. "Virus hunters: catching bugs in the field." Cell 147.6 (December 9, 2011): 1209-1211.
PMID
22153064
Source
pubmed
Published In
Cell
Volume
147
Issue
6
Publish Date
2011
Start Page
1209
End Page
1211
DOI
10.1016/j.cell.2011.11.037

Dam controversy: Remaking the Mekong.

Authors
Vaidyanathan, G
MLA Citation
Vaidyanathan, G. "Dam controversy: Remaking the Mekong. (Published online)" Nature 478.7369 (October 19, 2011): 305-307.
PMID
22012370
Source
pubmed
Published In
Nature
Volume
478
Issue
7369
Publish Date
2011
Start Page
305
End Page
307
DOI
10.1038/478305a

Applications of 211At and 223Ra in targeted alpha-particle radiotherapy.

Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Applications of 211At and 223Ra in targeted alpha-particle radiotherapy." Curr Radiopharm 4.4 (October 2011): 283-294. (Review)
PMID
22202151
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
4
Issue
4
Publish Date
2011
Start Page
283
End Page
294

An alternative and expedient synthesis of radioiodinated 4-iodophenylalanine.

Radiolabeled amino acids have been used extensively in oncology both as diagnostic and therapeutic agents. In our pursuit to develop radiopharmaceuticals to target breast cancer, we were interested in determining the uptake of radioiodinated 4-iodophenylalanine, among other labeled amino acids, in breast cancer cells. In this work, we have developed an alternative method for the synthesis of this agent. The novel tin precursor, (S)-tert-butyl 2-(tert-butoxycarbonylamino)-3-(4-(tributylstannyl)phenyl)propanoate (3) was synthesized from the known, corresponding iodo derivative. Initially, the labeled 4-iodophenylalanine was synthesized from the above tin precursor in two steps with radiochemical yields of 91.6 ± 2.7% and 83.7 ± 1.7% (n=5), for the radioiodination (first) and deprotection (second) step, respectively. Subsequently, it was synthesized in a single step with an average radiochemical yield of 94.8 ± 3.4% (n=5). After incubation with MCF-7 breast cancer cells for 60 min, an uptake of up to 49.0 ± 0.7% of the input dose was seen; in comparison, the uptake of [¹⁴C]phenylalanine under the same conditions was 55.9 ± 0.5%. Furthermore, the uptake of both tracers was inhibited to a similar degree in a concentration-dependent manner by both unlabeled phenylalanine and 4-iodophenylalanine. With [¹⁴C]phenylalanine as the tracer, IC₅₀ values of 1.45 and 2.50 mM were obtained for Phe and I-Phe, respectively, and these values for [¹²⁵I]I-Phe inhibition were 1.3 and 1.0 mM. In conclusion, an improved and convenient method for the synthesis of no-carrier-added 4-[(⁎)I]phenylalanine was developed and the radiotracer prepared by this route demonstrated an amino acid transporter-mediated uptake in MCF-7 breast cancer cells in vitro that was comparable to that of [¹⁴C]phenylalanine.

Authors
Vaidyanathan, G; McDougald, D; Grasfeder, L; Zalutsky, MR; Chin, B
MLA Citation
Vaidyanathan, G, McDougald, D, Grasfeder, L, Zalutsky, MR, and Chin, B. "An alternative and expedient synthesis of radioiodinated 4-iodophenylalanine." Appl Radiat Isot 69.10 (October 2011): 1401-1406.
PMID
21621415
Source
pubmed
Published In
Applied Radiation and Isotopes
Volume
69
Issue
10
Publish Date
2011
Start Page
1401
End Page
1406
DOI
10.1016/j.apradiso.2011.05.004

Apes in Africa: The cultured chimpanzees.

Authors
Vaidyanathan, G
MLA Citation
Vaidyanathan, G. "Apes in Africa: The cultured chimpanzees. (Published online)" Nature 476.7360 (August 17, 2011): 266-269.
PMID
21850081
Source
pubmed
Published In
Nature
Volume
476
Issue
7360
Publish Date
2011
Start Page
266
End Page
269
DOI
10.1038/476266a

Clinical spectrum and prognosis of follicular lymphoma with blastoid transformation: case series and a review of the literature.

Follicular lymphoma (FL) with blastoid transformation (FL-BT) is a rare entity. FL-BT has a dismal prognosis due to intrinsic biological characteristics, lack of evidence-based therapeutic guidelines, and exclusion from clinical trials. In order to understand the natural course of the disease and reconcile treatment strategies in patients with FL-BT, we reviewed available data. Thirty patients were identified, three from our institution (Roswell Park Cancer Institute) and 27 patients from peer-reviewed literature. Demographic, clinical, treatment, pathological, and cytogenetic characteristics were described. Most of the patients (90%) were treated with chemotherapy at transformation. Complete and partial responses to treatment were observed in 38.9% and 22.3% of the patients, respectively. The median overall survival for the entire group of patients was 11 months (range 0.8-30 months); half of the patients were found to have concurrent genetic alterations in the BCL-2 and C-MYC gene rearrangements (double hit). FL-BT with a double hit had a shorter median overall survival when compared to nondouble hit FL-BT (7 months vs. 26 months, respectively, P = 0.005). In our experience, FL-BT is a rare and grave clonal evolution in FL characterized by an aggressive clinical course, inferior response to standard chemoimmunotherapy, and poor clinical outcome. C-MYC rearrangements are common in FL-BT and may play a role in the progression from FL to FL-BT or the poor clinical outcomes observed. Periodic updates from academic institutions treating FL-BT may improve patient care.

Authors
Vaidyanathan, G; Ngamphaiboon, N; Hernandez-Ilizaliturri, FJ
MLA Citation
Vaidyanathan, G, Ngamphaiboon, N, and Hernandez-Ilizaliturri, FJ. "Clinical spectrum and prognosis of follicular lymphoma with blastoid transformation: case series and a review of the literature." Ann Hematol 90.8 (August 2011): 955-962. (Review)
PMID
21286717
Source
pubmed
Published In
Annals of Hematology
Volume
90
Issue
8
Publish Date
2011
Start Page
955
End Page
962
DOI
10.1007/s00277-011-1162-y

Science in Africa: The view from the front line.

Authors
Irikefe, V; Vaidyanathan, G; Nordling, L; Twahirwa, A; Nakkazi, E; Monastersky, R
MLA Citation
Irikefe, V, Vaidyanathan, G, Nordling, L, Twahirwa, A, Nakkazi, E, and Monastersky, R. "Science in Africa: The view from the front line. (Published online)" Nature 474.7353 (June 29, 2011): 556-559.
PMID
21720341
Source
pubmed
Published In
Nature
Volume
474
Issue
7353
Publish Date
2011
Start Page
556
End Page
559
DOI
10.1038/474556a

Science in Africa: The wheat stalker.

Authors
Vaidyanathan, G
MLA Citation
Vaidyanathan, G. "Science in Africa: The wheat stalker. (Published online)" Nature 474.7353 (June 29, 2011): 563-565.
PMID
21720343
Source
pubmed
Published In
Nature
Volume
474
Issue
7353
Publish Date
2011
Start Page
563
End Page
565
DOI
10.1038/474563a

TARGETED RADIOTHERAPY OF MEDULLOBLASTOMA USING SOMATOSTATIN RECEPTOR AVID RADIOLABELED PEPTIDES

Authors
Vaidyanathan, G; Li, J; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Li, J, Bigner, DD, and Zalutsky, MR. "TARGETED RADIOTHERAPY OF MEDULLOBLASTOMA USING SOMATOSTATIN RECEPTOR AVID RADIOLABELED PEPTIDES." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I27
End Page
I27

Radioiodinated O(6)-Benzylguanine derivatives containing an azido function.

INTRODUCTION: Drug resistance to alkylator chemotherapy has been primarily attributed to the DNA repair protein alkylguanine-DNA alkyltransferase (AGT); thus, personalizing chemotherapy could be facilitated if tumor AGT content could be quantified prior to administering chemotherapy. We have been investigating the use of radiolabeled O(6)-benzylguanine (BG) analogues to label and quantify AGT in vivo. BG derivatives containing an azido function were sought to potentially enhance the targeting of these analogues to AGT, which is primarily present in the cell nucleus, either by conjugating them to nuclear localization sequence (NLS) peptides or by pretargeting via bio-orthogonal approaches. METHODS: Two O(6)-(3-iodobenzyl)guanine (IBG) derivatives containing an azido moiety-O(6)-(4-azidohexyloxymethyl-3-iodobenzyl)guanine (AHOMIBG) and O(6)-(4-azido-3-iodobenzyl)guanine (AIBG)--and their tin precursors were synthesized in multiple steps and the tin precursors were converted to radioiodinated AHOMIBG and AIBG, respectively. Both unlabeled and radioiodinated AHOMIBG analogues were conjugated to alkyne-derivatized NLS peptide heptynoyl-PK(3)RKV. The ability of these radioiodinated compounds to bind to AGT was determined by a trichloroacetic acid precipitation assay and gel electrophoresis/phosphor imaging. Labeling of an AGT-AIBG conjugate via Staudinger ligation using the (131)I-labeled phosphine ligand, 2-(diphenylphosphino)phenyl 4-[(131)I]iodobenzoate, also was investigated. RESULTS: [(131)I]AHOMIBG was synthesized in two steps from its tin precursor in 52.2 ± 7.5% (n = 5) radiochemical yield and conjugated to the NLS peptide via click reaction in 50.7 ± 4.9% (n = 6) yield. The protected tin precursor of AIBG was radioiodinated in an average radiochemical yield of 69.6 ± 4.5% (n = 7); deprotection of the intermediate gave [(131)I]AIBG in 17.8 ± 4.2% (n = 9) yield. While both [(131)I]AHOMIBG and its NLS conjugate bound to AGT pure protein, their potency as a substrate for AGT was substantially lower than that of [(125)I]IBG. Uptake of [(131)I]AHOMIBG-NLS conjugate in DAOY medulloblastoma cells was up to eightfold higher than that of [(125)I]IBG; however, the uptake was not changed when the cellular AGT content was first depleted with BG treatment. [(131)I]AIBG was almost equipotent as [(125)I]IBG with respect to binding to pure AGT; however, attempts to radiolabel AGT by treatment with unlabeled AIBG followed by Staudinger ligation using the radiolabeled phosphine ligand, 2-(diphenylphosphino)phenyl 4-[(131)I]iodobenzoate were not successful. CONCLUSION: Although AHOMIBG, and AIBG were synthesized successfully in both unlabeled and radioiodinated forms, the radioiodinated compounds failed to label AGT either after NLS peptide conjugation or via Staundiger ligation. Currently, other bio-orthogonal approaches are being evaluated for labeling AGT by pretargeting.

Authors
Vaidyanathan, G; White, B; Affleck, DJ; McDougald, D; Zalutsky, MR
MLA Citation
Vaidyanathan, G, White, B, Affleck, DJ, McDougald, D, and Zalutsky, MR. "Radioiodinated O(6)-Benzylguanine derivatives containing an azido function." Nucl Med Biol 38.1 (January 2011): 77-92.
PMID
21220131
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
38
Issue
1
Publish Date
2011
Start Page
77
End Page
92
DOI
10.1016/j.nucmedbio.2010.07.006

Applications of 211AT and 223RA in targeted alpha-particle radiotherapy

Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy. © 2011 Bentham Science Publishers Ltd.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Applications of 211AT and 223RA in targeted alpha-particle radiotherapy." Current Radiopharmaceuticals 4.4 (2011): 283-294.
Source
scival
Published In
Current Radiopharmaceuticals
Volume
4
Issue
4
Publish Date
2011
Start Page
283
End Page
294

A tin precursor of SGMIB potentially useful in the direct modification of peptides and proteins before radiohalogenation

Authors
Vaidyanathan, G; McDougald, D; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Affleck, DJ, and Zalutsky, MR. "A tin precursor of SGMIB potentially useful in the direct modification of peptides and proteins before radiohalogenation." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 54 (2011): S64-S64.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
54
Publish Date
2011
Start Page
S64
End Page
S64

Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands.

INTRODUCTION: Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not on normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with (177)Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. MATERIALS AND METHODS: L8A4 mAb was labeled with (177)Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylene-triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.ΔEGFR glioma xenografts over a period of 1 to 8 days to directly compare (177)Lu-labeled L8A4 to L8A4 labeled with (125)I using N-succinimidyl 4-guanidinomethyl-3-[(125)I]iodobenzoate ([(125)I]SGMIB). RESULTS: Except with C-DOTA, tumor uptake for the (177)Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor/normal tissue ratios for (177)Lu-1B4M-DTPA-L8A4 and, to an even greater extent, (177)Lu-MeO-DOTA-L8A4 were higher than those for [(125)I]SGMIB-L8A4 in most other tissues. CONCLUSIONS: Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for (177)Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application.

Authors
Hens, M; Vaidyanathan, G; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Hens, M, Vaidyanathan, G, Zhao, X-G, Bigner, DD, and Zalutsky, MR. "Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands." Nucl Med Biol 37.7 (October 2010): 741-750.
PMID
20870149
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
37
Issue
7
Publish Date
2010
Start Page
741
End Page
750
DOI
10.1016/j.nucmedbio.2010.04.020

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas.

INTRODUCTION: Podoplanin/aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study was to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas. METHODS: The binding affinity of an anti-podoplanin antibody, NZ-1 (rat IgG(2a)), was determined by surface plasmon resonance and Scatchard analysis. NZ-1 was radioiodinated with (125)I using Iodogen [(125)I-NZ-1(Iodogen)] or N-succinimidyl 4-guanidinomethyl 3-[(131)I]iodobenzoate ([(131)I]SGMIB-NZ-1), and paired-label internalization assays of NZ-1 were performed. The tissue distribution of (125)I-NZ-1(Iodogen) and that of [(131)I]SGMIB-NZ-1 were then compared in athymic mice bearing glioblastoma xenografts. RESULTS: The dissociation constant (K(D)) of NZ-1 was determined to be 1.2 × 10(-10) M by surface plasmon resonance and 9.8 × 10(-10) M for D397MG glioblastoma cells by Scatchard analysis. Paired-label internalization assays in LN319 glioblastoma cells indicated that [(131)I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3 ± 0.8% of initially bound radioactivity at 8 h) compared to that from the (125)I-NZ-1(Iodogen) (10.0 ± 0.1% of initially bound radioactivity at 8 h). Likewise, tumor uptake of [(131)I]SGMIB-NZ-1 (39.9 ± 8.8 %ID/g at 24 h) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of (125)I-NZ-1(Iodogen) (29.7 ± 6.1 %ID/g at 24 h). CONCLUSIONS: The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma.

Authors
Kato, Y; Vaidyanathan, G; Kaneko, MK; Mishima, K; Srivastava, N; Chandramohan, V; Pegram, C; Keir, ST; Kuan, C-T; Bigner, DD; Zalutsky, MR
MLA Citation
Kato, Y, Vaidyanathan, G, Kaneko, MK, Mishima, K, Srivastava, N, Chandramohan, V, Pegram, C, Keir, ST, Kuan, C-T, Bigner, DD, and Zalutsky, MR. "Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas." Nucl Med Biol 37.7 (October 2010): 785-794.
PMID
20870153
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
37
Issue
7
Publish Date
2010
Start Page
785
End Page
794
DOI
10.1016/j.nucmedbio.2010.03.010

Radioiodinated O6-Benzylguanine Analogues Containing an Azido Function

Authors
Vaidyanathan, G; White, B; Affleck, DJ; McDougald, D; Zalutsky, MR
MLA Citation
Vaidyanathan, G, White, B, Affleck, DJ, McDougald, D, and Zalutsky, MR. "Radioiodinated O6-Benzylguanine Analogues Containing an Azido Function." October 2010.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
37
Publish Date
2010
Start Page
S265
End Page
S265

[177Lu]-DOTA0-Tyr3-octreotate: A potential targeted radiotherapeutic for the treatment of Medulloblastoma

Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [177Lu-DOTA0,Tyr3]octreotate ([177Lu]DOTA- TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate this possibility in preclinical models of D341 MED human medulloblastoma by comparing the properties of [177Lu]DOTA-TATE to those of glucose-[125I-Tyr3]-octreotate ([125I]Gluc-TOCA), a radiopeptide previously shown to target this cell line. In vitro assays indicated that both labeled peptides exhibited similar cell-associated and in- ternalized radioactivity after a 30-min incubation at 37oC; however, at the end of the 4 h incubation period, the internal- ized radioactivity for [177Lu]DOTA-TATE (6.22 ± 0.75%) was nearly twice that for [125I]Gluc-TOCA (3.16 ± 0.27%), with similar differences seen in total cell-associated radioactivity levels. Consistent with the results from the internaliza- tion assays, results from paired-label tissue distribution studies in athymic mice with subcutaneous D341 MED medul- loblastoma xenografts showed a similar degree of tumor accumulation for [177Lu]DOTA-TATE and [125I]Gluc-TOCA at early time points but by 24 h, a more than 5-fold advantage was observed for the 177Lu-labeled peptide. Tumor-to-normal tissue ratios generally were more favorable for [177Lu]DOTA-TATE at all time points, due in part to its lower accumula- tion in normal tissues except kidneys. Taken together, these results suggest that [177Lu]DOTA-TATE warrants further in- vestigation as a targeted radiotherapeutic for medulloblastoma treatment. ©2010 Bentham Science Publishers Ltd.

Authors
Vaidyanathan, G; Affleck, DJ; Zhao, XG; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Zhao, XG, Keir, ST, and Zalutsky, MR. "[177Lu]-DOTA0-Tyr3-octreotate: A potential targeted radiotherapeutic for the treatment of Medulloblastoma." Current Radiopharmaceuticals 3.1 (July 12, 2010): 29-36.
Source
scopus
Published In
Current Radiopharmaceuticals
Volume
3
Issue
1
Publish Date
2010
Start Page
29
End Page
36
DOI
10.2174/1874471011003010029

A case of curative-intent hepatectomy for colon cancer metastatic to the scapula and liver.

Colon cancer is the second leading cause of cancer death in the United States. Patients with colon cancer metastatic to liver and bone are deemed non-curable and have a poor prognosis. We present a case of recurrent colon cancer with synchronous hepatic and bony metastases treated with radiation, chemotherapy, and curative-intent hepatectomy. The patient is alive and free of disease recurrence, off chemotherapy, more than 2 years post-hepatectomy.

Authors
Vaidyanathan, G; Fakih, MG
MLA Citation
Vaidyanathan, G, and Fakih, MG. "A case of curative-intent hepatectomy for colon cancer metastatic to the scapula and liver." Anticancer Res 30.2 (February 2010): 677-679.
PMID
20332489
Source
pubmed
Published In
Anticancer research
Volume
30
Issue
2
Publish Date
2010
Start Page
677
End Page
679

[Lu]-DOTA-Tyr-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma.

Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [(177)Lu-DOTA(0),Tyr(3)]octreotate ([(177)Lu]DOTA-TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate this possibility in preclinical models of D341 MED human medulloblastoma by comparing the properties of [(177)Lu]DOTA-TATE to those of glucose-[(125)I-Tyr(3)]-octreotate ([(125)I]Gluc-TOCA), a radiopeptide previously shown to target this cell line. In vitro assays indicated that both labeled peptides exhibited similar cell-associated and internalized radioactivity after a 30-min incubation at 37°C; however, at the end of the 4 h incubation period, the internalized radioactivity for [(177)Lu]DOTA-TATE (6.22 " 0.75%) was nearly twice that for [(125)I]Gluc-TOCA (3.16 " 0.27%), with similar differences seen in total cell-associated radioactivity levels. Consistent with the results from the internalization assays, results from paired-label tissue distribution studies in athymic mice with subcutaneous D341 MED medulloblastoma xenografts showed a similar degree of tumor accumulation for [(177)Lu]DOTA-TATE and [(125)I]Gluc-TOCA at early time points but by 24 h, a more than 5-fold advantage was observed for the (177)Lu-labeled peptide. Tumor-to-normal tissue ratios generally were more favorable for [(177)Lu]DOTA-TATE at all time points, due in part to its lower accumulation in normal tissues except kidneys. Taken together, these results suggest that [(177)Lu]DOTA-TATE warrants further investigation as a targeted radiotherapeutic for medulloblastoma treatment.

Authors
Vaidyanathan, G; Affleck, DJ; Zhao, X-G; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Zhao, X-G, Keir, ST, and Zalutsky, MR. "[Lu]-DOTA-Tyr-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma." Curr Radiopharm 3.1 (2010): 29-36.
PMID
21243098
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
3
Issue
1
Publish Date
2010
Start Page
29
End Page
36
DOI
10.2174/1874471011003010029

Stop and go FOLFOX plus bevacizumab chemotherapy in the first-line treatment of metastatic colorectal cancer.

BACKGROUND: Infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) plus bevacizumab chemotherapy is commonly implemented in the first-line treatment of metastatic colorectal cancer. A stop and go oxaliplatin strategy has been recommended to reduce oxaliplatin-associated neuropathy. Despite the acceptance of this strategy by community and academic practices, efficacy data with this approach are limited. METHODS: We analyzed the efficacy of a stop and go FOLFOX regimen combined with bevacizumab in a single institute between January 2007 and December 2009. Oxaliplatin was withdrawn electively after 8 cycles of treatment and patients were maintained on 5-fluorouracil/leucovorin and bevacizumab until progression. When feasible, patients were rechallenged with oxaliplatin upon progression. RESULTS: Sixty-seven patients were treated and analyzed for outcome. The response rate of this group was 58%. The median progression-free and overall survival was 10.6 and 26.7 months, respectively. The median duration of disease control in the 18-patient subgroup that was rechallenged with oxaliplatin was 21.2 months. CONCLUSIONS: Elective withdrawal of oxaliplatin after 8 cycles in the setting of FOLFOX and bevacizumab does not appear to compromise the activity of this regimen. A stop and go approach of FOLFOX plus bevacizumab is effective and may reduce treatment costs and toxicity in comparison with a continuous FOLFOX treatment strategy.

Authors
Vaidyanathan, G; Groman, A; Wilding, G; Fakih, MG
MLA Citation
Vaidyanathan, G, Groman, A, Wilding, G, and Fakih, MG. "Stop and go FOLFOX plus bevacizumab chemotherapy in the first-line treatment of metastatic colorectal cancer." Oncology 79.1-2 (2010): 67-71.
PMID
21071992
Source
pubmed
Published In
Oncology
Volume
79
Issue
1-2
Publish Date
2010
Start Page
67
End Page
71
DOI
10.1159/000319549

Targeting aldehyde dehydrogenase: a potential approach for cell labeling.

INTRODUCTION: To advance the science and clinical application of stem cell therapy, the availability of a highly sensitive, quantitative and translational method for tracking stem cells would be invaluable. Because hematopoetic stem cells express high levels of the cytosolic enzyme aldehyde dehydrogenase-1A1 (ALDH1), we sought to develop an agent that is specific to ALDH1 and thus to cells expressing the enzyme. Such an agent might be also helpful in identifying tumors that are resistant to cyclophosphomide chemotherapy because ALDH1 is known to be responsible for this resistance. METHODS: We developed schemes for the synthesis of two radioiodinated aldehdyes - N-formylmethyl-5-[*I]iodopyridine-3-carboxamide ([*I]FMIC) and 4-diethylamino-3-[*I]iodobenzaldehyde ([*I]DEIBA)-at no-carrier-added levels from their respective tin precursors. These agents were evaluated using pure ALDH1 and tumor cells that expressed the enzyme. RESULTS: The average radiochemical yields for the synthesis of [(125)I]FMIC and [(125)I]DEIBA were 70+/-5% and 47+/-14%, respectively. ALDH1 converted both compounds to respective acids suggesting their suitability as ALDH1 imaging agents. Although ability of ALDH1 within the cells to oxidize one of these substrates was shown, specific uptake in ALDH-expressing tumor cells could not be demonstrated. CONCLUSION: To pursue this approach for ALDH1 imaging, radiolabeled aldehydes need to be designed such that, in addition to being good substrates for ALDH1, the cognate products should be sufficiently polar so as to be retained within the cells.

Authors
Vaidyanathan, G; Song, H; Affleck, D; McDougald, DL; Storms, RW; Zalutsky, MR; Chin, BB
MLA Citation
Vaidyanathan, G, Song, H, Affleck, D, McDougald, DL, Storms, RW, Zalutsky, MR, and Chin, BB. "Targeting aldehyde dehydrogenase: a potential approach for cell labeling." Nucl Med Biol 36.8 (November 2009): 919-929.
PMID
19875048
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
8
Publish Date
2009
Start Page
919
End Page
929
DOI
10.1016/j.nucmedbio.2009.08.001

Evaluation of an anti-p185(HER2) (scFv-C(H)2-C(H)3)2 fragment following radioiodination using two different residualizing labels: SGMIB and IB-Mal-D-GEEEK.

INTRODUCTION: A 105-kDa double mutant single-chain Fv-Fc fragment (scFv-Fc DM) derived from the anti-p185(HER2) hu4D5v8 antibody (trastuzumab; Herceptin) has been described recently. The goal of this study was to investigate whether improved tumor targeting could be achieved with this fragment through the use of residualizing radioiodination methods. METHODS: The scFv-Fc DM fragment was radioiodinated using N-succinimidyl 4-guanidinomethyl 3-[(131)I]iodobenzoate ([(131)I]SGMIB) and N(epsilon)-(3-[(131)I]iodobenzoyl)-Lys(5)-N(alpha)- maleimido-Gly(1)-GEEEK ([(131)I]IB-Mal-D-GEEEK), two residualizing radioiodination agents that have been used successfully with intact antibodies. Paired-label internalization assays of the labeled fragments were performed in vitro using MCF7 human breast cancer cells transfected to express HER2 (MCF7-HER2); comparisons were made to scFv-Fc DM directly radioiodinated using Iodogen. The tissue distribution of the scFv-Fc DM labeled with [(125)I]IB-Mal-d-GEEEK and [(131)I]SGMIB was compared in athymic mice bearing MCF7-HER2 xenografts. RESULTS: The scFv-Fc DM fragment was labeled with [(131)I]SGMIB and [(131)I]IB-Mal-d-GEEEK in conjugation yields of 53% and 25%, respectively, with preservation of immunoreactivity for HER2. Internalization assays indicated that labeling via SGMIB resulted in a 1.6- to 3.5-fold higher (P<.05) retention of radioactivity, compared to that from the directly labeled fragment, in HER2-expressing cells during a 24-h observation period. Likewise, the amount of radioactivity retained in cells from the IB-Mal-d-GEEEK-labeled fragment was 1.4- to 3.3-fold higher (P<.05). Tumor uptake of radioiodine activity in athymic mice bearing MCF7-HER2 xenografts in vivo was significantly higher for the [(125)I]IB-Mal-d-GEEEK-labeled scFv-Fc DM fragment compared with that of the [(131)I]SGMIB-labeled fragment, particularly at later time points. The uptake of (125)I was threefold (3.6+/-1.1 %ID/g vs. 1.2+/-0.4 %ID/g) and fourfold (3.1+/-1.7 %ID/g vs. 0.8+/-0.4 %ID/g) higher than that for (131)I at 24 and 48 h, respectively. However, the [(125)I]IB-Mal-d-GEEEK-labeled scFv-Fc DM fragment also exhibited considerably higher levels of radioiodine activity in liver, spleen and kidney. CONCLUSIONS: The overall results further demonstrate the potential utility of these two prosthetic groups for the radiohalogenation of internalizing monoclonal antibodies and their fragments. Specifically, the trastuzumab-derived double mutant fragment in combination with these residualizing agents warrants further evaluation for imaging and possibly treatment of HER2 expressing malignancies.

Authors
Vaidyanathan, G; Jestin, E; Olafsen, T; Wu, AM; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Jestin, E, Olafsen, T, Wu, AM, and Zalutsky, MR. "Evaluation of an anti-p185(HER2) (scFv-C(H)2-C(H)3)2 fragment following radioiodination using two different residualizing labels: SGMIB and IB-Mal-D-GEEEK." Nucl Med Biol 36.6 (August 2009): 671-680.
PMID
19647173
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
6
Publish Date
2009
Start Page
671
End Page
680
DOI
10.1016/j.nucmedbio.2009.04.002

Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with (177)Lu: in vitro comparison of acyclic and macrocyclic ligands.

INTRODUCTION: The monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor-specific mAb with the low-energy beta-emitter (177)Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized. MATERIALS AND METHODS: L8A4 mAb was labeled with (177)Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA), 2-(4-isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and alpha-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.DeltaEGFR glioma cells over 24 h to directly compare (177)Lu-labeled L8A4 to L8A4 labeled with (125)I using either iodogen or N-succinimidyl 4-guanidinomethyl-3-[(125)I]iodobenzoate ([(125)I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of (177)Lu to (125)I activity retained in U87.DeltaEGFR cells. RESULTS: All chelates demonstrated higher retention of internalized activity compared with mAb labeled using iodogen, with (177)Lu/(125)I ratios of >20 observed for the three DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for (125)I was higher than (177)Lu from 1-8 h with the opposite behavior observed thereafter. At 24 h, (177)Lu/(125)I ratios were between 1.5 and 3, with higher values observed for the three DTPA chelates. CONCLUSIONS: The nature of the chelate used to label this internalizing mAb with (177)Lu influenced intracellular retention in vitro, although at early time points, only MeO-DOTA provided more favorable results than radioiodination of the mAb via SGMIB.

Authors
Hens, M; Vaidyanathan, G; Welsh, P; Zalutsky, MR
MLA Citation
Hens, M, Vaidyanathan, G, Welsh, P, and Zalutsky, MR. "Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with (177)Lu: in vitro comparison of acyclic and macrocyclic ligands." Nucl Med Biol 36.2 (February 2009): 117-128.
PMID
19217523
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
2
Publish Date
2009
Start Page
117
End Page
128
DOI
10.1016/j.nucmedbio.2008.11.001

Propargyl 4-[F]fluorobenzoate: A Putatively More Stable Prosthetic group for the Fluorine-18 Labeling of Biomolecules via Click Chemistry.

Faster and more efficient approaches for radiolabeling biomolecules with short-lived (18)F are in dire need. Herein we report a new (18)F-labeled prosthetic group containing an acetylene function that permits the labeling of biomolecules via click chemistry. This template, propargyl 4-[(18)F]fluorobenzoate ([(18)F]PFB) was synthesized from a quaternary salt precursor in decay-corrected radiochemical yields of 58 +/- 31%. Several model compounds containing an azide moiety-benzyl azide, two lysine derivatives and a transglutaminase-reactive peptide-were labeled using [(18)F]PFB via a click reaction in decay-corrected radiochemical yields of 88 +/- 4%, 79 +/- 33%, 75 +/- 5%, and 37 +/- 31%, respectively. Our results suggest that the novel agent [(18)F]PFB is a potentially useful template for the (18)F-labeling of biomolecules via click chemistry.

Authors
Vaidyanathan, G; White, BJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, White, BJ, and Zalutsky, MR. "Propargyl 4-[F]fluorobenzoate: A Putatively More Stable Prosthetic group for the Fluorine-18 Labeling of Biomolecules via Click Chemistry." Curr Radiopharm 2.1 (January 1, 2009): 63-74.
PMID
20414475
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
2
Issue
1
Publish Date
2009
Start Page
63
End Page
74

DOTA-SIB, A TRIFUNCTIONAL PROSTHETIC GROUP FOR MULTI-MODAL LABELING

Authors
Vaidyanathan, G; White, B; Affleck, D; Zhao, X; Welsh, P; Zalutsky, M
MLA Citation
Vaidyanathan, G, White, B, Affleck, D, Zhao, X, Welsh, P, and Zalutsky, M. "DOTA-SIB, A TRIFUNCTIONAL PROSTHETIC GROUP FOR MULTI-MODAL LABELING." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 52 (2009): S70-S70.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
52
Publish Date
2009
Start Page
S70
End Page
S70

Meta-iodobenzylguanidine and analogues: chemistry and biology.

Meta-iodobenzylguanidine (MIBG) is a structural analogue of the neurotransmitter norepinephrine (NE) and is taken up by cells rich in sympathetic neurons by an active uptake process mediated by the NE transporter, which is referred to as uptake-1. It is a valuable agent in the diagnosis of myocardial abnormalities as well as that of several neuroendocrine tumors such as neuroblastoma, pheochromocytoma and carcinoid tumors. MIBG labeled with (131)I also is used extensively in the therapy of several neuroendocrine tumors. Over the years, a substantial amount of work has been undertaken to improve its clinical utility. Currently, radio-iodinated MIBG used in the clinic is prepared by an exchange radio-iodination method and, thus, is of low specific activity. For possible better targeting and to ward off pharmacological effects, its preparation at a no-carrier-added level both by solution-phase and solid-phase synthesis has been developed. For potential use in the treatment of micrometastatic diseases, synthesis of an analogue labeled with the a emitter (211)At was devised. Development of analogues labeled with positron emitting radionuclides such as (124)I, (18)F, and (76)Br has been reported. Further, efforts have been put in to improve its pharmacokinetic properties by structural modifications. Various aspects of these developments are reviewed herein.

Authors
Vaidyanathan, G
MLA Citation
Vaidyanathan, G. "Meta-iodobenzylguanidine and analogues: chemistry and biology." Q J Nucl Med Mol Imaging 52.4 (December 2008): 351-368. (Review)
PMID
19088690
Source
pubmed
Published In
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...
Volume
52
Issue
4
Publish Date
2008
Start Page
351
End Page
368

Practical outcomes of applying ensemble machine learning classifiers to High-Throughput Screening (HTS) data analysis and screening.

Over the years numerous papers have presented the effectiveness of various machine learning methods in analyzing drug discovery biological screening data. The predictive performance of models developed using these methods has traditionally been evaluated by assessing performance of the developed models against a portion of the data randomly selected for holdout. It has been our experience that such assessments, while widely practiced, result in an optimistic assessment. This paper describes the development of a series of ensemble-based decision tree models, shares our experience at various stages in the model development process, and presents the impact of such models when they are applied to vendor offerings and the forecasted compounds are acquired and screened in the relevant assays. We have seen that well developed models can significantly increase the hit-rates observed in HTS campaigns.

Authors
Simmons, K; Kinney, J; Owens, A; Kleier, DA; Bloch, K; Argentar, D; Walsh, A; Vaidyanathan, G
MLA Citation
Simmons, K, Kinney, J, Owens, A, Kleier, DA, Bloch, K, Argentar, D, Walsh, A, and Vaidyanathan, G. "Practical outcomes of applying ensemble machine learning classifiers to High-Throughput Screening (HTS) data analysis and screening." J Chem Inf Model 48.11 (November 2008): 2196-2206.
PMID
18983143
Source
pubmed
Published In
Journal of Chemical Information and Modeling
Volume
48
Issue
11
Publish Date
2008
Start Page
2196
End Page
2206
DOI
10.1021/ci800164u

TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation.

The high prevalence of TMPRSS2-ERG rearrangements ( approximately 60%) in prostate cancer (CaP) leads to androgenic induction of the ETS-related gene (ERG) expression. However, the biological functions of ERG overexpression in CaP remain to be understood. ERG knockdown in TMPRSS2-ERG expressing CaP cells induced striking morphological changes and inhibited cell growth both in cell culture and SCID mice. Evaluation of the transcriptome and specific gene promoters in ERG siRNA-treated cells and investigation of gene expression signatures of human prostate tumors revealed ERG-mediated activation of C-MYC oncogene and the repression of prostate epithelial differentiation genes (PSA and SLC45A3/Prostein). Taken together, these data combining cell culture and animal models and human prostate tumors reveal that ERG overexpression in prostate tumor cells may contribute to the neoplastic process by activating C-MYC and by abrogating prostate epithelial differentiation as indicated by prostate epithelial specific markers.

Authors
Sun, C; Dobi, A; Mohamed, A; Li, H; Thangapazham, RL; Furusato, B; Shaheduzzaman, S; Tan, S-H; Vaidyanathan, G; Whitman, E; Hawksworth, DJ; Chen, Y; Nau, M; Patel, V; Vahey, M; Gutkind, JS; Sreenath, T; Petrovics, G; Sesterhenn, IA; McLeod, DG; Srivastava, S
MLA Citation
Sun, C, Dobi, A, Mohamed, A, Li, H, Thangapazham, RL, Furusato, B, Shaheduzzaman, S, Tan, S-H, Vaidyanathan, G, Whitman, E, Hawksworth, DJ, Chen, Y, Nau, M, Patel, V, Vahey, M, Gutkind, JS, Sreenath, T, Petrovics, G, Sesterhenn, IA, McLeod, DG, and Srivastava, S. "TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation." Oncogene 27.40 (September 11, 2008): 5348-5353.
PMID
18542058
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
27
Issue
40
Publish Date
2008
Start Page
5348
End Page
5353
DOI
10.1038/onc.2008.183

Engineered modular recombinant transporters: application of new platform for targeted radiotherapeutic agents to alpha-particle emitting 211 At.

PURPOSE: To generate and evaluate a modular recombinant transporter (MRT) for targeting 211 At to cancer cells overexpressing the epidermal growth factor receptor (EGFR). METHODS AND MATERIALS: The MRT was produced with four functional modules: (1) human epidermal growth factor as the internalizable ligand, (2) the optimized nuclear localization sequence of simian vacuolating virus 40 (SV40) large T-antigen, (3) a translocation domain of diphtheria toxin as an endosomolytic module, and (4) the Escherichia coli hemoglobin-like protein (HMP) as a carrier module. MRT was labeled using N-succinimidyl 3-[211 At]astato-5-guanidinomethylbenzoate (SAGMB), its 125 I analogue SGMIB, or with 131 I using Iodogen. Binding, internalization, and clonogenic assays were performed with EGFR-expressing A431, D247 MG, and U87MG.wtEGFR human cancer cell lines. RESULTS: The affinity of SGMIB-MRT binding to A431 cells, determined by Scatchard analysis, was 22 nM, comparable to that measured before labeling. The binding of SGMIB-MRT and its internalization by A431 cancer cells was 96% and 99% EGFR specific, respectively. Paired label assays demonstrated that compared with Iodogen-labeled MRT, SGMIB-MRT and SAGMB-MRT exhibited more than threefold greater peak levels and durations of intracellular retention of activity. SAGMB-MRT was 10-20 times more cytotoxic than [211 At]astatide for all three cell lines. CONCLUSION: The results of this study have demonstrated the initial proof of principle for the MRT approach for designing targeted alpha-particle emitting radiotherapeutic agents. The high cytotoxicity of SAGMB-MRT for cancer cells overexpressing EGFR suggests that this 211 At-labeled conjugate has promise for the treatment of malignancies, such as glioma, which overexpress this receptor.

Authors
Rosenkranz, AA; Vaidyanathan, G; Pozzi, OR; Lunin, VG; Zalutsky, MR; Sobolev, AS
MLA Citation
Rosenkranz, AA, Vaidyanathan, G, Pozzi, OR, Lunin, VG, Zalutsky, MR, and Sobolev, AS. "Engineered modular recombinant transporters: application of new platform for targeted radiotherapeutic agents to alpha-particle emitting 211 At." Int J Radiat Oncol Biol Phys 72.1 (September 1, 2008): 193-200.
PMID
18722270
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
72
Issue
1
Publish Date
2008
Start Page
193
End Page
200
DOI
10.1016/j.ijrobp.2008.05.055

Astatine Radiopharmaceuticals: Prospects and Problems.

For the treatment of minimum residual diseases such micrometastases and residual tumor margins that remain after debulking of the primary tumor, targeted radiotherapy using radiopharmaceuticals tagged with alpha-particle-emitting radionuclides is very attractive. In addition to the their short range in tissue, which helps minimize harmful effects on adjacent normal tissues, alpha-particles, being high LET radiation, have several radiobiological advantages. The heavy halogen, astatine-211 is one of the prominent alpha-particle-emitting radionuclides in practice. Being a halogen, it can often be incorporated into biomolecules of interest by adapting radioiodination chemistry. A wide spectrum of compounds from the simple [(211)At]astatide ion to small organic molecules, peptides, and large proteins labeled with (211)At have been investigated with at least two reaching the stage of clinical evaluation. The chemistry, cytotoxic advantages, biodistribution studies, and microdosimetry/pharmacokinetic modeling of some of these agents will be reviewed. In addition, potential problems such as the harmful effect of radiolysis on the synthesis, lack of sufficient in vivo stability of astatinated compounds, and possible adverse effects when they are systemically administered will be discussed.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Astatine Radiopharmaceuticals: Prospects and Problems." Curr Radiopharm 1.3 (September 1, 2008): 177-.
PMID
20150978
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
1
Issue
3
Publish Date
2008
Start Page
177

Comparative study of machine-learning and chemometric tools for analysis of in-vivo high-throughput screening data.

High-throughput screening (HTS) has become a central tool of many pharmaceutical and crop-protection discovery operations. If HTS screening is carried out at the level of the intact organism, as is commonly done in crop protection, this strategy has the potential of uncovering a completely new mechanism of actions. The challenge in running a cost-effective HTS operation is to identify ways in which to improve the overall success rate in discovering new biologically active compounds. To this end, we describe our efforts directed at making full use of the data stream arising from HTS. This paper describes a comparative study in which several machine learning and chemometric methodologies were used to develop classifiers on the same data sets derived from in vivo HTS campaigns and their predictive performances compared in terms of false negative and false positive error profiles.

Authors
Simmons, K; Kinney, J; Owens, A; Kleier, D; Bloch, K; Argentar, D; Walsh, A; Vaidyanathan, G
MLA Citation
Simmons, K, Kinney, J, Owens, A, Kleier, D, Bloch, K, Argentar, D, Walsh, A, and Vaidyanathan, G. "Comparative study of machine-learning and chemometric tools for analysis of in-vivo high-throughput screening data." J Chem Inf Model 48.8 (August 2008): 1663-1668.
PMID
18681397
Source
pubmed
Published In
Journal of Chemical Information and Modeling
Volume
48
Issue
8
Publish Date
2008
Start Page
1663
End Page
1668
DOI
10.1021/ci800142d

A radioiodinated MIBG-octreotate conjugate exhibiting enhanced uptake and retention in SSTR2-expressing tumor cells.

Several neuroendocrine tumors are known to express both the somatostatin receptor subtype 2 (SSTR2) and the norepinephrine transporter (NET), and radiopharmaceuticals directed toward both these targets such as MIBG and octreotide derivatives are routinely used in the clinic. To investigate the possibility of targeting both NET and SSTR2 conjointly, a conjugate of radioiodinated MIBG and octreotate was synthesized. Attempts to synthesize the radioiodinated target compound (MIBG-octreotate; [ (131)I] 12a) from a tin precursor were futile; however, it could be accomplished from a bromo precursor by exchange radioiodination in 3-36% ( n = 10) radiochemical yields. The total uptake of [ (131)I] 12a in SK-N-SH human neuroblastoma cells transfected to express SSTR2 (SK-N-SHsst2) was similar to that for [ (125)I]MIBG at all time points (34.9 +/- 2.4% vs 43.8 +/- 1.2% at 4 h; p < 0.05), while it was substantially lower (5.4 +/- 0.3% vs 35.9 +/- 1.2%) in the SH-SY5Y cell line, a subclone of SK-N-SH line that is known to express SSTR2. The NET blocker desipramine reduced the uptake of [ (131)I] 12a only to a small extent, further suggesting a limited role of NET in its binding and accumulation. Uptake of [ (131)I] 12a in SK-N-SHsst2 cells was 8-10-fold higher ( p < 0.05) than that of [ (125)I]I-Gluc-TOCA, an octreotide analogue, at all time points over a 4 h period and was reduced to about 20% by 10 muM octreotide demonstrating that the uptake of [ (131)I] 12a in this cell line is predominantly mediated by SSTR2. The intracellularly trapped radioactivity in SK-N-SHsst2 cells was substantially higher for [ (131)I] 12a compared to that for [ (125)I]OIBG-octreotate, an isomeric congener of 12a. Because MIBG has more specific NET-mediated uptake than OIBG, this suggests at least a partial role for NET-mediated uptake of [ (131)I] 12a in this cell line. While further refinement in the structure of the conjugate-probably interposition of a flexible and/or cleavable linker between the MIBG and octreotate moieties-may be necessary to make it a substrate/ligand for both NET and SSTR2, this conjugate is demonstrated to be much superior than I-Gluc-TOCA with respect to the uptake in SSTR2-expressing cells.

Authors
Vaidyanathan, G; Affleck, DJ; Norman, J; O'Dorisio, S; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Norman, J, O'Dorisio, S, and Zalutsky, MR. "A radioiodinated MIBG-octreotate conjugate exhibiting enhanced uptake and retention in SSTR2-expressing tumor cells." Bioconjug Chem 18.6 (November 2007): 2122-2130.
PMID
17979223
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
18
Issue
6
Publish Date
2007
Start Page
2122
End Page
2130
DOI
10.1021/bc700240r

Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies.

An attractive feature of targeted radionuclide therapy is the ability to select radionuclides and targeting vehicles with characteristics that are best suited for a particular clinical application. One combination that has been receiving increasing attention is the use of monoclonal antibodies (mAbs) specifically reactive to receptors and antigens that are expressed in tumor cells to selectively deliver the alpha-particle-emitting radiohalogen astatine-211 (211At) to malignant cell populations. Promising results have been obtained in preclinical models with multiple 211At-labeled mAbs; however, translation of the concept to the clinic has been slow. Impediments to this process include limited radionuclide availability, the need for suitable radiochemistry methods operant at high activity levels and lack of data concerning the toxicity of alpha-particle emitters in humans. Nonetheless, two clinical trials have been initiated to date with 211At-labeled mAbs, and others are planned for the near future.

Authors
Zalutsky, MR; Reardon, DA; Pozzi, OR; Vaidyanathan, G; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Pozzi, OR, Vaidyanathan, G, and Bigner, DD. "Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies." Nucl Med Biol 34.7 (October 2007): 779-785. (Review)
PMID
17921029
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
7
Publish Date
2007
Start Page
779
End Page
785
DOI
10.1016/j.nucmedbio.2007.03.007

Targeted alpha-particle radiotherapy with At-211-labeled monoclonal antibodies

Authors
Zalutsky, MR; Reardon, DA; Pozzi, OR; Vaidyanathan, G; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Pozzi, OR, Vaidyanathan, G, and Bigner, DD. "Targeted alpha-particle radiotherapy with At-211-labeled monoclonal antibodies." October 2007.
Source
wos-lite
Published In
Nuclear Medicine and Biology
Volume
34
Issue
7
Publish Date
2007
Start Page
779
End Page
785
DOI
10.1016/j.nuemedbio.2007.03.007

[I-125] iodoquine uptake in tumor cell lines with high ALDH expression

Authors
Chin, BB; Storms, RW; Base, K; Lascola, C; Haystead, T; Zalutsky, MR; Vaidyanathan, G
MLA Citation
Chin, BB, Storms, RW, Base, K, Lascola, C, Haystead, T, Zalutsky, MR, and Vaidyanathan, G. "[I-125] iodoquine uptake in tumor cell lines with high ALDH expression." October 2007.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
34
Publish Date
2007
Start Page
S222
End Page
S222

Phase 1 study of radiation dosimetry and clearance of no carrier added 131I-MIBG (ultratrace iobenguane) in 7 carcinoid and 4 pheochromocytoma patients

Authors
Barrett, JA; Coleman, R; Morse, M; Borys, N; Kronauge, J; Stubbs, JB; Mok, H; Qi, F; Petry, NN; Petry, NN; Vaidyanathan, G; Babich, JW
MLA Citation
Barrett, JA, Coleman, R, Morse, M, Borys, N, Kronauge, J, Stubbs, JB, Mok, H, Qi, F, Petry, NN, Petry, NN, Vaidyanathan, G, and Babich, JW. "Phase 1 study of radiation dosimetry and clearance of no carrier added 131I-MIBG (ultratrace iobenguane) in 7 carcinoid and 4 pheochromocytoma patients." October 2007.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
34
Publish Date
2007
Start Page
S241
End Page
S241

A kit method for the high level synthesis of [211At]MABG.

meta-[(211)At]Astatobenzylguanidine ([(211)At]MABG), an analogue of meta-iodobenzylguanidine (MIBG) labeled with the alpha-emitter (211)At, targets the norepinephrine transporter. Because MABG has been shown to have excellent characteristics in preclinical studies, it has been considered to be a promising targeted radiotherapeutic for the treatment of tumors such as micrometastatic neuroblastoma that overexpress the norepinephrine transporter. To facilitate clinical evaluation of this agent, a convenient method for the high level synthesis of [(211)At]MABG that is adaptable for kit formulation has been developed. A tin precursor anchored to a solid-support was treated with a methanolic solution of (211)At in the presence of a mixture of H(2)O(2)/HOAc as the oxidant; [(211)At]MABG was isolated by simple solid-phase extraction. By using C-18 solid-phase extraction, the radiochemical yield from 25 batches was 63+/-13%; however, loss of radioactivity during evaporation of the methanolic solution was a problem. This difficulty was avoided by use of a cation exchange resin cartridge for isolation of [(211)At]MABG, which resulted in radiochemical yields of 63+/-9% in a shorter duration of synthesis. The radiochemical purity was more than 90% and no chemical impurity has been detected. The final doses were sterile and apyrogenic. These results demonstrate that [(211)At]MABG can be prepared via a kit method at radioactivity levels anticipated for initiation of clinical studies.

Authors
Vaidyanathan, G; Affleck, DJ; Alston, KL; Zhao, X-G; Hens, M; Hunter, DH; Babich, J; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Alston, KL, Zhao, X-G, Hens, M, Hunter, DH, Babich, J, and Zalutsky, MR. "A kit method for the high level synthesis of [211At]MABG." Bioorg Med Chem 15.10 (May 15, 2007): 3430-3436.
PMID
17387017
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
15
Issue
10
Publish Date
2007
Start Page
3430
End Page
3436
DOI
10.1016/j.bmc.2007.03.016

Identification and biochemical studies on novel non-nucleoside inhibitors of the enzyme adenosine kinase.

The enzyme adenosine kinase (AK) plays a key role in the regulation of intracellular and extracellular concentration of adenosine (Ado), which exhibits potent hormonal activity in cardiovascular, nervous and immune systems. In view of the pharmacological effects of Ado, there is much interest in identifying inhibitors of AK, which can augment its tissue-protective effects. In this study, we have screened 1040 compounds from a chemical library of putative kinase inhibitors for their effect on purified human recombinant AK. These studies have identified 8 novel, non-nucleoside AK inhibitors. Four of these compounds (viz. 2-tert-butyl-4H-benzo[1,2,4]thiadiazine-3-thione (2759-0749); N-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-yl)-propionamide (3998-0118); 3-[5,6-Bis-(4-methoxy-phenyl)-furo[2,3-d]pyrimidin-4-ylamino]-propan-1-ol (4072-2732); and 2-[2-(3,4-dihydroxy-phenyl)-5-phenyl-1H-imidazol-4-yl]-fluoren-9-one (8008-6198)), which inhibited human AK in a concentration-dependent manner in a low micromolar range (IC(50) = 0.38 approximately 1.98 microM) were further studied. Kinetic and structural studies on these compounds provide evidence that inhibition of AK by these compounds was competitive with respect to Ado and non-competitive for ATP. All of these compounds also inhibited uptake of Ado and its metabolism in cultured mammalian cells at comparable concentrations indicating their efficient cellular penetrability. These AK inhibitors, whose chemical structures differ significantly from all previously known inhibitors, provide useful lead compounds for identification of more potent but less toxic AK inhibitors that may prove useful for therapeutic purposes.

Authors
Park, J; Vaidyanathan, G; Singh, B; Gupta, RS
MLA Citation
Park, J, Vaidyanathan, G, Singh, B, and Gupta, RS. "Identification and biochemical studies on novel non-nucleoside inhibitors of the enzyme adenosine kinase." Protein J 26.3 (April 2007): 203-212.
PMID
17205396
Source
pubmed
Published In
The Protein Journal
Volume
26
Issue
3
Publish Date
2007
Start Page
203
End Page
212
DOI
10.1007/s10930-006-9062-z

Synthesis of N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate: a radio-iodination agent for labeling internalizing proteins and peptides.

This protocol describes a detailed procedure for the synthesis of N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB), an agent useful in the radio-iodination of proteins, including monoclonal Abs, and peptides that undergo internalization after receptor or antigen binding. In this procedure, the tin precursor N-succinimidyl 4-[N1,N2-bis(tert-butyloxycarbonyl)guanidinomethyl]-3-(trimethylstannyl)benzoate (Boc-SGMTB, 3) was first radio-iodinated to [*I]Boc-SGMIB, a derivative of [*I]SGMIB with the guanidine function protected with Boc groups. Treatment of [*I]Boc-SGMIB with trifluoroacetic acid delivered the final product. The total time for the synthesis and purification of [*I]Boc-SGMIB and its subsequent de-protection is approximately 140 min.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Synthesis of N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate: a radio-iodination agent for labeling internalizing proteins and peptides." Nat Protoc 2.2 (2007): 282-286.
PMID
17406587
Source
pubmed
Published In
Nature Protocols
Volume
2
Issue
2
Publish Date
2007
Start Page
282
End Page
286
DOI
10.1038/nprot.2007.20

A tin precursor for the synthesis of no-carrier-added [*I]MIBG and [211At]MABG

Radioiodinated MIBG has shown considerable promise as an imaging agent for cardiac and oncologic applications, and also as a targeted radio therapeutic for treating patients with neuroendocrine tumors. This radiolabeled agent, synthesized at a no-carrier-added level, has demonstrated advantages over the carrier-added preparation in preliminary clinical studies. Earlier we developed a silicon precursor from which both radioiodinated MIBG and the α-particle-emitting 211At analog [211At]MABG could be synthesized at a no-carrier-added level. In order to increase the practicality of this approach, we have developed a synthesis of a tin precursor in two steps from a readily available starting material. This tin precursor, N, N′-bis(tert-butyloxycarbonyl)-3-(trimethylstannyl)benzylguanidine (Bis-Boc MTMSBG) was evaluated for the synthesis of n.c.a. [*I]MIBG and [ 211At]MABG via halodestannylation. The radiochemical yields were 83 ± 9% (n = 7), 30 ± 21% (n = 2), 77 ± 2% (n = 2), and 66 ± 7% (n = 4) for labeling with 131I, 124I, 125I, and 211At, respectively. Copyright © 2007 John Wiley & Sons, Ltd.

Authors
Vaidyanathan, G; Affleck, DJ; Alston, KL; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Alston, KL, and Zalutsky, MR. "A tin precursor for the synthesis of no-carrier-added [*I]MIBG and [211At]MABG." Journal of Labelled Compounds and Radiopharmaceuticals 50.3 (2007): 177-182.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
50
Issue
3
Publish Date
2007
Start Page
177
End Page
182
DOI
10.1002/jlcr.1243

Nε-(3[*I]iodobenzoyl)-Lys5-N α-maleimido-Gly1-GEEEK([*I]IB-Mal-D-GEEEK): A radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies

Novel methods are needed for the radiohalogenation of cell-internalizing proteins and peptides because rapid loss of label occurs after lysosomal processing when these molecules are labeled using conventional radioiodination methodologies. We have developed a radiolabeled prosthetic group that contains multiple negatively charged D-amino acids to facilitate trapping of the radioactivity in the cell after proteolysis of the labeled protein. N ε-(3-[125I]iodobenzoyl-Lys5-N α-maleimido-Gly1-GEEEK ([125I]IB-Mal-D- GEEEK) was synthesized via iododestannylation in 90.3 ± 3.9% radiochemical yields. This radioiodinated agent was conjugated to iminothiolane-treated L8A4, an anti-epidermal growth factor receptor variant III (EGFRvIII) specific monoclonal antibody (mAb) in 54.3 ± 17.7% conjugation yields. In vitro assays with the EGFRvIII-expressing U87MGΔEGFR glioma cell line demonstrated that the internalized radioactivity for the [125I]IB-Mal-D-GEEEK-L8A4 conjugate increased from 14.1% at 1 h to 44.7% at 24 h and was about 15-fold higher than that of directly radioiodinated L8A4 at 24 h. A commensurately increased tumor uptake in vivo in athymic mice bearing subcutaneous U87MGΔEGFR xenografts (52.6 ± 14.3% injected dose per gram versus 17.4 ± 3.5% ID/g at 72 h) also was observed. These results suggest that [125I]IB-Mal-D-GEEEK is a promising reagent for the radioiodination of internalizing mAbs. © 2006 American Chemical Society.

Authors
Vaidyanathan, G; Alston, KL; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Alston, KL, Bigner, DD, and Zalutsky, MR. "Nε-(3[*I]iodobenzoyl)-Lys5-N α-maleimido-Gly1-GEEEK([*I]IB-Mal-D-GEEEK): A radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies." Bioconjugate Chemistry 17.4 (July 1, 2006): 1085-1092.
Source
scopus
Published In
Bioconjugate Chemistry
Volume
17
Issue
4
Publish Date
2006
Start Page
1085
End Page
1092
DOI
10.1021/bc0600766

Nepsilon-(3-[*I]Iodobenzoyl)-Lys5-Nalpha-maleimido-Gly1-GEEEK ([*I]IB-Mal-D-GEEEK): a radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies.

Novel methods are needed for the radiohalogenation of cell-internalizing proteins and peptides because rapid loss of label occurs after lysosomal processing when these molecules are labeled using conventional radioiodination methodologies. We have developed a radiolabeled prosthetic group that contains multiple negatively charged D-amino acids to facilitate trapping of the radioactivity in the cell after proteolysis of the labeled protein. N(epsilon)-(3-[(125)I]iodobenzoyl)-Lys(5)-N(alpha)-maleimido-Gly(1)-GEEEK ([(125)I]IB-Mal-D-GEEEK) was synthesized via iododestannylation in 90.3 +/- 3.9% radiochemical yields. This radioiodinated agent was conjugated to iminothiolane-treated L8A4, an anti-epidermal growth factor receptor variant III (EGFRvIII) specific monoclonal antibody (mAb) in 54.3 +/- 17.7% conjugation yields. In vitro assays with the EGFRvIII-expressing U87MGDeltaEGFR glioma cell line demonstrated that the internalized radioactivity for the [(125)I]IB-Mal-D-GEEEK-L8A4 conjugate increased from 14.1% at 1 h to 44.7% at 24 h and was about 15-fold higher than that of directly radioiodinated L8A4 at 24 h. A commensurately increased tumor uptake in vivo in athymic mice bearing subcutaneous U87MGDeltaEGFR xenografts (52.6 +/- 14.3% injected dose per gram versus 17.4 +/- 3.5% ID/g at 72 h) also was observed. These results suggest that [(125)I]IB-Mal-d-GEEEK is a promising reagent for the radioiodination of internalizing mAbs.

Authors
Vaidyanathan, G; Alston, KL; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Alston, KL, Bigner, DD, and Zalutsky, MR. "Nepsilon-(3-[*I]Iodobenzoyl)-Lys5-Nalpha-maleimido-Gly1-GEEEK ([*I]IB-Mal-D-GEEEK): a radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies." Bioconjug Chem 17.4 (July 2006): 1085-1092.
PMID
16848419
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
17
Issue
4
Publish Date
2006
Start Page
1085
End Page
1092
DOI
10.1021/bc0600766

Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine.

PURPOSE: An inverse correlation has been established between tumor levels of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) and a positive outcome after alkylator chemotherapy. Quantitative imaging of AGT could provide important information for patient-specific cancer treatment. Several radiolabeled analogues of O6-benzylguanine (BG), a potent AGT inactivator, have been developed and shown to be capable of labeling pure AGT protein. Herein, two of these analogues--O6-3-[*I]iodobenzylguanine ([*I]IBG) and O6-3-[*I]iodobenzyl-2'-deoxyguanosine ([*I]IBdG)--were further evaluated in two murine xenograft models. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, also was investigated as an alternative agent. METHODS: Several biodistribution studies of radioiodinated IBG and IBdG were performed in TE-671 human rhabdomyosarcoma and DAOY human medulloblastoma murine xenograft models. Mice were treated with BG or its nucleoside analogue dBG to deplete the tumor AGT content. The effect of unlabeled IBG and that of 7,8-benzoflavone (BF), an inhibitor of the cytochrome P-450 isozyme CYP1A2, on the tumor uptake of the tracers was determined. The uptake of (AcO)2-[131I]IBdG along with that of [125I]IBdG in DAOY cells in vitro was determined in the presence and absence of a nucleoside transporter inhibitor, dipyridamole. RESULTS: Pretreatment of mice either with BG or dBG failed to reduce tumor levels of [*I]IBG or [*I]IBdG even though such treatments completely depleted tumor AGT content. Treatment of mice with BF increased tumor uptake of [125I]IBG by 56%; however, differentiation of tumors with and without AGT still was not possible. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, had a higher uptake in vitro in DAOY tumor cells. However, its uptake, like that of [125I]IBdG, was blocked by dipyridamole. CONCLUSIONS: Taken together, these results suggest that labeled agents that are more specific for cellular AGT and that are more metabolically stable are needed.

Authors
Shankar, S; Zalutsky, MR; Friedman, H; Vaidyanathan, G
MLA Citation
Shankar, S, Zalutsky, MR, Friedman, H, and Vaidyanathan, G. "Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine." Nucl Med Biol 33.3 (April 2006): 399-407.
PMID
16631089
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
33
Issue
3
Publish Date
2006
Start Page
399
End Page
407
DOI
10.1016/j.nucmedbio.2005.12.015

Antiepidermal growth factor variant III scFv fragment: effect of radioiodination method on tumor targeting and normal tissue clearance.

INTRODUCTION: MR1-1 is a single-chain Fv (scFv) fragment that binds with high affinity to epidermal growth factor receptor variant III, which is overexpressed on gliomas and other tumors but is not present on normal tissues. The objective of this study was to evaluate four different methods for labeling MR1-1 scFv that had been previously investigated for the radioiodinating of an intact anti-epidermal growth factor receptor variant III (anti-EGFRvIII) monoclonal antibody (mAb) L8A4. METHODS: The MR1-1 scFv was labeled with (125)I/(131)I using the Iodogen method, and was also radiohalogenated with acylation agents bearing substituents that were positively charged--N-succinimidyl-3-[*I]iodo-5-pyridine carboxylate and N-succinimidyl-4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB)--and negatively charged--N-succinimidyl-3-[*I]iodo-4-phosphonomethylbenzoate ([*I]SIPMB). In vitro internalization assays were performed with the U87MGDeltaEGFR cell line, and the tissue distribution of the radioiodinated scFv fragments was evaluated in athymic mice bearing subcutaneous U87MGDeltaEGFR xenografts. RESULTS AND CONCLUSION: As seen previously with the anti-EGFRvIII IgG mAb, retention of radioiodine activity in U87MGDeltaEGFR cells in the internalization assay was labeling method dependent, with SGMIB and SIPMB yielding the most prolonged retention. However, unlike the case with the intact mAb, the results of the internalization assays were not predictive of in vivo tumor localization capacity of the labeled scFv. Renal activity was dependent on the nature of the labeling method. With MR1-1 labeled using SIPMB, kidney uptake was highest and most prolonged; catabolism studies indicated that this uptake primarily was in the form of epsilon-N-3-[*I]iodo-4-phosphonomethylbenzoyl lysine.

Authors
Shankar, S; Vaidyanathan, G; Kuan, C-T; Bigner, DD; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Kuan, C-T, Bigner, DD, and Zalutsky, MR. "Antiepidermal growth factor variant III scFv fragment: effect of radioiodination method on tumor targeting and normal tissue clearance." Nucl Med Biol 33.1 (January 2006): 101-110.
PMID
16459265
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
33
Issue
1
Publish Date
2006
Start Page
101
End Page
110
DOI
10.1016/j.nucmedbio.2005.08.004

Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor.

Carbohydration of N-terminus and substitution of a threonine for the threoninol residue at the C-terminus of Tyr3-octreotide (TOC) has resulted in improved pharmacokinetics and tumor targeting of its radioiodinated derivatives. Yet, these peptides are very susceptible to in vivo deiodination due to the similarity of monoiodotyrosine (MIT) to thyroid hormone. The goal of this work was to develop octreotate analogues containing both a sugar moiety and a nontyrosine prosthetic group on which a radioiodine or 211At can be introduced. Solid-phase synthesis and subsequent modifications delivered an iodo standard of the target peptide N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-iodobenzoyl)-Lys0-octreotate (GIBLO) and the corresponding tin precursor N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-[(3-tri-n-butylstannyl)benzoyl]-Lys0-octreotate (GTBLO). GIBLO displaced [125I]TOC from somatostatin receptor subtype 2 (SSTR2)-positive AR42J rat pancreatic tumor cell membranes with an IC50 of 0.46 +/- 0.05 nM suggesting that GIBLO retained affinity to SSTR2. GTBLO was radiohalogenated to [131I]GIBLO and N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-[211At]astatobenzoyl)-Lys0-octreotate ([211At]GABLO) in 21.2 +/- 4.9% and 46.8 +/- 9.5% radiochemical yields, respectively. From a paired-label internalization assay using D341 Med medulloblastoma cells, the maximum specific internalized radioactivity from [131I]GIBLO was 1.78 +/- 0.8% of input dose compared to 9.67 +/- 0.43% for N(alpha)-(1-deoxy-D-fructosyl)-[125I]iodo-Tyr3-octreotate ([125I]I-Gluc-TOCA). Over a 4 h period, the extent of internalization of [131I]GIBLO and [211At]GABLO was similar in this cell line. In D341 Med murine subcutaneous xenografts, the uptake of [125I]I-Gluc-TOCA at 0.5, 1 and 4 h was 21.5 +/- 4.0% ID/g, 18.8 +/- 7.7% ID/g, and 0.9 +/- 0.4% ID/g, respectively. In comparison, these values for [131I]GIBLO were 6.9 +/- 1.2% ID/g, 4.7 +/- 1.4% ID/g, and 0.8 +/- 0.5% ID/g. Both in vitro and in vivo catabolism studies did not suggest the severance of the lys0 along with its appendages from the peptide. Taken together, although GIBLO maintained affinity to SSTR2, its tumor uptake both in vitro and in vivo was substantially lower than that of I-Gluc-TOCA suggesting other factors such as net charge and overall geometry of the peptide may be important.

Authors
Vaidyanathan, G; Affleck, DJ; Schottelius, M; Wester, H; Friedman, HS; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Schottelius, M, Wester, H, Friedman, HS, and Zalutsky, MR. "Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor." Bioconjug Chem 17.1 (January 2006): 195-203.
PMID
16417269
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
17
Issue
1
Publish Date
2006
Start Page
195
End Page
203
DOI
10.1021/bc0502560

Preparation of N-succinimidyl 3-[*I]iodobenzoate: an agent for the indirect radioiodination of proteins.

A procedure for the synthesis of N-succinimidyl 3-iodobenzoate labeled with any iodine isotope ([*I]SIB), which is an agent used in the radioiodination of proteins and peptides, from its tin precursor N-succinimidyl 3-(tri-n-butylstannyl)benzoate (STB) is described. Also included are protocols for the synthesis of an unlabeled standard of SIB and the tin precursor. Radioiododestannylation of STB using tert-butylhydroperoxide as the oxidant gives [*I]SIB in 80% radiochemical yields. The total time for the synthesis of [*I]SIB from STB is approximately 95 min. Use of [*I]SIB yields radioiodinated proteins that are considerably more stable in vivo than those radioiodinated by the direct electrophilic method.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Preparation of N-succinimidyl 3-[*I]iodobenzoate: an agent for the indirect radioiodination of proteins." Nat Protoc 1.2 (2006): 707-713.
PMID
17406300
Source
pubmed
Published In
Nature Protocols
Volume
1
Issue
2
Publish Date
2006
Start Page
707
End Page
713
DOI
10.1038/nprot.2006.99

Synthesis of N-succinimidyl 4-[18F]fluorobenzoate, an agent for labeling proteins and peptides with 18F.

This protocol describes the step-by-step procedure for the synthesis of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB), an agent widely used for labeling proteins and peptides with the positron-emitting radionuclide 18F. The protocols for the synthesis of unlabeled SFB and the quaternary salt precursor 4-formyl-N,N,N-trimethyl benzenaminium trifluoromethane sulfonate also are described. For the [18F]SFB synthesis, the quaternary salt is first converted to 4-[18F]fluorobenzaldehyde. Oxidation of the latter provides 4-[18F]fluorobenzoic acid, which is converted to [18F]SFB by treatment with N,N-disuccinimidyl carbonate. Using this method, [18F]SFB can be synthesized in decay-corrected radiochemical yields of 30%-35% and a specific radioactivity of 11-12 GBq micromol(-1). The total synthesis and purification time required is about 80 min, starting from delivery of the [18F]fluoride. [18F]SFB remains an optimal reagent for labeling proteins and peptides with 18F because of good conjugation yields and metabolic stability.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Synthesis of N-succinimidyl 4-[18F]fluorobenzoate, an agent for labeling proteins and peptides with 18F." Nat Protoc 1.4 (2006): 1655-1661.
PMID
17487148
Source
pubmed
Published In
Nature Protocols
Volume
1
Issue
4
Publish Date
2006
Start Page
1655
End Page
1661
DOI
10.1038/nprot.2006.264

Enhanced cellular retention of an internalizing anti-EGFRvIII monoclonal antibody radioiodinated using LYS5-[*I]iodobenzoyl Gly(1)-maleimido GEEEK ([*I]IB-Mal-D-GEEEK), a prosthetic group containing negatively charged D-glutamates

Authors
Vaidyanathan, G; Alston, KL; Welsh, PC; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Alston, KL, Welsh, PC, and Zalutsky, MR. "Enhanced cellular retention of an internalizing anti-EGFRvIII monoclonal antibody radioiodinated using LYS5-[*I]iodobenzoyl Gly(1)-maleimido GEEEK ([*I]IB-Mal-D-GEEEK), a prosthetic group containing negatively charged D-glutamates." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
386
End Page
386

O6-3-[125I]iodobenzyl-2'-deoxyguanosine ([125I]IBdG): synthesis and evaluation of its usefulness as an agent for quantification of alkylguanine-DNA alkyltransferase (AGT).

The development of O(6)-(3-[(125)I]iodobenzyl)-2'-deoxyguanosine ([(125)I]IBdG), the glycosylated analogue of the O(6)-3-iodobenzylguanine (IBG), as an agent for the in vivo mapping of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) is described. Synthesis of its tin precursor, O(6)-3-trimethylstannylbenzyl-2'-deoxyguanosine (TBdG) was achieved in four steps from deoxyguanosine. Radioiodination of TBdG in a single step gave [(125)I]IBdG in 70-85% isolated radiochemical yield. [(125)I]IBdG bound specifically to pure AGT with an IC(50) of 7.1 microM. From paired-label assays, [(125)I]IBdG showed a 2- to 3-fold higher cellular uptake than [(131)I]IBG in DAOY medulloblastoma, TE-671 rhabdomyosarcoma, SK-Mel-28 melanoma, and HT-29 colon carcinoma human cell lines. Uptake of both labeled compounds in these cell lines decreased with increasing concentrations of unlabeled O(6)-benzylguanine (BG) when BG was present in the medium during incubation with the labeled compounds. Compared to BG, unlabeled IBdG diminished the uptake of [(125)I]IBdG and [(131)I]IBG in DAOY cells more efficiently (IC(50)<1 microM vs >10 microM for BG). There was no significant change in cell-bound activity of [(125)I]IBdG and [(131)I]IBG when BG was removed from the incubation medium before incubating cells with the tracers, suggesting that only a very small portion of radioactivity taken up by the cells is AGT bound. This was corroborated by gel-electrophoresis performed on extracts from cells treated with varying amounts of BG and then incubated with [(125)I]IBdG in the presence of BG. No radiolabeled AGT band was discernable by phosphor-imaging, signifying low cellular AGT binding of the radiotracer. In contrast, when cell extracts were prepared from BG pre-treated cells and aliquots were incubated with [(125)I]IBdG subsequently, the intensity of radiolabeled AGT band decreased linearly as a function of BG concentration. This suggests that the low level of [(125)I]IBdG that binds to AGT does so in a concentration dependent manner. These data suggest that IBdG is transported across the cell membrane to a higher degree than IBG. However, to be a practical tracer for quantifying cellular AGT, considerable localization of such derivatives need to occur within the cell nucleus where AGT is present predominantly.

Authors
Shankar, S; Zalutsky, MR; Vaidyanathan, G
MLA Citation
Shankar, S, Zalutsky, MR, and Vaidyanathan, G. "O6-3-[125I]iodobenzyl-2'-deoxyguanosine ([125I]IBdG): synthesis and evaluation of its usefulness as an agent for quantification of alkylguanine-DNA alkyltransferase (AGT)." Bioorg Med Chem 13.12 (June 2, 2005): 3889-3898.
PMID
15911305
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
13
Issue
12
Publish Date
2005
Start Page
3889
End Page
3898
DOI
10.1016/j.bmc.2005.04.014

0(6)-{4-(3-[F-18]fluoropropyl)-benzyl}-2 '-deoxyguanosine ([F-18]FPBdG) - Synthesis and evaluation of a potential DNA repair protein 0(6)-alkyguanine-DNA alkyltransferase (AGT) imaging agent.

Authors
Vaidyanathan, G; Base, K; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Base, K, and Zalutsky, MR. "0(6)-{4-(3-[F-18]fluoropropyl)-benzyl}-2 '-deoxyguanosine ([F-18]FPBdG) - Synthesis and evaluation of a potential DNA repair protein 0(6)-alkyguanine-DNA alkyltransferase (AGT) imaging agent." March 13, 2005.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
229
Publish Date
2005
Start Page
U182
End Page
U182

No-carrier-added synthesis of a 4-methyl-substituted meta-iodobenzylguanidine analogue.

Radioiodinated meta-iodobenzylguanidine (MIBG) is used in the diagnosis and therapy of various neuroendocrine tumors. As a part of our efforts to develop an MIBG analogue with improved characteristics for these applications, a synthesis of 3-[131I]iodo-4-methylbenzylguanidine ([131I]MeIBG) was developed. Unlabeled MeIBG and the tin precursor, N, N'-(bis-tert-butyloxycarbonyl)-N-(4-methyl-3-trimethylstannylbenzyl) guanidine were synthesized in two steps from 3-iodo-4-methylbenzylalcohol. Radioiodinated MeIBG was synthesized at a no-carrier-added level by the iododestannylation of the tin precursor in about 85% radiochemical yield. The accumulation of [131I]MeIBG (38.9+/-3.0% of input counts) by human neuroblastoma SK-N-SH cells in vitro was 87% that of [125I]MIBG (44.5+/-3.0%) and a number of Uptake-1 inhibiting conditions reduced the uptake of both tracers in this cell line to a similar degree suggesting that introduction of a methyl substituent at the 4-position of MIBG did not adversely affect its biological characteristics.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "No-carrier-added synthesis of a 4-methyl-substituted meta-iodobenzylguanidine analogue." Appl Radiat Isot 62.3 (March 2005): 435-440.
PMID
15607920
Source
pubmed
Published In
Applied Radiation and Isotopes
Volume
62
Issue
3
Publish Date
2005
Start Page
435
End Page
440
DOI
10.1016/j.apradiso.2004.07.001

Radioiodine and 211At-labeled guanidinomethyl halobenzoyl octreotate conjugates: potential peptide radiotherapeutics for somatostatin receptor-positive cancers.

Derivatives of the somatostatin analogues octreotide and octreotate labeled with radioiosotopes are used in the diagnosis and therapy of somatostatin receptor (SSTR)-positive tumors. A method has been devised to synthesize {N-(4-guanidinomethyl-3-iodobenzoyl)-Phe1-octreotate (GMIBO). Receptor binding assay and scatchard analysis yielded a Kd of 4.83 +/- 0.19 nM for this peptide. Derivatives of this peptide labeled with radioiodine ([*I]GMIBO) and the alpha-particle-emitting radiohalogen 211At N-(3-[211At]astato-4-guanidinomethylbenzoyl)-Phe1-octreotate; [211At]AGMBO} were prepared in a single step from a tin precursor in radiochemical yields of 30-35% and 15-20%, respectively. Paired-label internalization assays performed with the SSTR-positive D341 Med human medulloblastoma cell line demonstrated that [125I]GMIBO and [211At]AGMBO were specifically internalized 20-40% more than Nalpha-(1-deoxy-D-fructosyl)-[131I]I-Tyr3-octreotate ([131I]I-Glu-TOCA), the radioiodinated octreotide derivative previously shown to exhibit maximum internalization in this cell line. Uptake of [131I]GMIBO in D341 Med subcutaneous xenografts in a murine model (8.34 +/- 1.82 versus 8.10 +/- 2.23% ID/g at 1h) and SSTR-expressing normal tissues was comparable to that of [125I]I-Glu-TOCA and was shown to be specific. However, the uptake of [131I]GMIBO also was substantially higher in liver (16.9 +/- 3.15 versus 1.39 +/- 0.45% ID/g at 1 h) and in kidneys (44.33 +/- 6.47 versus 3.44 +/- 0.68% ID/g at 1h) compared to that of [125I]I-Glu-TOCA. These data suggest that these novel peptide conjugates retain their specificity for SSTR both in vitro and in vivo; however, because of their higher accumulation in normal tissues they would be best applied in settings amenable to loco-regional administration such as medulloblastoma neoplastic meningitis.

Authors
Vaidyanathan, G; Boskovitz, A; Shankar, S; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Boskovitz, A, Shankar, S, and Zalutsky, MR. "Radioiodine and 211At-labeled guanidinomethyl halobenzoyl octreotate conjugates: potential peptide radiotherapeutics for somatostatin receptor-positive cancers." Peptides 25.12 (December 2004): 2087-2097.
PMID
15572196
Source
pubmed
Published In
Peptides
Volume
25
Issue
12
Publish Date
2004
Start Page
2087
End Page
2097
DOI
10.1016/j.peptides.2004.08.018

A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells.

PURPOSE: As a part of our efforts to develop a meta-iodobenzylguanidine (MIBG) analogue with improved characteristics for the diagnosis and treatment of neuroendocrine tumours, 3-[131I]iodo-4-methyl-benzylguanidine ([131I]MeIBG) has been developed. The purpose of this study was to evaluate [131I]MeIBG in vitro using the uptake-1 positive SK-N-SH neuroblastoma cell line and in vivo in normal mice and mice bearing human neuroblastoma xenografts. METHODS: The ability of SK-N-SH human neuroblastoma cells to retain [131I]MeIBG in vitro over a period of 4 days, in comparison to [125I]MIBG, was determined by a paired-label assay. Paired-label biodistributions of [131I]MeIBG and [125I]MIBG were performed in normal mice as well as in athymic mice bearing SK-N-SH and IMR-32 human neuroblastoma xenografts. RESULTS: Retention of [131I]MeIBG by SK-N-SH cells in vitro was increased by factors of 1.2, 1.5, 2.0, 2.5 and 3.1 compared with [125I]MIBG at 8, 24, 48, 72 and 96 h, respectively. In normal mice, the uptake of [131I]MeIBG in the heart was similar to that of [125I]MIBG at 1 and 4 h; in contrast, myocardial uptake of [131I]MeIBG was 1.6-fold higher than that of [125I]MIBG (p<0.05) at 24 h. When mice were pre-treated with the uptake-1 inhibitor desipramine (DMI), the heart uptake of both tracers was reduced to about half that in untreated controls at 1 h post injection (p<0.05). The hepatic uptake of [131I]MeIBG was two- to threefold lower than that of [125I]MIBG. On the other hand, blood levels of [131I]MeIBG were substantially higher (up to sixfold), especially at early time points. Uptake of [131I]MeIBG in heart and tumour at 1 h in the murine SK-N-SH model was specific and comparable to that of [125I]MIBG. However, [131I]MeIBG uptake was 1.6- to 1.7-fold lower than that of [125I]MIBG over 4-48 h. While the uptake of both tracers in IMR32 xenografts was similar, it was not uptake-1 mediated. CONCLUSION: Introduction of a methyl group at the 4-position of MIBG seems to be advantageous in terms of higher tumour retention in vitro and lower hepatic uptake in vivo. However, the slower blood clearance of MeIBG may be problematic for some applications.

Authors
Vaidyanathan, G; Welsh, PC; Vitorello, KC; Snyder, S; Friedman, HS; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Welsh, PC, Vitorello, KC, Snyder, S, Friedman, HS, and Zalutsky, MR. "A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells." Eur J Nucl Med Mol Imaging 31.10 (October 2004): 1362-1370.
PMID
15205923
Source
pubmed
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
31
Issue
10
Publish Date
2004
Start Page
1362
End Page
1370
DOI
10.1007/s00259-004-1596-8

Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent.

Monoclonal antibodies such as L8A4, reactive with the epidermal growth factor receptor variant III, internalize after receptor binding resulting in proteolytic degradation by lysosomes. Labeling internalizing mAbs requires the use of methodologies that result in the trapping of labeled catabolites in tumor cells after intracellular processing. Herein we have investigated the potential utility of N-succinimidyl-3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), an acylation agent that couples the corresponding negatively charged acid [131I]IPMBA to the protein, for this purpose. Biodistribution studies demonstrated that [131I]IPMBA cleared rapidly from normal tissues and exhibited thyroid levels < or =0.1% injected dose, consistent with a low degree of dehalogenation. Biodistribution experiments in athymic mice bearing subcutaneous D-256 human glioma xenografts were performed to compare L8A4 labeled using [131I]SIPMB to L8A4 labeled with 125I using both the analogous positively charged acylation agent N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB) and Iodogen. Tumor uptake of [131I]SIPMB-L8A4 (41.9+/-3.5% ID/g) was nearly threefold that of L8A4 labeled using Iodogen (14.0+/-1.1% ID/g) after 2 days, and tumor to tissue ratios remained uniformly high throughout with [131I]SIPMB-L8A4. Thyroid uptake increased for the Iodogen labeled mAb (3.55+/-0.36 %ID at 5 days) whereas that of [131I]SIPMB labeled mAb remained low (0.21+/-0.04% ID at 5 days). In the second biodistribution, L8A4 labeled using [131I]SIPMB and [125I]SGMIB showed no difference in normal tissue uptake and had nearly identical tumor uptake ([131I]SIPMB, 41.8+/-14.2% ID/g; [125I]SGMIB, 41.6+/-15.8% ID/g, at 4 days). These results suggest that [131I]SIPMB may be a viable acylation agent for the radioiodination of internalizing mAbs.

Authors
Shankar, S; Vaidyanathan, G; Affleck, DJ; Peixoto, K; Bigner, DD; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Affleck, DJ, Peixoto, K, Bigner, DD, and Zalutsky, MR. "Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent." Nucl Med Biol 31.7 (October 2004): 909-919.
PMID
15464393
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
31
Issue
7
Publish Date
2004
Start Page
909
End Page
919
DOI
10.1016/j.nucmedbio.2004.04.007

Medulloblastoma neoplastic meningitis targeted radiotherapy with intrathecal alpha-emitter At-211-labeled thymidine analogue

Authors
Boskovitz, A; Vaidyanathan, G; Archer, GE; Ochiai, H; Okamura, T; Sampson, JH; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Vaidyanathan, G, Archer, GE, Ochiai, H, Okamura, T, Sampson, JH, Bigner, DD, and Zalutsky, MR. "Medulloblastoma neoplastic meningitis targeted radiotherapy with intrathecal alpha-emitter At-211-labeled thymidine analogue." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
403
End Page
403

Somatostatin targeted radiotherapeuiccs for medulloblastoma

Authors
Vaidyanathan, G; Boskovitz, A; Friedman, HS; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Boskovitz, A, Friedman, HS, Affleck, DJ, and Zalutsky, MR. "Somatostatin targeted radiotherapeuiccs for medulloblastoma." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
416
End Page
416

A validated chiral HPLC method for the enantiomeric separation of tolterodine tartarate.

An isocratic chiral HPLC method was developed for the separation of tolterodine tartarate enantiomers. The mobile phase consists of n-hexane and isopropyl alcohol in the ratio of 980:20 (v/v) with 1 ml diethylamine and 0.6 ml trifluoroacetic acid. Chiralcel OD-H (250 mm x 4.6mm) column was used at constant room temperature. Flow rate was kept at 0.5 ml/min. This method is capable of detecting the S-isomer up to 0.1 microg/ml. The method was validated in terms of linearity, precision, limit of detection (LOD) and limit of quantification (LOQ).

Authors
Kumar, YR; Ramulu, G; Vevakanand, VV; Vaidyanathan, G; Srinivas, K; Kumar, MK; Mukkanti, K; Reddy, MS; Venkatraman, S; Suryanarayana, MV
MLA Citation
Kumar, YR, Ramulu, G, Vevakanand, VV, Vaidyanathan, G, Srinivas, K, Kumar, MK, Mukkanti, K, Reddy, MS, Venkatraman, S, and Suryanarayana, MV. "A validated chiral HPLC method for the enantiomeric separation of tolterodine tartarate." J Pharm Biomed Anal 35.5 (September 3, 2004): 1279-1285.
PMID
15336373
Source
pubmed
Published In
Journal of Pharmaceutical and Biomedical Analysis
Volume
35
Issue
5
Publish Date
2004
Start Page
1279
End Page
1285
DOI
10.1016/j.jpba.2004.03.026

Catabolism of 4-fluoro-3-iodobenzylguanidine and meta-iodobenzylguanidine by SK-N-SH neuroblastoma cells.

BACKGROUND: A fluorine substituted derivative of meta-iodobenzylguanidine (MIBG), 4-fluoro-3-iodobenzylguanidine (FIBG), is retained in SK-N-SH human neuroblastoma cells in vitro to a higher degree than the MIBG. METHOD: To investigate whether the higher retention of FIBG is due to differences in the catabolic degradation of the two tracers, in vitro paired-label studies were performed using SK-N-SH cells. RESULTS: No detectable amount of benzyl amines, benzoic acids or hippuran derivatives, potential catabolites of these tracers, were seen in either case. Even after 48 h, the cell culture supernatants contained exclusively intact I-MIBG and I-FIBG. In contrast, in some cases, HPLC analysis of cell lysates indicated the presence of a very polar compound(s) as the predominant species with smaller quantities of intact tracers. The per cent total radioactivity in the lysate at each time point that was associated with intact I-FIBG was (average [range]) 25.4% [20.3-30.5], 22.5% [19.3-25.6], and 18.8% [14.3-23.3], at 0 h, 24 h and 48 h, respectively. The corresponding values for I-MIBG were 24.3% [21.0-27.5], 19.1% [11.7-26.5] and 17.4% [14.6-20.1]. No significant amount of activity was associated with high molecular weight species for either halobenzylguanidine, indicating that protein binding was not a major factor.

Authors
Vaidyanathan, G; Affleck, DJ; Alston, KL; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Alston, KL, Welsh, P, and Zalutsky, MR. "Catabolism of 4-fluoro-3-iodobenzylguanidine and meta-iodobenzylguanidine by SK-N-SH neuroblastoma cells." Nucl Med Commun 25.9 (September 2004): 947-955.
PMID
15319601
Source
pubmed
Published In
Nuclear Medicine Communications
Volume
25
Issue
9
Publish Date
2004
Start Page
947
End Page
955

An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects.

BACKGROUND: Targeted radiotherapy achieves malignant cell-specific concentration of radiation dosage by tumour-affinic molecules conjugated to radioactive atoms. Combining gene therapy with targeted radiotherapy is attractive because the associated cross-fire irradiation of the latter induces biological bystander effects upon neighbouring cells overcoming low gene transfer efficiency. METHODS: We sought to maximise the tumour specificity and efficacy of noradrenaline transporter (NAT) gene transfer combined with treatment using the radiopharmaceutical meta-[(131)I]iodobenzylguanidine ([(131)I]MIBG). Cell-kill was achieved by treatment with the beta-decay particle emitter [(131)I]MIBG or the alpha-particle emitter [(211)At]MABG. We utilised our novel transfected mosaic spheroid model (TMS) to determine whether this treatment strategy could result in sterilisation of spheroids containing only a small proportion of NAT-expressing cells. RESULTS: The concentrations of [(131)I]MIBG and [(211)At]MABG required to reduce to 0.1% the survival of clonogens derived from the TMS composed of 100% of NAT gene-transfected cells were 1.5 and 0.004 MBq/ml (RSV promoter), 8.5 and 0.0075 MBq/ml (hTR promoter), and 9.0 and 0.008 MBq/ml (hTERT promoter), respectively. The concentrations of radiopharmaceutical required to reduce to 0.1% the survival of clonogens derived from 5% RSV/NAT and 5% hTERT/NAT TMS were 14 and 23 MBq/ml, respectively, for treatment with [(131)I]MIBG and 0.018 and 0.028 MBq/ml, respectively, for treatment with [(211)At]MABG. CONCLUSIONS: These results indicate that the telomerase promoters have the capacity to drive the expression of the NAT. The potency of [(211)At]MABG is approximately three orders of magnitude greater than that of [(131)I]MIBG. Spheroids composed of only 5% of cells expressing NAT under the control of the RSV or hTERT promoter were sterilised by radiopharmaceutical treatment. This observation is indicative of bystander cell-kill.

Authors
Boyd, M; Mairs, RJ; Keith, WN; Ross, SC; Welsh, P; Akabani, G; Owens, J; Vaidyanathan, G; Carruthers, R; Dorrens, J; Zalutsky, MR
MLA Citation
Boyd, M, Mairs, RJ, Keith, WN, Ross, SC, Welsh, P, Akabani, G, Owens, J, Vaidyanathan, G, Carruthers, R, Dorrens, J, and Zalutsky, MR. "An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects." J Gene Med 6.8 (August 2004): 937-947.
PMID
15293352
Source
pubmed
Published In
The Journal of Gene Medicine
Volume
6
Issue
8
Publish Date
2004
Start Page
937
End Page
947
DOI
10.1002/jgm.578

The Ras-related protein AGS1/RASD1 suppresses cell growth.

AGS1/RASD1 is a Ras-related protein identified as a dexamethasone-inducible cDNA and as a signal regulator in various functional and protein-interaction screens. As an initial approach to define the role of AGS1/RASD1 as a Ras-family member, we determined its influence on cell growth/survival. In clonogenic assays with NIH-3T3 murine fibroblast cells, the MCF-7 human breast cancer cell line and the human lung adenocarcinoma cell line A549, AGS1/RASD1 markedly diminished the number of G418-resistant colonies, whereas the Ras subgroup member K-Ras was without effect. A549 cell infection with adenovirus engineered to express AGS1/RASD1 (Ad.AGS1) inhibited log phase growth in vitro and increased the percentage of cells undergoing apoptosis. The anti-growth action was also observed in vivo as the expression of AGS1/RASD1 inhibited the subcutaneous tumor growth of A549 cells in athymic nude mice. These data indicate that AGS1/RASD1, a member of the Ras superfamily of small G-proteins that often promotes cell growth and tumor expansion, plays an active role in preventing aberrant cell growth.

Authors
Vaidyanathan, G; Cismowski, MJ; Wang, G; Vincent, TS; Brown, KD; Lanier, SM
MLA Citation
Vaidyanathan, G, Cismowski, MJ, Wang, G, Vincent, TS, Brown, KD, and Lanier, SM. "The Ras-related protein AGS1/RASD1 suppresses cell growth." Oncogene 23.34 (July 29, 2004): 5858-5863.
PMID
15184869
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
23
Issue
34
Publish Date
2004
Start Page
5858
End Page
5863
DOI
10.1038/sj.onc.1207774

InfoEvolve: moving from data to knowledge using information theory and genetic algorithms.

InfoEvolve is a unified suite of data mining and empirical modeling tools capable of discovering low-bias and low-variance solutions to complex processes. The method is based on a common set of principles involving information theory and genetic algorithms. InfoEvolve can also discover multiple strategies embedded in complex data sets for achieving a desired target or goal. This latter aspect may prove to be very useful in drug design. The paper analyzes the following: InfoEvolve from a theoretical standpoint; a conceptual overview of InfoEvolve with a short description of the modeling method; the method using the example of homogeneous identification of DNA from an analysis of its melting curve behavior; and key learnings and additional applications of the technology for both drug design and genome analysis.

Authors
Vaidyanathan, G
MLA Citation
Vaidyanathan, G. "InfoEvolve: moving from data to knowledge using information theory and genetic algorithms." Ann N Y Acad Sci 1020 (May 2004): 227-238.
PMID
15208195
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1020
Publish Date
2004
Start Page
227
End Page
238
DOI
10.1196/annals.1310.019

Meta-iodobenzylguanidine derivatives containing a second guanidine moiety.

Radioiodinated meta-iodobenzylguanidine (MIBG) is used in the diagnosis and therapy of various neuroendocrine tumors. To investigate whether an additional guanidine function in the structure of MIBG will yield analogues that may potentially enhance tumor-to-target ratios, two derivatives-one with a guanidine moiety and another with a guanidinomethyl group at the 4-position of MIBG-were prepared. In the absence of any uptake-1 inhibiting conditions, the uptake of 4-guanidinomethyl-3-[(131)I]iodobenzylguanidine ([(131)I]GMIBG) by SK-N-SH cells in vitro was 1.7+/-0.1% of input counts, compared to a value of 40.3+/-1.4% for [(125)I[MIBG suggesting that guanidinomethyl group at the 4-position negated the biological properties of MIBG. On the other hand, 4-guanidino-3-[(131)I]iodobenzylguanidine ([(131)I]GIBG) had an uptake (5.6+/-0.3%) that was 12-13% that of [(125)I]MIBG (46.1+/-2.7%), and the ratio of uptake by control over DMI-treated (nonspecific) cultures was higher for [(131)I]GIBG (20.9+/-0.3) than [(125)I]MIBG itself (15.0+/-2.7). The exocytosis of [(131)I]GIBG and [(125)I]MIBG from SK-N-SH cells was similar. The uptake of [(131)I]GIBG in the mouse target tissues, heart and adrenals, as well as in a number of other tissues was about half that of [(125)I]MIBG. These results suggest that substitution of guanidine functions, especially a guanidinomethyl group, in MIBG structure may not be advantageous.

Authors
Vaidyanathan, G; Shankar, S; Affleck, DJ; Alston, K; Norman, J; Welsh, P; LeGrand, H; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Shankar, S, Affleck, DJ, Alston, K, Norman, J, Welsh, P, LeGrand, H, and Zalutsky, MR. "Meta-iodobenzylguanidine derivatives containing a second guanidine moiety." Bioorg Med Chem 12.7 (April 1, 2004): 1649-1656.
PMID
15028258
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
12
Issue
7
Publish Date
2004
Start Page
1649
End Page
1656
DOI
10.1016/j.bmc.2004.01.026

O6-3-[131I]iodobenzylguanine: improved synthesis and further evaluation of a potential agent for imaging of alkylguanine-DNA alkyltransferase.

O(6)-Benzylguanine derivatives with suitable radionuclides attached to the benzyl ring are potentially useful in the noninvasive imaging of the DNA repair protein, alkylguanine-DNA alkyltransferase (AGT). Previously, O(6)-3-[(131)I]iodobenzylguanine ([(131)I]IBG) was prepared using a two-step approach; we now report its synthesis in a single step by the radioiododestannylation of O(6)-3-(trimethylstannyl)benzylguanine in 85-95% radiochemical yield. The in vitro specific uptake of [(131)I]IBG in DAOY human medulloblastoma cells, in TE-671 human rhabdomyosarcoma cells and a CHO cell line transfected to express AGT was linear (r(2) = 0.9-1.0) as a function of cell density. After intravenous injection of [(131)I]IBG in athymic mice bearing TE-671 xenografts, tumor uptake was 1.38 +/- 0.34% ID/g at 0.5 h and declined at 2 and 4 h. Preadministration of O(6)-(3-iodobenzyl)guanine (IBG) at 0.5 h increased uptake not only in tumor but also in several normal tissues. Notable exceptions were thyroid (p < 0.05), lung (p <0.05) and stomach. After intratumoral injection of [(131)I]IBG in the same xenograft model, the uptake in tumors that were depleted of AGT by BG treatment (165.8 +/- 27.5% ID/g) was about 60% of that in control mice (272.4 +/- 48.2% ID/g; p < 0.05).

Authors
Vaidyanathan, G; Affleck, DJ; Norman, J; Welsh, P; Liu, W; Johnson, SP; Friedman, HS; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Norman, J, Welsh, P, Liu, W, Johnson, SP, Friedman, HS, and Zalutsky, MR. "O6-3-[131I]iodobenzylguanine: improved synthesis and further evaluation of a potential agent for imaging of alkylguanine-DNA alkyltransferase." Bioconjug Chem 15.2 (March 2004): 402-408.
PMID
15025538
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
15
Issue
2
Publish Date
2004
Start Page
402
End Page
408
DOI
10.1021/bc0341977

Imaging drug resistance with radiolabeled molecules.

A major obstacle to successful cancer chemotherapy is drug resistance. Multidrug resistance (MDR) is often seen with chemotherapeutic agents such as anthracycline derivatives, vinca alkaloids and taxanes. Multiple aspects of cellular biochemistry have been implicated in the MDR process. Cellular mechanisms of resistance are due to the presence of efflux pumps, P-glycoprotein (P-gp) and multiple resistance-associated protein (MRP), which belong to the ATP-binding cassette (ABC) family of transporters. Another form of drug resistance is involved in the chemotherapy of cancers with alkylating agents such as nitrosourea derivatives and nitrogen mustards. The cytotoxicity of these agents is primarily due to alkylation of the DNA guanine residues at their O6-position, which leads, via a cascade of events, to DNA strand breaks. The DNA repair protein, alkylguanine-DNA alkyl transferase (AGT) removes the alkyl groups from the lesions stoichiometrically to a cysteine in its active site. This process is irreversible and results in the degradation of the protein and its recovery is entirely from de novo synthesis. Noninvasive methodologies for monitoring the transport activity of these efflux pumps and determining tumor content of AGT could serve as critical tools for optimizing chemotherapeutic protocols on a patient-specific basis and gaining an understanding of the dynamics of resistance in living patients. In this review, we will describe the efforts made to date to synthesize radioactive probes of chemotherapy resistance and their use to quantitate these transporters and DNA repair protein by radionuclide imaging.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Imaging drug resistance with radiolabeled molecules." Curr Pharm Des 10.24 (2004): 2965-2979. (Review)
PMID
15379662
Source
pubmed
Published In
Current Pharmaceutical Design
Volume
10
Issue
24
Publish Date
2004
Start Page
2965
End Page
2979

Astatine-211 Labeled Radiopharmaceuticals, invited

Authors
Vaidyanathan, G
MLA Citation
Vaidyanathan, G. "Astatine-211 Labeled Radiopharmaceuticals, invited." Transactions of the American Nuclear Society 91 (2004): 856--.
Source
scival
Published In
Transactions- American Nuclear Society
Volume
91
Publish Date
2004
Start Page
856-

A validated LC method for imatinib mesylate.

An isocratic reversed-phase liquid chromatography method with UV detection has been developed for the purity evaluation of imatinib mesylate in bulk drug. The method is selective and is capable of detecting all process intermediates and other related compounds, which may be present at trace levels in the drug substance. The method was validated on a Symmetry Shield RP18 analytical column (150 x 4.6 mm, 5 microm), mobile phase consisting of 30 mM sodium octane sulphonic acid in 10 mM aqueous KH2PO4 (pH 2.5 with H3PO4): MeOH in the ratio of 42:58 v/v. The flow rate was set at 1.0 ml/min and the column was maintained at room temperature. The injection volume was set to 10 microl and the detector was set at a wavelength of 237 nm. The method was validated in terms of system precision, method precision, linearity, accuracy, limit of detection and limit of quantification.

Authors
Vivekanand, VV; Sreenivas Rao, D; Vaidyanathan, G; Sekhar, NM; Avijit Kelkar, S; Ramachandra Puranik, P
MLA Citation
Vivekanand, VV, Sreenivas Rao, D, Vaidyanathan, G, Sekhar, NM, Avijit Kelkar, S, and Ramachandra Puranik, P. "A validated LC method for imatinib mesylate." J Pharm Biomed Anal 33.5 (December 4, 2003): 879-889.
PMID
14656579
Source
pubmed
Published In
Journal of Pharmaceutical and Biomedical Analysis
Volume
33
Issue
5
Publish Date
2003
Start Page
879
End Page
889

Specific and high-level targeting of radiolabeled octreotide analogues to human medulloblastoma xenografts.

PURPOSE: The objective of this study was to determine the feasibility of exploiting the overexpression of somatostatin subtype-2 receptors (sstr(2)) on human medulloblastoma cells to develop targeted radiodiagnostics and radiotherapeutics for this disease. EXPERIMENTAL DESIGN: The following radioiodinated peptides were prepared using chloramine-T and evaluated: [(131)I-Tyr(3)]octreotide ([(131)I]TOC), [(131)I-Tyr(3)]octreotate ([(131)I]TOCA), involving substitution of Thr(ol)(8) in TOC with Thr(8), and glucose-[(131)I-Tyr(3)]octreotide ([(131)I]Gluc-TOC) and glucose-[(131)I-Tyr(3)]octreotate ([(131)I]Gluc-TOCA), prepared by conjugation of glucose to the peptide NH(2) terminus. Specific internalization of the peptides by sstr(2)-expressing AR42J rat pancreatic carcinoma cells in vitro was evaluated in paired-label assays. The tissue distribution of i.v. administered [(131)I]TOC, [(131)I]TOCA, [(131)I]Gluc-TOC, and [(131)I]Gluc-TOCA was evaluated in athymic mice bearing s.c. D341 Med human medulloblastoma xenografts. RESULTS: Compared with [(125)I]TOC, internalized radioiodine levels were higher for the other three peptides. For example, internalized counts were 1.9 +/- 0.2, 2.0 +/- 0.3, and 5.7 +/- 1.9 times higher for [(131)I]Gluc-TOC, [(131)I]TOCA, and [(131)I]Gluc-TOCA after a 3-h incubation, respectively, demonstrating that carbohydration and COOH-terminus modification significantly improved the retention of radioiodine activity in sstr(2)-expressing tumor cells. COOH-terminus modification significantly increased (131)I localization in D341 Med medulloblastoma xenografts [[(131)I]TOCA, 8.1 +/- 2.2% of injected dose/g (% ID/g); [(131)I]TOC, 3.9 +/- 0.5% ID/g at 1 h], whereas carbohydration of the NH(2) terminus resulted in even higher gains in tumor accumulation ([(131)I]Gluc-TOC, 11.1 +/- 1.8% ID/g; [(131)I]Gluc-TOCA, 21.4 +/- 7.3% ID/g). In addition, the three modified peptides exhibited liver activity levels that were less than half those of [(131)I]TOC. Uptake of the two glucose-peptide conjugates in this human medulloblastoma xenograft was blocked by coinjection of 100 micro g of octreotide, demonstrating that it was receptor-specific. Tumor:normal tissue uptake ratios for [(131)I]Gluc-TOCA generally were higher that those for [(131)I]Gluc-TOC. At 1 h, tumor:normal tissue ratios for [(131)I]Gluc-TOCA were 29:1, 15:1, 8:1, 8:1, 240:1, and 82:1 for blood, liver, kidney, spleen, brain, and muscle, respectively. CONCLUSIONS: Our findings suggest that additional investigation of radiolabeled Gluc-TOCA analogues for the imaging and targeted radiotherapy of medulloblastoma is warranted.

Authors
Vaidyanathan, G; Friedman, HS; Affleck, DJ; Schottelius, M; Wester, H-J; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Affleck, DJ, Schottelius, M, Wester, H-J, and Zalutsky, MR. "Specific and high-level targeting of radiolabeled octreotide analogues to human medulloblastoma xenografts." Clin Cancer Res 9.5 (May 2003): 1868-1876.
PMID
12738745
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
5
Publish Date
2003
Start Page
1868
End Page
1876

N-succinimidyl 3-[211At]astato-4-guanidinomethylbenzoate: an acylation agent for labeling internalizing antibodies with alpha-particle emitting 211At.

The objective of this study was to develop a method for labeling internalizing monoclonal antibodies (mAbs) such as those reactive to the anti-epidermal growth factor receptor variant III (EGFRvIII) with the alpha-particle emitting radionuclide (211)At. Based on previous work utilizing the guanidine-containing acylation agent, N-succinimidyl 4-guanidinomethyl-3-[(131)I]iodobenzoate ([(131)I]SGMIB), we have now investigated the potential utility of its astato analogue for labeling the anti-EGFRvIII mAb L8A4. N-succinimidyl 3-[(211)At]astato-4-guanidinomethylbenzoate ([(211)At]SAGMB) in its Boc-protected form was prepared from a tin precursor in 61.7 +/- 13.1% radiochemical yield, in situ deprotected to [(211)At]SAGMB, which was coupled to L8A4 in 36.1 +/- 1.9% yield. Paired-label internalization assays demonstrated that tumor cell retention of radioactivity for L8A4 labeled using [(211)At]SAGMB was almost identical to L8A4 labeled using [(131)I]SGMIB, and 3-4-fold higher than for mAb radioiodinated using Iodogen. Paired-label biodistribution of L8A4 labeled using [(211)At]SAGMB and [(131)I]SGMIB in athymic mice hosting U87MGdeltaEGFR xenografts resulted in identical uptake of both (211)At and (131)I in tumor tissues over 24 h. Although higher levels of (211)At compared with (131)I were sometimes seen in tissues known to sequester free astatide, these (211)At/(131)I uptake ratios were considerably lower than those seen with other labeling methods. These results suggest that [(211)At]SAGMB may be a useful acylation agent for labeling internalizing mAbs with (211)At.

Authors
Vaidyanathan, G; Affleck, DJ; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Bigner, DD, and Zalutsky, MR. "N-succinimidyl 3-[211At]astato-4-guanidinomethylbenzoate: an acylation agent for labeling internalizing antibodies with alpha-particle emitting 211At." Nucl Med Biol 30.4 (May 2003): 351-359.
PMID
12767391
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
30
Issue
4
Publish Date
2003
Start Page
351
End Page
359

N-succinimidyl 3-[(131)I]iodo-4-phosphonomethylbenzoate ([(131)I]SIPMB), a negatively charged substituent-bearing acylation agent for the radioiodination of peptides and mAbs.

An important criterion in design of acylation agents for the radioiodination of internalizing monoclonal antibodies (mAbs) is to maximize the retention of radioiodine in the tumor following mAb intracellular processing. We have previously shown that labeling methods that generate positively charged catabolites have enhanced tumor retention. Herein we have extended this strategy to investigate the potential utility of labeling internalizing mAbs with an acylation agent that yielded labeled catabolites that would be negatively charged at lysosomal pH. The negatively charged acylation agent, N-succinimidyl 3-[(131)I]iodo-4-phosphonomethylbenzoate ([(131)I]SIPMB), was prepared from its tin precursor, N-succinimidyl 4-di-tert-butylphosphonomethyl-3-trimethylstannylbenzoate (tBu-SPMTB), in 40% radiochemical yield. The free acid, 3-[(131)I]iodo-4-phosphonomethylbenzoic acid ([(131)I]IPMBA), was also prepared from the corresponding precursor, 4-di-tert-butylphosphonomethyl-3-trimethylstannylbenzoic acid (tBu-PMTBA), in 80% radiochemical yield. The rapidly internalizing mAb L8A4 was conjugated to [(131)I]SIPMB in 25-40% yield with preservation of its immunoreactivity. Internalization and processing in the U87DeltaEGFR glioma cell line was studied in a paired label format with L8A4 labeled with (125)I using the Iodogen method. Retention of initially bound radioactivity in these cells at 24 h from [(131)I]SIPMB-labeled mAb was approximately 6-fold higher than that for directly labeled mAb. Catabolite analysis demonstrated that this difference reflected an order of magnitude higher retention of low molecular weight species in these cells. The [(131)I]SIPMB-L8A4 conjugate was intact over the first 2 h; thereafter, lysine-[(131)I]SIPMB was the predominant catabolite. In contrast, L8A4 labeled using Iodogen rapidly gave rise to mono-[(125)I]iodotyrosine within 2 h, which then cleared rapidly from the cells. These results suggest that SIPMB could be a potent candidate for labeling internalizing mAbs and warrant further study.

Authors
Shankar, S; Vaidyanathan, G; Affleck, D; Welsh, PC; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Affleck, D, Welsh, PC, and Zalutsky, MR. "N-succinimidyl 3-[(131)I]iodo-4-phosphonomethylbenzoate ([(131)I]SIPMB), a negatively charged substituent-bearing acylation agent for the radioiodination of peptides and mAbs." Bioconjug Chem 14.2 (March 2003): 331-341.
PMID
12643743
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
14
Issue
2
Publish Date
2003
Start Page
331
End Page
341
DOI
10.1021/bc025636p

N-succinimidyl 3-[211AT]astato-4-guanidinomethylbenzoate: An acylation agent for labeling internalizing antibodies with alpha-particle emitting (211)AT.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "N-succinimidyl 3-[211AT]astato-4-guanidinomethylbenzoate: An acylation agent for labeling internalizing antibodies with alpha-particle emitting (211)AT." March 2003.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
225
Publish Date
2003
Start Page
U265
End Page
U265

Synthesis and in vitro evaluation of glycated octreotate conjugates labeled with radioiodine and At-211 via a tin precursor.

Authors
Vaidyanathan, G; Affleck, DJ; Welsh, P; Schottelius, M; Wester, H; Norman, JA; Alston, KL; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Welsh, P, Schottelius, M, Wester, H, Norman, JA, Alston, KL, and Zalutsky, MR. "Synthesis and in vitro evaluation of glycated octreotate conjugates labeled with radioiodine and At-211 via a tin precursor." JOURNAL OF NUCLEAR MEDICINE 43.5 (May 2002): 92P-92P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
43
Issue
5
Publish Date
2002
Start Page
92P
End Page
92P

Negatively charged substituent-bearing acylation agent for the radiohalogenation of mAbs.

Authors
Shankar, S; Vaidyanathan, G; Affleck, DJ; Welsh, P; LeGrand, H; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Affleck, DJ, Welsh, P, LeGrand, H, and Zalutsky, MR. "Negatively charged substituent-bearing acylation agent for the radiohalogenation of mAbs." JOURNAL OF NUCLEAR MEDICINE 43.5 (May 2002): 366P-366P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
43
Issue
5
Publish Date
2002
Start Page
366P
End Page
366P

Improved xenograft targeting of tumor-specific anti-epidermal growth factor receptor variant III antibody labeled using N-succinimidyl 4-guanidinomethyl-3-iodobenzoate.

Monoclonal antibodies (mAbs) such as the tumor-specific anti-epidermal growth factor receptor variant III (EGFRvIII) that are internalized and degraded after cell binding necessitate the use of radioiodination methods that minimize the loss of radioactivity from the tumor cell after intracellular processing. The purpose of the current study was to determine the suitability of N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) for labeling this internalizing mAb. A series of paired-label biodistribution experiments were performed in athymic mice bearing subcutaneous, EGFRvIII-expressing, D-256 human glioma and U87 Delta EGFR xenografts. The tissue distribution of radioiodine activity following injection of anti-EGFRvIII mAb L8A4 labeled using N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) were compared to those for mAb labeled using Iodogen, N-succinimidyl 3-iodo-5-pyridinecarboxylate (SIPC) as well as the Boc-protected precursor of SGMIB. Tumor uptake of radioiodine activity for mAb labeled via SGMIB was significantly higher than co-administered L8A4 radioiodinated by other methods. For example, 3 days after injection, D-256 tumor uptake of L8A4 labeled via SGMIB was 20.4 +/- 4.6% ID/g compared with 11.7 +/- 5.5% ID/g when the SIPC method was used. Thyroid uptake for L8A4 (SGMIB) was up to 36 times lower than L8A4 (Iodogen) and less than 0.35% in all experiments, indicating a low degree of deiodination in vivo. These results suggest that SGMIB may be a useful reagent for the radioiodination of this internalizing anti-EGFRvIII mAb.

Authors
Vaidyanathan, G; Affleck, DJ; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Bigner, DD, and Zalutsky, MR. "Improved xenograft targeting of tumor-specific anti-epidermal growth factor receptor variant III antibody labeled using N-succinimidyl 4-guanidinomethyl-3-iodobenzoate." Nucl Med Biol 29.1 (January 2002): 1-11.
PMID
11786270
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
29
Issue
1
Publish Date
2002
Start Page
1
End Page
11

Purification of G protein beta gamma from bovine brain.

Authors
Dingus, J; Tatum, BS; Vaidyanathan, G; Hilderbrandt, JD
MLA Citation
Dingus, J, Tatum, BS, Vaidyanathan, G, and Hilderbrandt, JD. "Purification of G protein beta gamma from bovine brain." Methods Enzymol 344 (2002): 194-208.
PMID
11771384
Source
pubmed
Published In
Methods in Enzymology
Volume
344
Publish Date
2002
Start Page
194
End Page
208

Biological evaluation of ring- and side-chain-substituted m-iodobenzylguanidine analogues.

A number of ring- and side-chain-substituted m-iodobenzylguanidine analogues were evaluated for their lipophilicity, in vitro stability, uptake by SK-N-SH human neuroblastoma cells in vitro, and biodistribution in normal mice. As expected, the lipophilicity of m-iodobenzylguanidine increased when a halogen was introduced onto the ring and decreased with the addition of polar hydroxyl, amino, and nitro substitutents. Most of the derivatives showed reasonable stability up to 24 h in PBS at 37 degrees C. While N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine and 3,4-dihydroxy-5-[(131)I]iodobenzylguanidine generated a more nonpolar product in addition to the free iodide, 3-[(131)I]iodo-4-nitrobenzylguanidine decomposed to a product more polar than the parent compound. The specific uptake of 4-chloro-3-[(131)I]iodobenzylguanidine, 3-[(131)I]iodo-4-nitrobenzylguanidine, and N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine by SK-N-SH human neuroblastoma cells in vitro, relative to that of m-[(125)I]iodobenzylguanidine, was 117 +/- 10%, 50 +/- 4%, and 12 +/- 2%, respectively. The specific uptake of the known m-iodobenzylguanidine analogues 4-hydroxy-3-[(131)I]iodobenzylguanidine and 4-amino-3-[(131)I]iodobenzylguanidine was 80 +/- 4% and 66 +/- 4%, respectively. None of the other m-iodobenzylguanidine derivatives showed any significant specific uptake by SK-N-SH cells. Heart uptake of 4-chloro-3-[(131)I]iodobenzylguanidine in normal mice was higher than that of m-[(125)I]iodobenzylguanidine at later time points (11 +/- 1% ID/g versus 3 +/- 1% ID/g at 24 h; p < 0.05) while uptake of 3-[(131)I]iodo-4-nitrobenzylguanidine and of N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine in the heart was lower than that of m-iodobenzylguanidine at all time points. In accordance with the in vitro results, none of the other novel m-iodobenzylguanidine derivatives showed any significant myocardial or adrenal uptake in vivo.

Authors
Vaidyanathan, G; Shankar, S; Affleck, DJ; Welsh, PC; Slade, SK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Shankar, S, Affleck, DJ, Welsh, PC, Slade, SK, and Zalutsky, MR. "Biological evaluation of ring- and side-chain-substituted m-iodobenzylguanidine analogues." Bioconjug Chem 12.5 (September 2001): 798-806.
PMID
11562198
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
12
Issue
5
Publish Date
2001
Start Page
798
End Page
806

Synthesis of ring- and side-chain-substituted m-iodobenzylguanidine analogues.

With the goal of developing MIBG analogues with improved targeting properties especially for oncologic applications, several radioiodinated ring- and side-chain-substituted MIBG analogues were synthesized. Except for 3-[(131)I]iodo-4-nitrobenzylguanidine and N-hydroxy-3-[(131)I]iodobenzylguanidine, the radioiodinated analogues were prepared at no-carrier-added levels from their respective tin precursors. The radiochemical yields generally were in the range of 70-90% except for 3-amino-5-[(131)I]iodobenzylguanidine for which a radiochemical yield of about 40% was obtained. While the silicon precursor N(1),N(2)-bis(tert-butyloxycarbonyl)-N(1)-(4-nitro-3-trimethylsilylbenzyl)guanidine did not yield 3-[(131)I]iodo-4-nitrobenzylguanidine, its deprotected derivative, N(1)-(4-nitro-3-trimethylsilylbenzyl)guanidine was radioiodinated in a modest yield of 20% providing 3-[(131)I]iodo-4-nitrobenzylguanidine. Exchange radioiodination of 3-iodo-4-nitrobenzylguanidine gave 3-[(131)I]iodo-4-nitrobenzylguanidine in 80% radiochemical yield. No-carrier-added [(131)I]NHIBG was prepared from its silicon precursor N(1)-hydroxy-N(3)-(3-trimethylsilylbenzyl)guanidine in 85% radiochemical yield.

Authors
Vaidyanathan, G; Shankar, S; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Shankar, S, and Zalutsky, MR. "Synthesis of ring- and side-chain-substituted m-iodobenzylguanidine analogues." Bioconjug Chem 12.5 (September 2001): 786-797.
PMID
11562197
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
12
Issue
5
Publish Date
2001
Start Page
786
End Page
797

A polar substituent-containing acylation agent for the radioiodination of internalizing monoclonal antibodies: N-succinimidyl 4-guanidinomethyl-3-[131I]iodobenzoate ([131I]SGMIB).

The objective of this study was to develop an acylation agent for the radioiodination of monoclonal antibodies that would maximize retention of the label in tumor cells following receptor- or antigen-mediated internalization. The strategy taken was to add a polar substituent to the labeled aromatic ring to impede transport of labeled catabolites across lysosomal and cell membranes after antibody degradation. Preparation of unlabeled N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) was achieved in six steps from 3-iodo-4-methylbenzoic acid. Preparation of 4-guanidinomethyl-3-[131I]iodobenzoic acid from the silicon precursor, 4-(N1,N2-bis-tert-butyloxycarbonyl)guanidinomethyl-3-trimethylsilylbenzoic acid proceeded in less than 5% radiochemical yield. A more successful approach was to prepare [131I]SGMIB directly from the tin precursor, N-succinimidyl 4-(N1,N2-bis-tert-butyloxycarbonyl)guanidinomethyl-3-trimethylstannylbenzoate, which was achieved in 60-65% radiochemical yield. A rapidly internalizing anti-epidermal growth factor receptor variant III antibody L8A4 was labeled using [131I]SGMIB in 65% conjugation efficiency and with preservation of immunoreactivity. Paired-label in vitro internalization assays demonstrated that the amount of radioactivity retained in cells after internalization for L8A4 labeled with [131I]SGMIB was 3-4-fold higher than that for L8A4 labeled with 125I using either Iodogen or [125I]SIPC. Catabolite assays documented that the increased retention of radioiodine in tumor cells for antibody labeled using [131I]SGMIB was due to positively charged, low molecular weight species. These results suggest that [131I]SGMIB warrants further evaluation as a reagent for labeling internalizing antibodies.

Authors
Vaidyanathan, G; Affleck, DJ; Li, J; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Li, J, Welsh, P, and Zalutsky, MR. "A polar substituent-containing acylation agent for the radioiodination of internalizing monoclonal antibodies: N-succinimidyl 4-guanidinomethyl-3-[131I]iodobenzoate ([131I]SGMIB)." Bioconjug Chem 12.3 (May 2001): 428-438.
PMID
11353542
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
12
Issue
3
Publish Date
2001
Start Page
428
End Page
438

Radiolabeled guanine derivatives for the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase: 6-(4-[(18)F]Fluoro-benzyloxy)-9H-purin-2-ylamine and 6-(3-[(131)I]Iodo-benzyloxy)-9H-purin-2-ylamine.

Two radiolabeled analogues of 6-benzyloxy-9H-purin-2-ylamine (O(6)-benzylguanine; BG) potentially useful in the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase (AGT) were synthesized. Fluorine-18 labeling of the known 6-(4-fluoro-benzyloxy)-9H-purin-2-ylamine (FBG; 6) was accomplished by the condensation of 4-[(18)F]fluorobenzyl alcohol with 2-aminopurin-6-yltrimethylammonium chloride (4) or 2-amino-6-chloropurine in average decay-corrected radiochemical yields of 40 and 25%, respectively. Unlabeled 6-(3-iodo-benzyloxy)-9H-purin-2-ylamine (IBG; 7) was prepared from 4 and 3-iodobenzyl alcohol. Radioiodination of 9, prepared from 7 in two steps, and subsequent deprotection gave [(131)I]7 in about 70% overall radiochemical yield. The IC(50) values for the inactivation of AGT from CHO cells transfected with pCMV-AGT were 15 nM for IBG and 50 nM for FBG. The binding of [(18)F]6 and [(131)I]7 to purified AGT was specific and saturable with both exhibiting similar IC(50) values (5-6 microM).

Authors
Vaidyanathan, G; Affleck, DJ; Cavazos, CM; Johnson, SP; Shankar, S; Friedman, HS; Colvin, MO; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Cavazos, CM, Johnson, SP, Shankar, S, Friedman, HS, Colvin, MO, and Zalutsky, MR. "Radiolabeled guanine derivatives for the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase: 6-(4-[(18)F]Fluoro-benzyloxy)-9H-purin-2-ylamine and 6-(3-[(131)I]Iodo-benzyloxy)-9H-purin-2-ylamine." Bioconjug Chem 11.6 (November 2000): 868-875.
PMID
11087336
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
11
Issue
6
Publish Date
2000
Start Page
868
End Page
875

Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy.

Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of alpha-particles such as the heavy halogen astatine-211 (211At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include [211At]astatide, 211At- labeled particulates, 211At-labeled naphthoquinone derivatives, 211At-labeled methylene blue, 211At-labeled DNA precursors, meta-[211At]astatobenzylguanidine, 211At-labeled biotin conjugates, 211At-labeled bisphosphonates, and 211At-labeled antibodies and antibody fragments. The status of these 211At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211At-labeled targeted therapeutic, 211At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

Authors
Zalutsky, MR; Vaidyanathan, G
MLA Citation
Zalutsky, MR, and Vaidyanathan, G. "Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy." Curr Pharm Des 6.14 (September 2000): 1433-1455. (Review)
PMID
10903402
Source
pubmed
Published In
Current Pharmaceutical Design
Volume
6
Issue
14
Publish Date
2000
Start Page
1433
End Page
1455

Radioiodination and astatination of octreotide by conjugation labeling.

Octreotide was coupled to 3-iodobenzoyl and 3-iodonicotinoyl moieties to obtain [N-(3-iodobenzoyl)-D-Phe(1)]octreotide (IBO) and [N-(3-iodonicotinoyl)-D-Phe(1)]octreotide (INO), respectively. The IC(50) values for the binding of IBO and INO to CA20948 rat pancreatic tumor membranes were 0.90 and 0.13 nM, respectively, compared with 0.35 nM for octreotide itself. Starting from N-succinimidyl 3-[(131)I]iodobenzoate and N-succinimidyl 5-[(131)I]iodopyridine-3- carboxylate, [(131)I]IBO and [(131)I]INO were prepared in overall radiochemical yields of 35%-50%. Likewise, ¿N-(3-[(211)At]astatobenzoyl)-D-Phe(1)¿octreotide ([(211)At]ABO) was prepared in similar yield from N-succinimidyl 3-[(211)At]astatobenzoate. In vitro assays with AR42J rat pancreatic tumor cells demonstrated a higher retention of cell-internalized radioiodine activity for [(131)I]INO compared with [(125)I]IBO. Tissue distribution studies with both conjugates revealed low levels of activity in the thyroid suggesting that dehalogenation of these peptides was minimal.

Authors
Vaidyanathan, G; Affleck, D; Welsh, P; Srinivasan, A; Schmidt, M; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, D, Welsh, P, Srinivasan, A, Schmidt, M, and Zalutsky, MR. "Radioiodination and astatination of octreotide by conjugation labeling." Nucl Med Biol 27.4 (May 2000): 329-337.
PMID
10938466
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
27
Issue
4
Publish Date
2000
Start Page
329
End Page
337

Radioiodination and astatination of octreotide by conjugation labeling

Octreotide was coupled to 3-iodobenzoyl and 3-iodonicotinoyl moieties to obtain [N-(3-iodobenzoyl)-D-Phe1]octreotide (IBO) and [N-(3-iodonicotinoyl)-D-Phe1]octreotide (INO), respectively. The IC50 values for the binding of IBO and INO to CA20948 rat pancreatic tumor membranes were 0.90 and 0.13 nM, respectively, compared with 0.35 nM for octreotide itself. Starting from N-succinimidyl 3-[131I]iodobenzoate and N-succinimidyl 5-[131I]iodopyridine-3-carboxylate, [131I]IBO and [131I]INO were prepared in overall radiochemical yields of 35%-50%. Likewise, {N-(3-[11At]astatobenzoyl)-D-Phe1}octreotide ([211At]ABO) was prepared in similar yield from N-succinimidyl 3-[211At]astatobenzoate. In vitro assays with AR42J rat pancreatic tumor cells demonstrated a higher retention of cell-internalized radioiodine activity for [131I]INO compared with [125I]IBO. Tissue distribution studies with both conjugates revealed low levels of activity in the thyroid suggesting that dehalogenation of these peptides was minimal. (C) 2000 Elsevier Science Inc.

Authors
Vaidyanathan, G; Affleck, D; Welsh, P; Srinivasan, A; Schmidt, M; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, D, Welsh, P, Srinivasan, A, Schmidt, M, and Zalutsky, MR. "Radioiodination and astatination of octreotide by conjugation labeling." Journal of Inorganic Biochemistry 78.3 (2000): 329-337.
Source
scival
Published In
Journal of Inorganic Biochemistry
Volume
78
Issue
3
Publish Date
2000
Start Page
329
End Page
337

Dosimetry and microdosimetry of targeted radiotherapy

Dosimetry in targeted radiotherapy (TR) uses different calculation methods, whose degree of refinement is closely conditioned by the particular objective sought. It is more generally performed to establish a correlation between the quantity of radiation delivered to a target and the biological damage observed or that can be reliably predicted. It can thus be used to optimise treatments and allow comparison of different therapeutic approaches, as well as to study the basic methods of irradiation of biological matter. Two broad types of investigations can be found in the literature: microdosimetric ones (stochastic approaches used to study energy deposits) and macrodosimetric ones (non-stochastic or deterministic approaches). The mathematical formalism is consistent between these two types, and the calculation methods currently used are often similar. This review presents different approaches to the dosimetry of radionuclides used in TR. The introduction defines the general problem, the role of dosimetry in TR and the specific problems raised by targeting (non-uniformity of source distributions). The first part considers the types of calculation methods found in TR in relation to the basic quantities used to represent stochastic energy deposit on a cellular scale. In particular, it compares the formalism and the methods used in microdosimetric or conventional macrodosimetric approches. Although microdosimetry, or even track structure calculations, can provide the basic elements for modelling the absorbed dose process, a simplified dosimetric approach may be adequate to describe the phenomena observed. The scheme proposed by the MIRD committee relates to such an approach and is presented together with other methods allowing the calculation of the mean dose delivered (analytic methods, dose point kernels, Monte-Carlo, etc.). The second part shows the application range for the various methods, providing selected examples of dosimetric approaches in TR on different scales, from the organ (or tissues) to the cell or even DNA, and a brief presentation of bone marrow dosimetry.

Authors
Zalutsky, MR; Vaidyanathan, G
MLA Citation
Zalutsky, MR, and Vaidyanathan, G. "Dosimetry and microdosimetry of targeted radiotherapy." Current Pharmaceutical Design 6.14 (2000): 1469-1502.
PMID
10903404
Source
scival
Published In
Current Pharmaceutical Design
Volume
6
Issue
14
Publish Date
2000
Start Page
1469
End Page
1502

Low molecular weight radiopharmaceuticals: Radiohalogenated MIBG and IUdR analogues.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Low molecular weight radiopharmaceuticals: Radiohalogenated MIBG and IUdR analogues." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 217 (March 21, 1999): U41-U41.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
217
Publish Date
1999
Start Page
U41
End Page
U41

Octreotide analogues labeled with radioiodine and astatine-211

Authors
Vaidyanathan, G; Srinivasan, A; Affleck, DJ; Welsh, PC; Slade, SK; Schmidt, MA; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Srinivasan, A, Affleck, DJ, Welsh, PC, Slade, SK, Schmidt, MA, and Zalutsky, MR. "Octreotide analogues labeled with radioiodine and astatine-211." Journal of Labelled Compounds and Radiopharmaceuticals 42.SUPPL. 1 (1999): S33-S35.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
42
Issue
SUPPL. 1
Publish Date
1999
Start Page
S33
End Page
S35

Iodopyridine-for-iodobenzene substitution for use with low molecular weight radiopharmaceuticals: application to m-iodobenzylguanidine.

Substituting a pyridine ring for a benzene ring in the acylation agent N-succinimidyl 3-iodobenzoate has resulted in a useful approach for the radiohalogenation of monoclonal antibodies, peptides, and labeled biotin conjugates. It was hypothesized that such a substitution in m-iodobenzylguanidine (MIBG), a radiotracer used in the detection and treatment of neuroendocrine tumors, might result in an analogue with more rapid normal tissue clearance, thereby facilitating its use for tumor therapy. For the preparation of this analogue, 3-guanidinomethyl-5-iodopyridine (GMIP; 9b), the silicon precursor 4 was synthesized starting from 5-bromonicotinic acid. Attempts to convert 4 to 9b under various conditions were not successful. Radioiodinated 9b could be prepared by the iododestannylation of the tin precursor 8 in 65-70% radiochemical yield. A number of in vitro, in vivo, and ex vivo studies showed that pyridine-for-benzene substitution in MIBG yielded a compound that no longer was taken up by the uptake-1 pathway.

Authors
Vaidyanathan, G; Zalutsky, MR; DeGrado, TR
MLA Citation
Vaidyanathan, G, Zalutsky, MR, and DeGrado, TR. "Iodopyridine-for-iodobenzene substitution for use with low molecular weight radiopharmaceuticals: application to m-iodobenzylguanidine." Bioconjug Chem 9.6 (November 1998): 758-764.
PMID
9815170
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
9
Issue
6
Publish Date
1998
Start Page
758
End Page
764
DOI
10.1021/bc980037x

Survival and DNA damage in Chinese hamster V79 cells exposed to alpha particles emitted by DNA-incorporated astatine-211.

Asynchronous Chinese hamster V79 lung fibroblasts were incubated at 37 degrees C for 30 min with the thymidine analog 5-[211At]astato-2'-deoxyuridine (211AtdU, exposure from DNA-incorporated activity) or with [211At]astatide (211At-, exposure from extracellular activity), and DNA-incorporated activity was determined. The 211AtdU content in cellular DNA increased as a function of extracellular concentration. Incorporation of 211At- was less than 1% of that of 211AtdU. After exposure, cells were frozen in the presence of 10% DMSO. One month later, survival was determined by the colony-forming assay, and DNA double-strand breaks (DSBs) were measured by the neutral elution method (pH 9.6). The survival curve for 211AtdU was biphasic (D37 = 2.8 decays per cell), reflecting killing of 211At-DNA-labeled cells and of unlabeled cells irradiated by 211At in neighboring labeled cells. The toxicity of 211At- decaying outside the cell (30-min exposure) was negligible. Analysis of the survival curve produced a D0 of 1.3 decays/cell for 211At-labeled cells. The yield of DSBs from the decay of DNA-incorporated 211At was compared with that from DNA-incorporated 125I. Each decay of 211At produced at least 10 times the number of DSBs as that obtained per 125I decay. The extreme radiotoxicity of DNA-incorporated 211AtdU seems to be associated with considerable damage to the mammalian cell genome.

Authors
Walicka, MA; Vaidyanathan, G; Zalutsky, MR; Adelstein, SJ; Kassis, AI
MLA Citation
Walicka, MA, Vaidyanathan, G, Zalutsky, MR, Adelstein, SJ, and Kassis, AI. "Survival and DNA damage in Chinese hamster V79 cells exposed to alpha particles emitted by DNA-incorporated astatine-211." Radiat Res 150.3 (September 1998): 263-268.
PMID
9728654
Source
pubmed
Published In
Radiation Research
Volume
150
Issue
3
Publish Date
1998
Start Page
263
End Page
268

Preparation of 5-[131I]iodo- and 5-[211At]astato-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil by a halodestannylation reaction.

To circumvent the in vivo instability of 5-iodo-2'-deoxyuridine (IUdR), a 2'-fluorine-substituted analogue, 5-iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (FIAU) recently has been introduced. To facilitate the preparation of radioiodinated FIAU as well as its astatinated analogue, a tin precursor, 5-trimethylstannyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)ura cil (FTAU) was synthesized. Both [125/131I]FIAU and 5-[211At]astato-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (FAAU) were prepared from FTAU in more than 85% radiochemical yield under mild conditions. The in vitro serum stability of both fluorine-substituted derivatives was higher than that of the corresponding unsubstituted parents. The enhanced stability of fluorinated derivatives was even more apparent in whole blood. The uptake of [125I]FIAU in D-247 MG human glioma cells in vitro was 20-fold higher than that of [125I]IUdR over an activity concentration range of 5-100 kBq/mL; the uptake of FAAU was not significantly different from that of 5-[211At]astato-2'-deoxyuridine (AUdR). Accumulation of radioiodine in mouse thyroid in vivo with [131I]FIAU was fivefold lower than [125I]IUdR, indicating that the former was less susceptible to deiodination. The tissue uptake of FAAU was similar to that reported for AUdR.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Preparation of 5-[131I]iodo- and 5-[211At]astato-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil by a halodestannylation reaction." Nucl Med Biol 25.5 (July 1998): 487-496.
PMID
9720667
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
25
Issue
5
Publish Date
1998
Start Page
487
End Page
496

Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions.

Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [131I]MIBG is now widely used in the treatment of neuroblastoma, but other radioconjugates of benzylguanidine have been little studied. We have investigated the cytotoxic efficacy of beta, alpha and Auger electron-emitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced 123I-, 125I-, 131I- and 211At-labelled benzylguanidines and compared their in vitro toxicity to the neuroblastoma cell line SK-N-BE(2c) grown in monolayer and spheroid culture. The Auger electron-emitting conjugates ([123I]MIBG and [125I]MIBG) and the alpha-emitting conjugate ([211At]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [131I]MIBG was relatively ineffective. The Auger emitters were more effective than expected if the cellular localization of MIBG is cytoplasmic. As dosimetrically predicted however, [211At]MABG was found to be extremely potent in terms of both concentration of radioactivity and number of atoms ml(-1) administered. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids, while the beta emitter showed greater efficacy. These findings suggest that short-range emitters would be well suited to the treatment of circulating tumour cells or small clumps, whereas beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. These experimental results provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy.

Authors
Cunningham, SH; Mairs, RJ; Wheldon, TE; Welsh, PC; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Cunningham, SH, Mairs, RJ, Wheldon, TE, Welsh, PC, Vaidyanathan, G, and Zalutsky, MR. "Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions." Br J Cancer 77.12 (June 1998): 2061-2068.
Website
http://hdl.handle.net/10161/11051
PMID
9649115
Source
pubmed
Published In
British Journal of Cancer
Volume
77
Issue
12
Publish Date
1998
Start Page
2061
End Page
2068

Myocardial kinetics of meta-[I-131]iodobenzylguanidine in an adriamycin cardiomyopathy rat model.

Authors
Berry, CR; Vaidyanathan, G; Fisher, PE; Zalutsky, MR; Coleman, RE; DeGrado, TR
MLA Citation
Berry, CR, Vaidyanathan, G, Fisher, PE, Zalutsky, MR, Coleman, RE, and DeGrado, TR. "Myocardial kinetics of meta-[I-131]iodobenzylguanidine in an adriamycin cardiomyopathy rat model." JOURNAL OF NUCLEAR MEDICINE 39.5 (May 1998): 47P-47P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
39
Issue
5
Publish Date
1998
Start Page
47P
End Page
47P

Targeted therapy using astatinated radiopharmaceuticals.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Targeted therapy using astatinated radiopharmaceuticals." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 215 (April 2, 1998): U946-U946.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
215
Publish Date
1998
Start Page
U946
End Page
U946

Effects of specific activity on meta-[(131)I]iodobenzylguanidine kinetics in isolated rat heart.

The effects of specific activity of meta-[(131)I]iodobenzylguanidine (MIBG) were studied in uptake-2 blocked isolated perfused rat heart. [(131)I]MIBG was administered in the perfusate as an 8-min pulse, followed by an 80-min washout period. Kinetic analysis of the externally monitored time-activity curves gave estimates of uptake rate and multiexponential clearance. Uptake rate showed an MIBG concentration dependence that is sigmoidal, yielding Michaelis-Menten constants KM = 52 nM and Vmax = 0.23 nmol/min/g. Clearance rate was also dependent on loading MIBG concentrations; the primary effect of increasing loading concentration was an increase in the rate of the slowest clearance component, possibly reflecting nonspecific turnover. No effect of specific activity was observed on tissue uptake and retention of [(131)I]MIBG for loading concentrations of MIBG in the heart tissue under 0.5 nmol/g. Extrapolation of these results to human studies indicates that isotope-exchange-labeled [123I]MIBG has a specific activity sufficiently high to avoid mass effects on its heart retention.

Authors
DeGrado, TR; Zalutsky, MR; Coleman, RE; Vaidyanathan, G
MLA Citation
DeGrado, TR, Zalutsky, MR, Coleman, RE, and Vaidyanathan, G. "Effects of specific activity on meta-[(131)I]iodobenzylguanidine kinetics in isolated rat heart." Nucl Med Biol 25.1 (January 1998): 59-64.
PMID
9466363
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
25
Issue
1
Publish Date
1998
Start Page
59
End Page
64

Method for radioiodination of proteins using N-succinimidyl 3-hydroxy-4-iodobenzoate.

A conjugation method has been developed for the radioiodination of proteins which should be adaptable to kit formulation. m-Hydroxybenzoic acid was converted to 3-hydroxy-4-[131I]iodobenzoic acid in 65% radiochemical yield using Chloramine-T as the oxidant. This intermediate was then converted to N-succinimidyl 3-hydroxy-4-[131I]iodobenzoate ([131I]mSHIB) in 75% yield by reaction with N-hydroxysuccinimide and dicyclohexylcarbodiimide in a reaction time of only 10 min. Monoclonal antibody (mAb) 81C6 was labeled in 40-60% yield by reaction with [131I]mSHIB. Performing purifications of radioiodinated compounds using cartridges instead of HPLC did not alter conjugation efficiency, mAb immunoreactivity, or tissue distribution. Thyroid uptake of labeled mAb was low but up to 2.4 times higher than that seen when the mAb was labeled with N-succinimidyl 3-[125I]-iodobenzoate. These results suggest that [131I]mSHIB may be a useful reagent for the radioiodination of proteins, particularly in contexts when less complicated purification methods would be advantageous.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "Method for radioiodination of proteins using N-succinimidyl 3-hydroxy-4-iodobenzoate." Bioconjug Chem 8.5 (September 1997): 724-729.
PMID
9327137
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
8
Issue
5
Publish Date
1997
Start Page
724
End Page
729
DOI
10.1021/bc9700502

A new route to guanidines from bromoalkanes

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "A new route to guanidines from bromoalkanes." JOURNAL OF ORGANIC CHEMISTRY 62.14 (July 11, 1997): 4867-4869.
Source
wos-lite
Published In
The Journal of Organic Chemistry
Volume
62
Issue
14
Publish Date
1997
Start Page
4867
End Page
4869
DOI
10.1021/jo9704164

Cytotoxicity of alpha-particle-emitting 5-[211At]astato-2'-deoxyuridine in human cancer cells.

This study was performed to determine the cytotoxicity of alpha-particle-emitting 5-[211At]astato-2-deoxyuridine (i.e. [211At]AUdR) for monolayers of D-247 MG human glioma cells and SK-MEL-28 human melanoma cells. Cells in exponential growth were exposed to varying activity concentrations of [211At]AUdR and for comparison [211At]astatide and the Auger electron-emitting analogue, 5-[125I]iodo-2'-deoxyuridine (i.e. [125I]IUdR). Cell uptake, DNA binding and clonogenic survival as a function of activity concentration in the medium were determined following 2 and 20-h incubations. None of the survival curves had detectable shoulders, an observation consistent with high-LET effects. The A37 (initial activity concentration yielding 37% cell survival) were significantly lower for both cell lines following 20-h exposure of [211At]AUdR than [211At]astatide. After correcting for effects from non-cell-associated activity in the medium, the specific cytotoxicity of cell-associated and DNA-bound [211At]AUdR was estimated. In the 20-h incubation experiments, the A37 for DNA-associated [211At]AUdR corresponded to about one 211At atom bound per cell for both cell lines. Unlike [211At]AUdR, there was a biphasic survival response to [125I]IUdR, consistent with the lower fractional uptake of [125I]IUdR at higher activity concentrations. These studies suggest that [211At]AUdR warrants further evaluation as an endoradiotherapeutic agent for the treatment of rapidly proliferating cancers.

Authors
Larsen, RH; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Larsen, RH, Vaidyanathan, G, and Zalutsky, MR. "Cytotoxicity of alpha-particle-emitting 5-[211At]astato-2'-deoxyuridine in human cancer cells." Int J Radiat Biol 72.1 (July 1997): 79-90.
PMID
9246197
Source
pubmed
Published In
International Journal of Radiation Biology (Informa)
Volume
72
Issue
1
Publish Date
1997
Start Page
79
End Page
90

3-[At-211]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells

Authors
Vaidyanathan, G; Zhao, XG; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Zhao, XG, Larsen, RH, and Zalutsky, MR. "3-[At-211]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells." BRITISH JOURNAL OF CANCER 76.2 (July 1997): 226-233.
Source
wos-lite
Published In
British Journal of Cancer
Volume
76
Issue
2
Publish Date
1997
Start Page
226
End Page
233
DOI
10.1038/bjc.1997.366

Survival and DNA damage in V79 cells exposed to the alpha emitters 5-[At-211]astato-2'-deoxy-uridine and [At-211]astatide.

Authors
Kassis, AI; Walicka, MA; Vaidyanathan, G; Zalutsky, MR; Adelstein, SJ
MLA Citation
Kassis, AI, Walicka, MA, Vaidyanathan, G, Zalutsky, MR, and Adelstein, SJ. "Survival and DNA damage in V79 cells exposed to the alpha emitters 5-[At-211]astato-2'-deoxy-uridine and [At-211]astatide." JOURNAL OF NUCLEAR MEDICINE 38.5 (May 1997): 964-964.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
5
Publish Date
1997
Start Page
964
End Page
964

Mechanisms of uptake in isolated rat heart of potential radiotherapeutic agent [At-211]meta-astatobenzylguanidine (MABG).

Authors
DeGrado, TR; Zalutsky, MR; Vaidyanathan, G
MLA Citation
DeGrado, TR, Zalutsky, MR, and Vaidyanathan, G. "Mechanisms of uptake in isolated rat heart of potential radiotherapeutic agent [At-211]meta-astatobenzylguanidine (MABG)." JOURNAL OF NUCLEAR MEDICINE 38.5 (May 1997): 106-106.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
5
Publish Date
1997
Start Page
106
End Page
106

Fluorine-18-labeled [Nle4,D-Phe7]-alpha-MSH, an alpha-melanocyte stimulating hormone analogue.

The alpha-melanocyte stimulating hormone (alpha-MSH) analogue [Nle4,D-Phe7]-alpha-MSH was labeled with 18F using N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) in > 80% radiochemical yield. The IC50 values of [Nle4,D-Phe7]-alpha-MSH and para-fluorobenzoyl-[Nle4, D-Phe7]-alpha-MSH ([Nle4,D-Phe7, Lys 11 -(18F)PFB]-alpha-MSH) for inhibiting the binding of meta-[131I]iodobenzoyl -[Nle4,D-Phe7]-alpha-MSH ([Nle4,D-Phe7, Lys11-(131I)MIB]-alpha-MSH) to B16-F1 murine melanoma cells were 89 +/- 9 pM and 112 +/- 22 pM, respectively, suggesting that addition of 4-fluorobenzoate did not compromise alpha-MSH receptor binding affinity. Binding of [Nle4,D-Phe7,Lys11-(18F)PFB]-alpha-MSH was influenced by the specific activity of the preparation (400-1000 Ci/mmol). The normal tissue clearance of [Nle4, D-Phe7, Lys11-(18F) PFB]-alpha-MSH in mice was quite rapid, with little evidence for defluorination.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Fluorine-18-labeled [Nle4,D-Phe7]-alpha-MSH, an alpha-melanocyte stimulating hormone analogue." Nucl Med Biol 24.2 (February 1997): 171-178.
PMID
9089709
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
24
Issue
2
Publish Date
1997
Start Page
171
End Page
178

No-carrier-added iodine-131-FIBG: evaluation of an MIBG analog.

UNLABELLED: The purpose of this study was to evaluate the properties of 4-fluoro-3-[131I]iodobenzylguanidine ([131I]FIBG), a potential neuroendocrine tumor and myocardial imaging radiopharmaceutical. METHODS: The binding of [131I]FIBG and [125I]MIBG was compared in vitro using the SK-N-SH human neuroblastoma cell line. The role of the active uptake-1 mechanism was investigated by determining the effect on cell binding of desipramine (DMI), ouabain, norepinephrine (NE), unlabeled MIBG and FIBG and by incubation at 4 degrees C. Finally, the tissue distributions of [131I]FIBG and [125I]MIBG were compared in normal mice. RESULTS: The specific binding of [131I]FIBG remained fairly constant (45%-60%) over a 2-3-log activity range and consistently was 11%-14% higher (p < 0.05) than that of [125I]MIBG. The uptake of [131I]FIBG was reduced to 13% of control values by 1.5 microM DMI, to 31% by 1 mM ouabain, to 8% by lower temperature, to 8% by 50 microM NE and to 6% and 5% by 10 microM each of unlabeled MIBG and FIBG, respectively. The amount of [131I]FIBG retained by SK-N-SH cells was significantly higher than that of [125I]MIBG with the maximum difference observed at 72 hr. In mice, the uptake of [131I]FIBG was higher than that of [125I]MIBG not only in target tissues (heart and adrenals) but also in many other normal tissues; conversely, thyroidal uptake of [131I]FIBG was 2-3-fold lower than that of [125I]MIBG. The uptake of [131I]FIBG in the heart and adrenals was reduced by DMI. CONCLUSION: Iodine-131-FIBG is an analog of MIBG with prolonged binding to neuroblastoma cells in vitro and retention in the myocardium in vivo.

Authors
Vaidyanathan, G; Zhao, XG; Strickland, DK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Zhao, XG, Strickland, DK, and Zalutsky, MR. "No-carrier-added iodine-131-FIBG: evaluation of an MIBG analog." J Nucl Med 38.2 (February 1997): 330-334.
PMID
9025764
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
2
Publish Date
1997
Start Page
330
End Page
334

3-[211At]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells.

An analogue of meta-iodobenzylguanidine (MIBG) in which an aromatic hydrogen was replaced with fluorine has been found to possess many properties similar to those of the parent compound. Moreover, 4-fluoro-3-iodobenzylguanidine (FIBG) was retained in vitro by human neuroblastoma cells to a much greater extent than MIBG itself. Since alpha-emitters such as 211At could be valuable for the treatment of micrometastatic disease, an FIBG analogue in which the iodine atom is replaced by 211At would be of interest. In this study, we have evaluated the in vitro and in vivo properties of 3-[211At]astato-4-fluorobenzylguanidine ([211At]AFBG). The specific binding of [211At]AFBG to SK-N-SH human neuroblastoma cells remained fairly constant over 2- to 3-log activity range and was similar to that of [131I]MIBG. The uptake of [211At]AFBG by this cell line was reduced by desipramine, ouabain, 4 degrees C incubation, noradrenaline, unlabelled MIBG and FIBG, suggesting that its uptake is specifically mediated through an active uptake-1 mechanism. Over the 16 h period studied, the amount of [211At]AFBG retained was similar to that of [131I]FIBG, whereas the per cent of retained meta-[211At]astatobenzylguanidine ([211At]MABG) was considerably less than that of [131I]FIBG (53% vs 75%; P < 0.05). The IC50 values for the inhibition of uptake of [131I]MIBG, [211At]MABG, [125I]FIBG and [211At]AFBG by unlabelled MIBG were 209, 300, 407 and 661 nM respectively, suggesting that the affinities of these tracers for the noradrenaline transporter in SK-N-SH cells increase in that order. Compared with [211At]MABG, higher uptake of [211At]AFBG was seen in vivo in normal mouse target tissues such as heart and, to a certain extent, in adrenals. That the uptake of [211At]AFBG in these tissues was related to the uptake-1 mechanism was demonstrated by its reduction when mice were pretreated with desipramine. However, the stability of [211At]AFBG towards in vivo dehalogenation was less than that of [211At]MABG, as evidenced by the higher uptake of 211At in thyroid, spleen, lungs and stomach.

Authors
Vaidyanathan, G; Zhao, XG; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Zhao, XG, Larsen, RH, and Zalutsky, MR. "3-[211At]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells." Br J Cancer 76.2 (1997): 226-233.
Website
http://hdl.handle.net/10161/11044
PMID
9231923
Source
pubmed
Published In
British Journal of Cancer
Volume
76
Issue
2
Publish Date
1997
Start Page
226
End Page
233

Fluorine-18-labeled [Nle4,D-Phe7]-α-MSH, an α-melanocyte stimulating hormone analogue

The α-melanocyte stimulating hormone (α-MSH) analogue [Nle4,D-Phe7]-α-MSH was labeled with 18F using N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) in >80% radiochemical yield. The IC50 values of [Nle4,D-Phe7]-α-MSH and para-fluorobenzoyl-[Nle4,D-Phe7]-α-MSH ([Nle4,D-Phe7,Lys11-(18F)PFB]-α-MSH for inhibiting the binding of meta-[131I]iodobenzoyl-[Nle4,D-Phe7]-α-MSH ([Nle4,D-Phe7,Lys11-(131I)MIB]-α-MSH to B16-F1 murine melanoma cells were 89 ± 9 pM and 112 ± 22 pM, respectively, suggesting that addition of 4-fluorobenzoate did not compromise α-MSH receptor binding affinity. Binding of [Nle4,D-Phe7,Lys11-(18F)PFB]-α-MSH was influenced by the specific activity of the preparation (400-1000 Ci/mmol). The normal tissue clearance of [Nle4,D-Phe7,Lys11-(18F)PFB]-α-MSH in mice was quite rapid, with little evidence for defluorination.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Fluorine-18-labeled [Nle4,D-Phe7]-α-MSH, an α-melanocyte stimulating hormone analogue." Nuclear Medicine and Biology 24.2 (1997): 171-178.
Source
scival
Published In
Nuclear Medicine and Biology
Volume
24
Issue
2
Publish Date
1997
Start Page
171
End Page
178
DOI
10.1016/S0969-8051(96)00211-9

3-[211At]astato-4-fluorobenzylguanidine: A potential therapeutic agent with prolonged retention by neuroblastoma cells

Authors
Vaidyanathan, G; Zhao, XG; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Zhao, XG, Larsen, RH, and Zalutsky, MR. "3-[211At]astato-4-fluorobenzylguanidine: A potential therapeutic agent with prolonged retention by neuroblastoma cells." British Journal of Cancer 76.2 (1997): 226-233.
Source
scival
Published In
British Journal of Cancer
Volume
76
Issue
2
Publish Date
1997
Start Page
226
End Page
233

Targeted therapy using alpha emitters.

Radionuclides such as 211At and 212Bi which decay by the emission of alpha-particles are attractive for certain applications of targeted radiotherapy. The tissue penetration of 212Bi and 211At alpha-particles is equivalent to only a few cell diameters, offering the possibility of combining cell-specific targeting with radiation of similar range. Unlike the beta-particles emitted by radionuclides such as 131I and 90Y, alpha-particles are radiation of high linear energy transfer and thus greater biological effectiveness. Several approaches have been explored for targeted radiotherapy with 212Bi- and 211At-labelled substances including colloids, monoclonal antibodies, metabolic precursors, receptor-avid ligands and other lower molecular weight molecules. An additional agent which exemplifies the promise of alpha-emitting radiopharmaceuticals is meta-[211At]astatobenzylguanidine. The toxicity of this compound under single-cell conditions, determined both by [3H]thymidine incorporation and by limiting dilution clonogenic assays, for human neuroblastoma cells is of the order of 1000 times higher than that of meta-[131I] iodobenzylguanidine. For meta-[211At] astatobenzylguanidine, the Do value was equivalent to only 6-7 211At atoms bound per cell. These results suggest that meta-[211At] astatobenzylguanidine might be valuable for the targeted radiotherapy of micrometastatic neuroblastomas.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Targeted therapy using alpha emitters." Phys Med Biol 41.10 (October 1996): 1915-1931. (Review)
PMID
8912371
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
41
Issue
10
Publish Date
1996
Start Page
1915
End Page
1931

Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model.

A paired-label biodistribution was performed in athymic mice bearing SK-N-SH human neuroblastoma xenografts to compare the tissue uptake of meta-[211At]astatobenzylguanidine ([211At]MABG) and [131I]MIBG. Significantly higher (p < 0.05) uptake of [211At]MABG was seen in tumor (3.8 +/- 0.8% ID/g vs. 3.1 +/- 0.7% ID/g at 8 h) compared to [131I]MIBG. Desipramine reduced tumor uptake of [211At] MABG by 43%, suggesting that its accumulation was related to the specific uptake-1 mechanism. Higher uptake of [211At]MABG was also seen in normal tissue targets such as heart (6.0 +/- 0.9% ID/g vs. 4.5 +/- 0.8% ID/g at 8 h; p < 0.05). Pretreatment of mice with unlabeled MIBG increased tumor uptake of [211At]MABG by 1.5-fold while reducing uptake in heart and several other normal tissues. The vesicular uptake inhibitor tetrabenazine reduced heart uptake by 30% without reducing the tumor uptake. These results suggest such strategies might be useful for improving [211At]MABG tumor-to-normal tissue ratios.

Authors
Vaidyanathan, G; Friedman, HS; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Keir, ST, and Zalutsky, MR. "Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model." Nucl Med Biol 23.6 (August 1996): 851-856.
PMID
8940730
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
23
Issue
6
Publish Date
1996
Start Page
851
End Page
856

Localisation of [131I]MIBG in nude mice bearing SK-N-SH human neuroblastoma xenografts: effect of specific activity.

The biodistribution of no-carrier-added (n.c.a.) meta-[131I]iodobenzylguanidine ([131I]MIBG) and that prepared by the standard isotopic exchange method were compared in athymic mice bearing SK-N-SH human neuroblastoma xenografts. No advantage in tumour uptake was observed for the n.c.a. preparation. BALB/c nu/nu mice exhibited lower uptake in highly innervated normal tissues (heart and adrenals) than normal BALB/c mice. In another experiment, the distribution of n.c.a. [131I]MIBG in the absence or presence (3-9 micrograms) of MIBG carrier was determined. At both 4 h and 24 h, the heart uptake was reduced by a factor of 1.5 even at a dose of 3 micrograms MIBG. Tumour uptake was not significantly altered by various amounts of unlabelled MIBG at either time point.

Authors
Vaidyanathan, G; Friedman, HS; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Keir, ST, and Zalutsky, MR. "Localisation of [131I]MIBG in nude mice bearing SK-N-SH human neuroblastoma xenografts: effect of specific activity." Br J Cancer 73.10 (May 1996): 1171-1177.
Website
http://hdl.handle.net/10161/11050
PMID
8630274
Source
pubmed
Published In
British Journal of Cancer
Volume
73
Issue
10
Publish Date
1996
Start Page
1171
End Page
1177

Effects of specific activity on uptake and retention of metaiodobenzylguanidine (MIBG) in the heart: Revisited

Authors
DeGrado, TR; Zalutsky, MR; Coleman, RE; Vaidyanathan, G
MLA Citation
DeGrado, TR, Zalutsky, MR, Coleman, RE, and Vaidyanathan, G. "Effects of specific activity on uptake and retention of metaiodobenzylguanidine (MIBG) in the heart: Revisited." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 701-701.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
701
End Page
701

Meta-[At-211]astatobenzylguanidine (MABG): In vivo evaluation in an athymic mouse human neuroblastoma xenograft model.

Authors
Vaidyanathan, G; Friedman, HS; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Keir, ST, and Zalutsky, MR. "Meta-[At-211]astatobenzylguanidine (MABG): In vivo evaluation in an athymic mouse human neuroblastoma xenograft model." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 236-236.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
236
End Page
236

Iodine-120-mIBG: Production and NCA labelling of a new PET radiotracer.

Authors
Zweit, J; Flower, M; Brown, A; Carnochan, P; Luthra, S; Brady, F; Pike, V; Vaidyanathan, G; Zalutsky, M; Ott, R; Jones, T
MLA Citation
Zweit, J, Flower, M, Brown, A, Carnochan, P, Luthra, S, Brady, F, Pike, V, Vaidyanathan, G, Zalutsky, M, Ott, R, and Jones, T. "Iodine-120-mIBG: Production and NCA labelling of a new PET radiotracer." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 874-874.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
874
End Page
874

Fluorine-18 labeling of [Nle(4),D-Phe(7)]-alpha-MSH, an alpha-melanocyte stimulating hormone (alpha-MSH) analogue.

Authors
Vaidyanathan, G; Affleck, DJ; Welsh, PC; Slade, SA; Alston, KL; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Welsh, PC, Slade, SA, Alston, KL, and Zalutsky, MR. "Fluorine-18 labeling of [Nle(4),D-Phe(7)]-alpha-MSH, an alpha-melanocyte stimulating hormone (alpha-MSH) analogue." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 875-875.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
875
End Page
875

5-[211 At]astato-2'-deoxyuridine, an alpha particle-emitting endoradiotherapeutic agent undergoing DNA incorporation.

When labeled with the subcellular range Auger electron emitters 125I and 123I, the thymidine analogue 5-iodo-2'deoxyuridine (IUdR) is highly cytotoxic but only to cells going through S-phase during exposure to these radiopharmaceuticals. Since 211 At emits alpha-particles of high linear energy transfer, but with a range of a few cell diameters, an IUdR analogue labeled with 211At could markedly improve the homogeneity of tumor dose deposition. Herein we describe the synthesis of 5-[211 At]astato-2'-deoxyuridine ([211 At]AUdR) in 85-90% radiochemical yield via the astatodestannylation of 5-(trimethylstannyl)-2'-deoxyuridine. In vitro studies using the human glioma cell line D-247 MG demonstrated that [211 At]AUdR was virtually identical to [131I]IUdr; both exhibited a linear increase in cell uptake with activity concentration, an inhibition of uptake by 10 micrometers IUdR, and the incorporation of about 50% of cell-bound activity into DNA. In a clonogenic assay, [211 At]AUdR exhibited a high cytotoxicity for D-247 MG cells, with a D(0) equivalent to less than 3 211At atoms/cell.

Authors
Vaidyanathan, G; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Larsen, RH, and Zalutsky, MR. "5-[211 At]astato-2'-deoxyuridine, an alpha particle-emitting endoradiotherapeutic agent undergoing DNA incorporation." Cancer Res 56.6 (March 15, 1996): 1204-1209.
PMID
8640798
Source
pubmed
Published In
Cancer Research
Volume
56
Issue
6
Publish Date
1996
Start Page
1204
End Page
1209

5-[At-211]astato-2'-deoxyuridine, an alpha-particle-emitting endoradiotherapeutic agent undergoing DNA incorporation

Authors
Vaidyanathan, G; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Larsen, RH, and Zalutsky, MR. "5-[At-211]astato-2'-deoxyuridine, an alpha-particle-emitting endoradiotherapeutic agent undergoing DNA incorporation." CANCER RESEARCH 56.6 (March 15, 1996): 1204-1209.
Source
wos-lite
Published In
Cancer Research
Volume
56
Issue
6
Publish Date
1996
Start Page
1204
End Page
1209

No-carrier-added (4-fluoro-3-[131I]iodobenzyl)guanidine and (3-[211At]astato-4-fluorobenzyl)guanidine.

With 3-bromo-4-fluorotoluene as starting material, [4-fluoro-3-(trimethylsilyl)benzyl]guanidine was prepared in five steps in 1.5% overall yield. Radioiodination of this silicon precursor using N-chlorosuccinimide in trifluoroacetic acid at room temperature for 5 min gave (4-fluoro-3-[131I]-iodobenzyl)guanidine ([131I]FIBG) in 50-60% radiochemical yield. A byproduct which had a retention time in two HPLC systems similar to that of (m-iodobenzyl)guanidine (MIBG) was formed in about 30% yield. [131I]FIBG was stable up to 3 h under these conditions of iodination, indicating that the byproduct is not generated as a result of [131I]FIBG degradation. Using hydrogen peroxide as the oxidant in aqueous medium and a reaction time of 30 min at 50 degrees C, yields of [131I]FIBG could be increased to 75-80%, with less than 7% of the byproduct formed under these conditions. Astatination of the silicon precursor using N-chlorosuccinimide in trifluoroacetic acid at 70 degrees C gave 65-70% radiochemical yield of (3-[211At]astato-4-fluorobenzyl)guanidine ([211At]AFBG) in 10-15 min; about 17% of the byproduct formation was seen. Astatination of the silicon precursor under aqueous conditions using hydrogen peroxide was not successful.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "No-carrier-added (4-fluoro-3-[131I]iodobenzyl)guanidine and (3-[211At]astato-4-fluorobenzyl)guanidine." Bioconjug Chem 7.1 (January 1996): 102-107.
PMID
8741997
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
7
Issue
1
Publish Date
1996
Start Page
102
End Page
107
DOI
10.1021/bc950078i

Particle-emitting endoradiotherapeutic agent undergoing DNA incorporation

When labeled with the subcellular range Auger electron emitters 125I and 123I, the thymidine analogue 5-iodo-2′-deoxyuridine (IUdR) is highly cytotoxic but only to cells going through S-phase during exposure to these radiopharmaceuticals. Since 211At emits α-particles of high linear energy transfer, but with a range of a few cell diameters, an IUdR analogue labeled with 211At could markedly improve the homogeneity of tumor dose deposition. Herein we describe the synthesis of 5-[211At]astato-2′-deoxyuridine ([211At]AUdR) in 85-90% radiochemical yield via the astatodestannylation of 5-(trimethylstannyl)-2′-deoxyuridine. In vitro studies using the human glioma cell line D-247 MG demonstrated that [211At]AUdR was virtually identical to [131I]IUdR; both exhibited a linear increase in cell uptake with activity concentration, an inhibition of uptake by 10 μM IUdR, and the incorporation of about 50% of cell-bound activity into DNA. In a clonogenic assay, [211At]AUdR exhibited a high cytotoxicity for D-247 MG cells, with a D0 equivalent to less than 3 211At atoms/cell.

Authors
Vaidyanathan, G; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Larsen, RH, and Zalutsky, MR. "Particle-emitting endoradiotherapeutic agent undergoing DNA incorporation." Cancer Research 56.6 (1996): 1204-1209.
Source
scival
Published In
Cancer Research
Volume
56
Issue
6
Publish Date
1996
Start Page
1204
End Page
1209

Tumor-specific anti-epidermal growth factor receptor variant III monoclonal antibodies: use of the tyramine-cellobiose radioiodination method enhances cellular retention and uptake in tumor xenografts.

Amplification and rearrangement of the epidermal growth factor receptor (EGFR) gene are characteristics of many types of tumors. One class of EGFR mutations, EGFRvIII, is characterized by an in-frame deletion resulting in a truncated external domain of the receptor. EGFRvIII was first identified in a subset of gliomas and has since been found in some non-small cell lung carcinomas and breast carcinomas. mAbs specific for this variant form of EGFR but unreactive with the wild-type EGFR have been reported from our laboratory. This study further characterizes three of these antibodies. We determined, via radiolabeling techniques and immunofluorescence microscopy, that, after cell binding in vitro, the anti-EGFRvIII-specific mAbs internalize at 37 degrees C. Furthermore, subsequent to internalization, the antibodies were processed intracellularly, presumably by lysosomal degradation. We also examined the use of an alternative radiolabeling procedure that uses nonmetabolizable radio-iodinated tyramine cellobiose. Our results show that the tyramine cellobiose labeling method allows for greater tumor cell retention of radiolabel in vitro (76% for tyramine cellobiose and 27% for Iodo-Gen after 24 h). Paired-label biodistribution studies in athymic mice indicate that anti-EGFRvIII mAb L8A4 localizes specifically to EGFRvIII-expressing tumor xenografts with a maximum of 34.3 +/- 7.6% injected dose/g when labeled using tyramine cellobiose compared with a maximum of 14.9 +/- 4.3% injected dose/g using Iodo-Gen; similar results were obtained with mAb H10. These results suggest that the anti-EGFRvIII mAbs may serve as potential carriers for radioconjugate- and immunotoxin-based therapies for tumors expressing EGFRvIII.

Authors
Reist, CJ; Archer, GE; Kurpad, SN; Wikstrand, CJ; Vaidyanathan, G; Willingham, MC; Moscatello, DK; Wong, AJ; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Archer, GE, Kurpad, SN, Wikstrand, CJ, Vaidyanathan, G, Willingham, MC, Moscatello, DK, Wong, AJ, Bigner, DD, and Zalutsky, MR. "Tumor-specific anti-epidermal growth factor receptor variant III monoclonal antibodies: use of the tyramine-cellobiose radioiodination method enhances cellular retention and uptake in tumor xenografts." Cancer Res 55.19 (October 1, 1995): 4375-4382.
PMID
7671250
Source
pubmed
Published In
Cancer Research
Volume
55
Issue
19
Publish Date
1995
Start Page
4375
End Page
4382

Fluorine-18 labeled chemotactic peptides: a potential approach for the PET imaging of bacterial infection.

A potent chemotactic peptide, formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine was derivatized by reaction with N-succinimidyl 4-fluorobenzoate. This derivatized peptide bound to human polymorphonuclear leukocytes in vitro and exhibited biological activity in a superoxide production assay. Peptide labeling using N-succinimidyl 4-[18F]fluorobenzoate was accomplished in reasonable yields with 10-15 mCi of labeled peptide available per 100 Ci of [18F]fluoride. With the exception of the gastrointestinal tract, clearance of activity from tissues following injection of this peptide in normal mice was rapid. Although preliminary in nature, these results suggest that 18F-labeled chemotactic peptides should be investigated as potential agents for positron emission tomographic imaging of bacterial infections.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Fluorine-18 labeled chemotactic peptides: a potential approach for the PET imaging of bacterial infection." Nucl Med Biol 22.6 (August 1995): 759-764.
PMID
8535336
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
6
Publish Date
1995
Start Page
759
End Page
764

Validation of 4-[fluorine-18]fluoro-3-iodobenzylguanidine as a positron-emitting analog of MIBG.

UNLABELLED: This study evaluates the potential utility of 4-[18F]fluoro-3-iodobenzylguanidine ([18F]FIBG) as an MIBG analog. METHODS: In vitro assays of tracer binding were carried out using the SK-N-SH human neuroblastoma cell line in a paired-label format to compare [18F]FIBG directly with no-carrier-added [125I]MIBG. To ascertain whether [18F]FIBG, like MIBG, is taken up by the uptake-1 mechanism, the effects of desipramine, norepinephrine, and carrier MIBG and FIBG on cell binding were determined. Preincubation with ouabain and incubation at 4 degrees C was used to evaluate the energy-dependence of [18F]FIBG uptake by SK-N-SH cells. The tissue distribution of [18F]FIBG in mice was compared with no-carrier-added [125I]MIBG in a paired-label study. RESULTS: In paired-label binding studies, the percent binding of [18F]FIBG to neuroblastoma cells remained constant over a three-log activity range and the level was somewhat higher than that of no-carrier-added [125I]MIBG. Binding was blocked by desipramine, norepinephrine, carrier MIBG and FIBG, ouabain and by incubating at 4 degrees C, suggesting that [18F]FIBG is taken up by the uptake-1 mechanism. Radiation dosimetry calculations suggest that higher doses of [18F]FIBG, unlike [124I]MIBG, could be administered to patients. CONCLUSION: These in vitro and in vivo evaluations show that [18F]FIBG is an excellent analog of MIBG, suggesting that [18F]FIBG should be further evaluated for use in PET imaging of neuroendocrine tumors and cardiac abnormalities.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "Validation of 4-[fluorine-18]fluoro-3-iodobenzylguanidine as a positron-emitting analog of MIBG." J Nucl Med 36.4 (April 1995): 644-650.
PMID
7699460
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
36
Issue
4
Publish Date
1995
Start Page
644
End Page
650

Uptake mechanisms of meta-[123I]iodobenzylguanidine in isolated rat heart.

In order to clarify the uptake and retention mechanisms of radioiodinated meta-iodobenzylguanidine (MIBG) in heart, the kinetics of no-carrier-added [123I]MIBG were studied in the isolated working rat heart in interaction with pharmacologic agents. The tracer was administered in the perfusate as a 10-min pulse, followed by a 90-min washout period. Kinetic analysis of the externally monitored time-activity curves of control hearts showed avid uptake (Ki = 4.4 +/- 0.7 mL/min/g), and monoexponential clearance (ko = 0.0056 +/- 0.0017 l/min), indicating a distribution volume (Vd = Ki/ko) of 834 +/- 214 mL/g. Blocking experiments (n = 41) were performed with neuronal uptake (uptake-1) inhibitor desipramine (DMI; 50-100 nM) and the extraneuronal uptake (uptake-2) inhibitor N-(9-fluorenyl)-N-methyl-beta-chloroethylamine (SKF550; 0.4-0.8 microM). Uptake rate was 27% reduced (P < 0.05) by 50 nM DMI but not significantly affected by 0.4 microM SKF550. Distribution volume was 88% reduced (P < 0.0005) by 50 nM DMI and 28% reduced (P < 0.05) by 0.4 microM SKF550. In DMI-blocked hearts, uptake rate was dramatically decreased (-80%, P < 0.0005) by SKF550 (0.4 microM), indicating uptake-2 transport contributed predominantly to the extraneuronal uptake of the tracer. The slow uptake rate seen with concomitant inhibition of uptake-1 and uptake-2 was further decreased by addition of unlabeled MIBG (1-10 microM) in a concentration-dependent manner, yet unaffected by addition of the vesicular uptake inhibitor Ro 4-1284 (1 microM). Thus, the uptake rate of [123I]MIBG is primarily dependent on uptake-1 and uptake-2 activity. Other possible mechanisms of uptake such as passive diffusion in association with intracellular binding are significant only in conditions where uptake-1 and uptake-2 mechanisms are largely inhibited.

Authors
Degrado, TR; Zalutsky, MR; Vaidyanathan, G
MLA Citation
Degrado, TR, Zalutsky, MR, and Vaidyanathan, G. "Uptake mechanisms of meta-[123I]iodobenzylguanidine in isolated rat heart." Nucl Med Biol 22.1 (January 1995): 1-12.
PMID
7735158
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
1
Publish Date
1995
Start Page
1
End Page
12

No-carrier-added meta-[123I]iodobenzylguanidine: synthesis and preliminary evaluation.

No-carrier-added [123I]MIBG was prepared from 3-(trimethylsilyl)benzylguanidine in 80-90% yield. Binding of this tracer to SK-N-SH human neuroblastoma cells maintained a constant level of > 50% over 2-3 log activity range. In comparison, the binding of [123I]MIBG prepared by isotopic exchange steadily decreased with dose. Biodistribution studies in normal mice demonstrated maximal concentrations in heart and adrenals for both preparations. In heart, significant 1.5-3.0 times higher levels (P < 0.05) were seen for the no-carrier-added preparation. Radiation dosimetry calculations suggest that the no-carrier-added preparation would increase the dose received by several tissues, most notably the heart where a 91% increase in dose is predicted.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "No-carrier-added meta-[123I]iodobenzylguanidine: synthesis and preliminary evaluation." Nucl Med Biol 22.1 (January 1995): 61-64.
PMID
7735171
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
1
Publish Date
1995
Start Page
61
End Page
64

Quantitation of 211At in small volumes for evaluation of targeted radiotherapy in animal models.

We have evaluated SPECT and two planar imaging methods, geometric mean (GM) and buildup factor (BF), for their potential to quantitate in vivo 211At distributions in rat spinal subarachnoid spaces using phantom studies. The use of medium-energy collimators and the small diameter (3 mm) of the subarachnoid space complicate quantitation. Net activities from distributions in various backgrounds were obtained using a large region of interest with background subtraction. Results showed quantitation accuracy within 10% for SPECT and BF in low backgrounds increasing to 25% at higher background levels while GM errors ranged from 20 to 45%. We have also obtained images of [211At]astatide distributions, administered intrathecally, in rats.

Authors
Johnson, EL; Turkington, TG; Jaszczak, RJ; Gilland, DR; Vaidyanathan, G; Greer, KL; Coleman, RE; Zalutsky, MR
MLA Citation
Johnson, EL, Turkington, TG, Jaszczak, RJ, Gilland, DR, Vaidyanathan, G, Greer, KL, Coleman, RE, and Zalutsky, MR. "Quantitation of 211At in small volumes for evaluation of targeted radiotherapy in animal models." Nucl Med Biol 22.1 (January 1995): 45-54.
PMID
7735169
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
1
Publish Date
1995
Start Page
45
End Page
54

Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131I]meta-iodobenzylguanidine: implications for the targeted radiotherapy of neuroblastoma.

In vitro and in vivo neuroblastoma models were used to determine whether improvements in tumour targeting in vivo and therapeutic efficacy in vitro could result from the use of no-carrier-added (n.c.a.) [131I]MIBG. Results were compared with use of the conventional therapy MIBG preparation (ex. [131I]MIBG) of lower specific activity which is produced by iodide exchange reaction. The efficacy of n.c.a. [131I]MIBG was compared with that of [131I]MIBG over a range of specific activities by the assessment of neuroblastoma spheroid growth delay. Whereas n.c.a. [131I]MIBG at a radioactivity concentration of 2 MBq/ml prevented the regrowth of 84% of spheroids, toxicity was significantly reduced by the addition of non-radiolabelled MIBG to the incubation medium. The time-dependent biodistribution of n.c.a. [131I]MIBG in nude mice bearing human neuroblastoma xenografts was compared with that of the conventional therapy radiopharmaceutical. The n.c.a. agent gave improved tumour uptake but also significantly greater accumulation in normal tissues known to accumulate MIBG such as heart, adrenal and skin. However, uptake and retention in the blood was unaltered. For all tissues examined, the 3-day calculations were undertaken to predict organ to tumour dose ratios which would result in human neuroblastoma patients with each of the [131I]MIBG preparations. These results suggest that significant therapeutic gain may be achieved by the use of n.c.a. [131I]MIBG as a treatment agent in neuroblastoma. neuroblastoma.

Authors
Mairs, RJ; Russell, J; Cunningham, S; O'Donoghue, JA; Gaze, MN; Owens, J; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Mairs, RJ, Russell, J, Cunningham, S, O'Donoghue, JA, Gaze, MN, Owens, J, Vaidyanathan, G, and Zalutsky, MR. "Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131I]meta-iodobenzylguanidine: implications for the targeted radiotherapy of neuroblastoma." Eur J Cancer 31A.4 (1995): 576-581.
PMID
7576972
Source
pubmed
Published In
European Journal of Cancer
Volume
31A
Issue
4
Publish Date
1995
Start Page
576
End Page
581

Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines.

Uptake of radioiodinated meta-iodobenzylguanidine (MIBG) has been demonstrated in the neural crest tumors, including neuroblastoma, pheochromocytoma, and carcinoid tumors, and is presently in use diagnostically and therapeutically in these settings. Cells comprising medulloblastoma, the most common central nervous system malignancy in childhood, may be derived from a common germinal neuroepithelial cell as neural crest tissue, and as a result, also may have the capacity for accumulating MIBG. To investigate this hypothesis, we measured the in vitro binding of [131I]MIBG to 9 medulloblastoma-derived cell lines and the SK-N-SH neuroblastoma line known to accumulate MIBG. Seven of the medulloblastoma lines exhibited MIBG binding. The cell line with the greatest uptake, D384 Med, bound 11.2 +/- 0.9% of added [131I]MIBG activity compared with 47.1 +/- 2.3% for the SK-N-SH cell line. When 2 of the cell lines, D384 Med and D458 Med, were treated with the alpha-particle emitting analogue meta-[211At]astatobenzylguanidine ([211At]MABG), as much as a 3-log cell kill was observed in limiting dilution clonogenic assays. Exposure to considerably higher activity levels of [211At]astatide was required to achieve a similar degree of cell kill, suggesting that this cytotoxicity was not related to nonspecific effects of alpha-particle irradiation. We conclude that the uptake capacity of medulloblastoma cell lines for [131I]MIBG uptake in vitro, while lower than that seen in SK-N-SH neuroblastoma cells, is sufficient to permit [211At]MABG to be used with significant therapeutic effectiveness.

Authors
Strickland, DK; Vaidyanathan, G; Friedman, HS; Zalutsky, MR
MLA Citation
Strickland, DK, Vaidyanathan, G, Friedman, HS, and Zalutsky, MR. "Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines." J Neurooncol 25.1 (1995): 9-17.
PMID
8523094
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
25
Issue
1
Publish Date
1995
Start Page
9
End Page
17

Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines

Uptake of radioiodinated mefa-iodobenzylguanidine (MIBG) has been demonstrated in the neural crest tumors, including neuroblastoma, pheochromocytoma, and carcinoid tumors, and is presently in use diagnostically and therapeutically in these settings. Cells comprising medulloblastoma, the most common central nervous system malignancy in childhood, may be derived from a common germinal neuroepithelial cell as neural crest tissue, and as a result, also may have the capacity for accumulating MIBG. To investigate this hypothesis, we measured the in vitro binding of [131I]MIBG to 9 medulloblastoma-derived cell lines and the SK-N-SH neuroblastoma line known to accumulate MIBG. Seven of the medulloblastoma lines exhibited MIBG binding. The cell line with the greatest uptake, D384 Med, bound 11.2 ± 0.9% of added [131I]MIBG activity compared with 47.1 ± 2.3% for the SK-N-SH cell line. When 2 of the cell lines, D384 Med and D458 Med, were treated with the a-particle emitting analogue meta-[211At]astatobenzylguanidine ([211At]MABG), as much as a 3-log cell kill was observed in limiting dilution clonogenic assays. Exposure to considerably higher activity levels of [211At]astatide was required to achieve a similar degree of cell kill, suggesting that this cytotoxicity was not related to nonspecific effects of α-particle irradiation. We conclude that the uptake capacity of medulloblastoma cell lines for [131I]MIBG uptake in vitro, while lower than that seen in SK-N-SH neuroblastoma cells, is sufficient to permit [211At]MABG to be used with significant therapeutic effectiveness. © 1995 Kluwer Academic Publishers.

Authors
Strickland, DK; Vaidyanathan, G; Friedman, HS; Zalutsky, MR
MLA Citation
Strickland, DK, Vaidyanathan, G, Friedman, HS, and Zalutsky, MR. "Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines." Journal of Neuro-Oncology 25.1 (1995): 9-17.
Source
scival
Published In
Journal of Neuro-Oncology
Volume
25
Issue
1
Publish Date
1995
Start Page
9
End Page
17
DOI
10.1007/BF01054718

Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131i] metaiodobenzylguanidine: Implications for the targeted radiotherapy of neuroblastoma

In vitro and in vivo neuroblastoma models were used to determine whether improvements in tumour targeting in vivo and therapeutic efficacy in vitro could result from the use of no-carrier-added (n.c.a.) [131I]MIBG. Results were compared with use of the conventional therapy MIBG preparation (ex. [131I]MIBG) of lower specific activity which is produced by iodide exchange reaction. The efficacy of n.c.a. [131I]MIBG was compared with that of [131I]MIBG over a range of specific activities by the assessment of neuroblastoma spheroid growth delay. Whereas n.c.a. [131I]MIBG at a radioactivity concentration of 2 MBq/ml prevented the regrowth of 84% of spheroids, toxicity was significantly reduced by the addition of non-radiolabelled MIBG to the incubation medium. The time-dependent biodistribution of n.c.a. [131I]MIBG in nude mice bearing human neuroblastoma xenografts was compared with that of the conventional therapy radiopharmaceutical. The n.c.a. agent gave improved tumour uptake but also significantly greater accumulation in normal tissues known to accumulate MIBG such as heart, adrenal and skin. However, uptake and retention in the blood was unaltered. For all tissues examined, the 3-day cumulative tumour to normal tissue radiation dose ratio was greater for n.c.a. [131I]MIBG. Theoretical calculations were undertaken to predict organ to tumour dose ratios which would result in human neuroblastoma patients with each of the [131I]MIBG preparations. These results suggest that significant therapeutic gain may be achieved by the use of n.c.a. [131I]MIBG as a treatment agent in neuroblastoma. © 1995.

Authors
Mairs, RJ; Russell, J; Cunningham, S; O'Donoghue, JA; Gaze, MN; Owens, J; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Mairs, RJ, Russell, J, Cunningham, S, O'Donoghue, JA, Gaze, MN, Owens, J, Vaidyanathan, G, and Zalutsky, MR. "Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131i] metaiodobenzylguanidine: Implications for the targeted radiotherapy of neuroblastoma." European Journal of Cancer 31.4 (1995): 576-581.
Source
scival
Published In
European Journal of Cancer
Volume
31
Issue
4
Publish Date
1995
Start Page
576
End Page
581

Cytotoxicity of alpha-particle-emitting m-[211At]astatobenzylguanidine on human neuroblastoma cells.

Radioiodinated m-iodobenzylguanidine (MIBG) has been used with only limited success for the treatment of neural crest tumors including neuroblastoma. Use of an MIBG analogue labeled with 211At could be advantageous because of the shorter range and higher linear energy transfer of its alpha-particle emissions compared with the beta-particles emitted by 131I. The potential utility of m-[211At]astatobenzylguanidine for the treatment of neuroblastoma was investigated in vitro using 3 human neuroblastoma cell lines known to take up MIBG [SK-N-SH, SK-N-BE(2C), and SK-SY5Y] and a control line lacking MIBG uptake (SK-N-MC). Maximum binding of m-[211At]astatobenzylguanidine ([211At] MABG) to 5 x 10(5) cells after a 2-h incubation ranged from 61% for SK-N-SH to 1% for SK-N-MC. Using a limiting dilution clonogenic assay, the cytotoxicity for SK-N-SH cells of [211At]MABG was compared with [211At]astatide and no-carrier-added [131I]MIBG. A D0 of 5.8 nCi/ml was calculated for [211At]MABG compared with 482 nCi/ml for [211At] astatide, indicating a more than 80-fold enhanced cytotoxicity for the specifically targeted alpha-particles of [211At]MABG. For [211At]MABG, the D0 corresponded to only 6.4 211At atoms bound/cell compared with 9000 atoms/cell for no-carrier-added [131I]MIBG. The D0 values measured for [211At]MABG treatment of SK-SY5Y, SK-N-BE(2C), and SK-N-MC cells were 50, 5.8, and 11,043 nCi/ml, respectively, corresponding to 7.04, 6.46, and 171.79 211At atoms bound/cell. In conclusion, these results have demonstrated that [211At]MABG is considerably more cytotoxic than [131I]MIBG and that [211At]MABG could have great potential as a radiotherapeutic agent for the treatment of neuroblastoma.

Authors
Strickland, DK; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Strickland, DK, Vaidyanathan, G, and Zalutsky, MR. "Cytotoxicity of alpha-particle-emitting m-[211At]astatobenzylguanidine on human neuroblastoma cells." Cancer Res 54.20 (October 15, 1994): 5414-5419.
PMID
7923174
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
20
Publish Date
1994
Start Page
5414
End Page
5419

(4-[18F]fluoro-3-iodobenzyl)guanidine, a potential MIBG analogue for positron emission tomography.

The aims of this investigation were to develop a no-carrier-added (nca) synthesis of (4-[18F]-fluoro-3-iodobenzyl)guanidine ([18F]FIBG) and to evaluate its potential as an MIBG analogue useful for positron emission tomography. [18F]FIBG was prepared in four steps starting from 4-cyano-2-iodo-N,N,N-trimethylanilinium trifluoromethanesulfonate in 5% decay-corrected radiochemical yield in a total synthesis time of 130 min. The specific activity was more than 1500 Ci per mmol. In vitro binding studies showed that the percent binding of [18F]FIBG to SK-N-SH human neuroblastoma cells remained constant over a 3-log activity range and was similar to that of nca [131I]MIBG. Specific and high uptake of FIBG was also seen in mouse heart and adrenals. The in vitro and in vivo properties of [18F]FIBG suggest that this compound may be a useful positron-emitting analogue of MIBG.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "(4-[18F]fluoro-3-iodobenzyl)guanidine, a potential MIBG analogue for positron emission tomography." J Med Chem 37.21 (October 14, 1994): 3655-3662.
PMID
7932592
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
37
Issue
21
Publish Date
1994
Start Page
3655
End Page
3662

(4-[F-18]FLUORO-3-IODOBENZYL) GUANIDINE, A POTENTIAL MIBG ANALOG FOR POSITRON EMISSION TOMOGRAPHY

Authors
VAIDYANATHAN, G; AFFLECK, DJ; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, AFFLECK, DJ, and ZALUTSKY, MR. "(4-[F-18]FLUORO-3-IODOBENZYL) GUANIDINE, A POTENTIAL MIBG ANALOG FOR POSITRON EMISSION TOMOGRAPHY." JOURNAL OF MEDICINAL CHEMISTRY 37.21 (October 14, 1994): 3655-3662.
Source
wos-lite
Published In
Journal of Medicinal Chemistry
Volume
37
Issue
21
Publish Date
1994
Start Page
3655
End Page
3662
DOI
10.1021/jm00047a022

Preclinical evaluation and PET imaging of 18F-labeled Mel-14 F(ab')2 fragment in normal dogs.

The F(ab')2 fragment of monoclonal antibody Mel-14, reactive with human melanomas and gliomas, was labeled with 18F using two acylation agents, N-succinimidyl 8-[(4'-[18F]fluorobenzyl)amino]suberate (SFBS) and N-succinimidyl 4-[18F]fluorobenzoate (SFB). The immunoreactivity and affinity for Mel-14 F(ab')2 labeled using the two methods were similar. As a prelude to human clinical evaluation, PET imaging, tissue distribution and pharmacokinetic measurements were performed in two groups of normal foxhounds. Similar in vivo behavior was seen for Mel-14 F(ab')2 labeled using SFBS and SFB. Radiation dosimetry calculations suggest that a 10 mCi dose could be used for this F(ab')2 fragment labeled using either acylation agent.

Authors
Page, RL; Garg, PK; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Page, RL, Garg, PK, Vaidyanathan, G, and Zalutsky, MR. "Preclinical evaluation and PET imaging of 18F-labeled Mel-14 F(ab')2 fragment in normal dogs." Nucl Med Biol 21.7 (October 1994): 911-919.
PMID
9234344
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
21
Issue
7
Publish Date
1994
Start Page
911
End Page
919

Improved synthesis of N-succinimidyl 4-[18F]fluorobenzoate and its application to the labeling of a monoclonal antibody fragment.

Our previously reported method for the 18F labeling of antibodies using N-succinimidyl 4-[18F]fluorobenzoate (SFB) involved a rather long synthesis time. Here we present an improved method for the synthesis of SFB which reduces the synthesis time by about 45 min. A reaction time of 5-8 min (versus 25 min for the original procedure) was sufficient in the fluorination step to form 4-[18F]fluorobenzaldehyde in high yield. In the original method, 30-35 min was necessary to convert 4-[18F]fluorobenzoic acid to SFB using dicyclohexylcarbodiimide and N-hydroxysuccinimide. When N,N'-disuccinimidyl carbonate was used, facile conversion of 4-fluorobenzoic acid to SFB was seen at a micromolar level. At a tracer level, no product was formed at room temperature; however, complete consumption of starting material was observed. Heating at 150 degrees C resulted in the formation of SFB in more than 80% yield in 1-3 min. HPLC purification of SFB was necessary since use of crude SFB, or SFB purified using a silica solid-phase cartridge column, resulted in lower protein coupling yields. Furthermore, use of crude SFB resulted in cross-linking and lower immunoreactivity of antibody. Largely as a result of the considerable reduction in total labeling time, these modifications have increased the amount of 18F-labeled antibody available per 100 mCi of [18F]fluoride by 30-35%.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Improved synthesis of N-succinimidyl 4-[18F]fluorobenzoate and its application to the labeling of a monoclonal antibody fragment." Bioconjug Chem 5.4 (July 1994): 352-356.
PMID
7948102
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
5
Issue
4
Publish Date
1994
Start Page
352
End Page
356

Meta-[211At]astatobenzylguanidine: further evaluation of a potential therapeutic agent.

Meta-[211At]astatobenzylguanidine ([211At]MABG) is an astatinated analogue of meta-iodobenzylguanidine (MIBG) that could be of value for therapeutic applications. The initial goal of this study was to determine whether [211At]MABG is taken up, like MIBG, by a specific uptake-I mechanism. Norepinephrine and desipramine (DMI) decreased [211At]MABG uptake in SK-N-SH human neuroblastoma cells. This uptake was found to be energy-dependent: In mice, pre-treatment with DMI reduced uptake of [211At]MABG at 1 hr post-injection in the adrenal and in the heart. Tetrabenazine at a dose of 40 mg/kg reduced uptake of [211At]MABG in the mouse heart in vivo (69% of control) whereas up to 100 microM of tetrabenazine did not affect the in vitro uptake of [211At]MABG in SK-N-SH cells. In SK-N-SH cells, 53% and 38%, respectively, of the initial uptake of [211At]MABG was retained at 4 hr and 6 hr. For no-carrier-added (n.c.a.) [131I]MIBG these values were similar, 60% and 48%. The ability of SK-N-SH cells to incorporate [3H]thymidine was reduced to less than 50% of control values when treated with as little as 3.2 nCi of [211At]MABG. In contrast, no significant reduction in the thymidine uptake was observed, even with 80 nCi of n.c.a. MIBG.

Authors
Vaidyanathan, G; Strickland, DK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Strickland, DK, and Zalutsky, MR. "Meta-[211At]astatobenzylguanidine: further evaluation of a potential therapeutic agent." Int J Cancer 57.6 (June 15, 1994): 908-913.
PMID
8206683
Source
pubmed
Published In
International Journal of Cancer
Volume
57
Issue
6
Publish Date
1994
Start Page
908
End Page
913

QUANTITATIVE IMAGING OF AT-211 RADIOTHERAPEUTIC AGENTS IN SMALL VOLUMES

Authors
JOHNSON, EL; TURKINGTON, TG; JASZCZAK, RJ; ZALUTSKY, MR; GILLAND, DR; VAIDYANATHAN, G; GREER, KL; COLEMAN, RE
MLA Citation
JOHNSON, EL, TURKINGTON, TG, JASZCZAK, RJ, ZALUTSKY, MR, GILLAND, DR, VAIDYANATHAN, G, GREER, KL, and COLEMAN, RE. "QUANTITATIVE IMAGING OF AT-211 RADIOTHERAPEUTIC AGENTS IN SMALL VOLUMES." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P180-P180.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P180
End Page
P180

SYNTHESIS AND PRELIMINARY EVALUATION OF 4-[F-18]FLUORO-3-IODOBENZYLGUANIDINE (FIBG) - A METAIODOBENZYLGUANIDINE ANALOG FOR PET

Authors
VAIDYANATHAN, G; AFFLECK, DJ; SLADE, SA; WELSH, PC; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, AFFLECK, DJ, SLADE, SA, WELSH, PC, and ZALUTSKY, MR. "SYNTHESIS AND PRELIMINARY EVALUATION OF 4-[F-18]FLUORO-3-IODOBENZYLGUANIDINE (FIBG) - A METAIODOBENZYLGUANIDINE ANALOG FOR PET." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P248-P248.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P248
End Page
P248

MECHANISTIC STUDIES OF METAIODOBENZYLGUANIDINE (METAIODOBENZYLGUANIDINE) UPTAKE AND RETENTION IN ISOLATED RAT-HEART

Authors
DEGRADO, TR; ZALUTSKY, MR; AFFLECK, DJ; VAIDYANATHAN, G
MLA Citation
DEGRADO, TR, ZALUTSKY, MR, AFFLECK, DJ, and VAIDYANATHAN, G. "MECHANISTIC STUDIES OF METAIODOBENZYLGUANIDINE (METAIODOBENZYLGUANIDINE) UPTAKE AND RETENTION IN ISOLATED RAT-HEART." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P57-P57.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P57
End Page
P57

Carrier-free 131I-meta-iodobenzylguanidine: comparison of production from meta-diazobenzylguanidine and from meta-trimethylsilylbenzylguanidine.

Meta-iodobenzylguanidine (MIBG) is a drug which is selectively accumulated by the uptake-1 process in adrenergic tissues. When labelled with 131I, it may be used for the targetted radiotherapy of tumours such as phaeochromocytoma and neuroblastoma. This paper describes the preparation of carrier-free 131I-MIBG by radioiodination of meta-diazobenzylguanidine, and compares this process with one involving iododesilylation of meta-trimethylsilylbenzylguanidine. Both processes result in the formation of carrier-free 131I-MIBG whose specific activity at greater than 3 x 10(16) Bq mol-1 is at least 100 times higher than that of commercially available 131I-MIBG for therapeutic use. The therapeutic use of 131I-MIBG with a higher than usual specific activity is predicted to result in a greater target-to-nontarget ratio, and therefore enhanced efficacy because of an increased therapeutic index. As the radiochemical yield of the process involving the metadiazobenzylguanidine intermediate is only 13%, compared with 98% for the iododesilylation reaction, the latter is the preferred synthetic route.

Authors
Mairs, RJ; Gaze, MN; Watson, DG; Skellern, GG; Constable, P; McKellar, K; Owens, J; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Mairs, RJ, Gaze, MN, Watson, DG, Skellern, GG, Constable, P, McKellar, K, Owens, J, Vaidyanathan, G, and Zalutsky, MR. "Carrier-free 131I-meta-iodobenzylguanidine: comparison of production from meta-diazobenzylguanidine and from meta-trimethylsilylbenzylguanidine." Nucl Med Commun 15.4 (April 1994): 268-274.
PMID
8072739
Source
pubmed
Published In
Nuclear Medicine Communications
Volume
15
Issue
4
Publish Date
1994
Start Page
268
End Page
274

Preparation and screening of an arrayed human genomic library generated with the P1 cloning system.

We describe here the construction and initial characterization of a 3-fold coverage genomic library of the human haploid genome that was prepared using the bacteriophage P1 cloning system. The cloned DNA inserts were produced by size fractionation of a Sau3AI partial digest of high molecular weight genomic DNA isolated from primary cells of human foreskin fibroblasts. The inserts were cloned into the pAd10sacBII vector and packaged in vitro into P1 phage. These were used to generate recombinant bacterial clones, each of which was picked robotically from an agar plate into a well of a 96-well microtiter dish, grown overnight, and stored at -70 degrees C. The resulting library, designated DMPC-HFF#1 series A, consists of approximately 130,000-140,000 recombinant clones that were stored in 1500 microtiter dishes. To screen the library, clones were combined in a pooling strategy and specific loci were identified by PCR analysis. On average, the library contains two or three different clones for each locus screened. To date we have identified a total of 17 clones containing the hypoxanthine-guanine phosphoribosyltransferase, human serum albumin-human alpha-fetoprotein, p53, cyclooxygenase I, human apurinic endonuclease, beta-polymerase, and DNA ligase I genes. The cloned inserts average 80 kb in size and range from 70 to 95 kb, with one 49-kb insert and one 62-kb insert.

Authors
Shepherd, NS; Pfrogner, BD; Coulby, JN; Ackerman, SL; Vaidyanathan, G; Sauer, RH; Balkenhol, TC; Sternberg, N
MLA Citation
Shepherd, NS, Pfrogner, BD, Coulby, JN, Ackerman, SL, Vaidyanathan, G, Sauer, RH, Balkenhol, TC, and Sternberg, N. "Preparation and screening of an arrayed human genomic library generated with the P1 cloning system." Proc Natl Acad Sci U S A 91.7 (March 29, 1994): 2629-2633.
PMID
8146166
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
91
Issue
7
Publish Date
1994
Start Page
2629
End Page
2633

Meta-[211At]astatobenzylguanidine: Further validation of in vitro and in vivo uptake mechanisms

Authors
Vaidyanathan, G; Strickland, DK; Affleck, DA; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Strickland, DK, Affleck, DA, Welsh, P, and Zalutsky, MR. "Meta-[211At]astatobenzylguanidine: Further validation of in vitro and in vivo uptake mechanisms." January 1, 1994.
Source
scopus
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
35
Publish Date
1994
Start Page
589
End Page
591

Monoclonal antibody F(ab')2 fragment labeled with N-succinimidyl 2,4-dimethoxy-3-halobenzoates: in vivo comparison of iodinated and astatinated fragments.

N-Succinimidyl 3-[211At]astato-2, 4-dimethoxybenzoate (SADMB) was prepared from a trialkylstannyl precursor in about 70-75% yield. With either trimethyl or tri-n-butylstannyl precursor, no temporal effect was found in the astatodestannylation yield. However, the methyl analog gave slightly better yield which was found to be not statistically significant. A monoclonal antibody (MAb) fragment, Mel-14 F(ab')2, could be labeled using SADMB in 28% coupling efficiency. The specific binding of this labeled fragment to tumor homogenates in vitro was 61.0 +/- 0.5% (62.8 +/- 0.9% for the 131I labeled fragment). Paired-label tissue distribution in normal mice showed similar uptake of 131I and 211 At in many tissues. However, by 14.5 h selectivity of spleen, lungs and stomach for Mel-14 F(ab')2 labeled with 211At compared to 131I was 4.1, 3.8 and 6.4, respectively.

Authors
Vaidyanathan, G; Affleck, D; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, D, and Zalutsky, MR. "Monoclonal antibody F(ab')2 fragment labeled with N-succinimidyl 2,4-dimethoxy-3-halobenzoates: in vivo comparison of iodinated and astatinated fragments." Nucl Med Biol 21.1 (January 1994): 105-110.
PMID
9234271
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
21
Issue
1
Publish Date
1994
Start Page
105
End Page
110

Synthesis of carrier-free 131I-meta-iodobenzyl-guanidine by novel routes to enhance therapeutic efficiency in neuroblastoma.

Authors
Gaze, MN; Mairs, RJ; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Gaze, MN, Mairs, RJ, Vaidyanathan, G, and Zalutsky, MR. "Synthesis of carrier-free 131I-meta-iodobenzyl-guanidine by novel routes to enhance therapeutic efficiency in neuroblastoma." Prog Clin Biol Res 385 (1994): 347-353.
PMID
7972229
Source
pubmed
Published In
Progress in Clinical and Biological Research
Volume
385
Publish Date
1994
Start Page
347
End Page
353

Meta-[211At]astatobenzylguanidine: Further validation of in vitro and in vivo uptake mechanisms

Authors
Vaidyanathan, G; Strickland, DK; Affleck, DA; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Strickland, DK, Affleck, DA, Welsh, P, and Zalutsky, MR. "Meta-[211At]astatobenzylguanidine: Further validation of in vitro and in vivo uptake mechanisms." Journal of Labelled Compounds and Radiopharmaceuticals 35 (1994): 589-591.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
35
Publish Date
1994
Start Page
589
End Page
591

Fluorine-18 labeled chemotactic peptide: A potential agent for the PET imaging of focal infection

Authors
Vaidyanathan, G; Affleck, DA; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DA, Welsh, P, and Zalutsky, MR. "Fluorine-18 labeled chemotactic peptide: A potential agent for the PET imaging of focal infection." Journal of Labelled Compounds and Radiopharmaceuticals 35 (1994): 365-367.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
35
Publish Date
1994
Start Page
365
End Page
367

Meta-[211At]astatobenzylguanidine: Further evaluation of a potential therapeutic agent

Meta-[211At]astatobenzylguanidine ([211At]MABG) is an astatinated analogue of meta-iodobenzylguanidine (MIBG) that could be of value for therapeutic applications. The initial goal of this study was to determine whether [211At]MABG is taken up, like MIBG, by a specific uptake-I mechanism. Norepinephrine and desipramine (DMI) decreased [211At]MABG uptake in SK-N-SH human neuroblastoma cells. This uptake was found to be energy-dependent: In mice, pre-treatment with DMI reduced uptake of [211At]MABG at 1 hr post-injection in the adrenal and in the heart. Tetrabenazine at a dose of 40 mg/kg reduced uptake of [211At]MABG in the mouse heart in vivo (69% of control) whereas up to 100 μM of tetrabenazine did not affect the in vitro uptake of [211At]MABG in SK-N-SH cells. In SK- N-SH cells, 53% and 38%, respectively, of the initial uptake of [211At]MABG was retained at 4 hr and 6 hr. For no-carrier-added (n.c.a.) [131I]MIBG these values were similar, 60% and 48%. The ability of SK-N-SH cells to incorporate [3H]thymidine was reduced to less than 50% of control values when treated with as little as 3.2 nCi of [211At]MABG. In contrast, no significant reduction in the thymidine uptake was observed, even with 80 nCi of n.c.a. MIBG.

Authors
Vaidyanathan, G; Strickland, DK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Strickland, DK, and Zalutsky, MR. "Meta-[211At]astatobenzylguanidine: Further evaluation of a potential therapeutic agent." International Journal of Cancer 57.6 (1994): 908-913.
Source
scival
Published In
International Journal of Cancer
Volume
57
Issue
6
Publish Date
1994
Start Page
908
End Page
913
DOI
10.1002/ijc.2910570622

(4-[18F]fluoro-3-iodobenzyl)guanidine, a potential mibg analogue for positron emission tomography

The aims of this investigation were to develop a no-carrier-added (nca) synthesis of (4-[18F]-fluoro-3-iodobenzyl)guanidine ([18F]FIBG) and to evaluate its potential as an MIBG analogue useful for positron emission tomography. [18F]FIBG was prepared in four steps starting from 4-cyano-2-iodo-N,N,N-trimethylanilinium trifluoromethanesulfonate in 5% decay-corrected radiochemical yield in a total synthesis time of 130 min. The specific activity was more than 1500 Ci per mmol. In vitro binding studies showed that the percent binding of [18F]FIBG to SK-N-SH human neuroblastoma cells remained constant over a 3-log activity range and was similar to that of nca [131I]MIBG. Specific and high uptake of FIBG was also seen in mouse heart and adrenals. The in vitro and in vivo properties of [18F]FIBG suggest that this compound may be a useful positron-emitting analogue of MIBG. © 1994 American Chemical Society.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "(4-[18F]fluoro-3-iodobenzyl)guanidine, a potential mibg analogue for positron emission tomography." Journal of Medicinal Chemistry 37.21 (1994): 3655-3662.
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
37
Issue
21
Publish Date
1994
Start Page
3655
End Page
3662

NO-CARRIER-ADDED 4-FLUORO-3-IODOBENZYLGUANIDINE LABELED WITH I-131 ([I-131]FIBG) AND F-18 ([F-18]FIBG - POTENTIAL MIBG ANALOGS FOR PET IMAGING AND THERAPY OF NEUROENDOCRINE TUMORS

Authors
VAIDYANATHAN, G; AFFLECK, DJ; SLADE, SA; WELSH, P; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, AFFLECK, DJ, SLADE, SA, WELSH, P, and ZALUTSKY, MR. "NO-CARRIER-ADDED 4-FLUORO-3-IODOBENZYLGUANIDINE LABELED WITH I-131 ([I-131]FIBG) AND F-18 ([F-18]FIBG - POTENTIAL MIBG ANALOGS FOR PET IMAGING AND THERAPY OF NEUROENDOCRINE TUMORS." 1994.
Source
wos-lite
Published In
PROCEEDINGS OF THE XVI INTERNATIONAL CANCER CONGRESS - FREE PAPERS AND POSTERS, TOMES 1-4
Publish Date
1994
Start Page
3013
End Page
3017

UPTAKE MECHANISMS OF I-123 METAIODOBENZYLGUANIDINE (METAIODOBENZYLGUANIDINE) IN ISOLATED RAT-HEART

Authors
DEGRADO, TR; ZALUTSKY, MR; AFFLECK, DJ; VAIDYANATHAN, G
MLA Citation
DEGRADO, TR, ZALUTSKY, MR, AFFLECK, DJ, and VAIDYANATHAN, G. "UPTAKE MECHANISMS OF I-123 METAIODOBENZYLGUANIDINE (METAIODOBENZYLGUANIDINE) IN ISOLATED RAT-HEART." CIRCULATION 88.4 (October 1993): 355-355.
Source
wos-lite
Published In
Circulation
Volume
88
Issue
4
Publish Date
1993
Start Page
355
End Page
355

Measuring astatine-211 distributions with SPECT.

We have investigated standard SPECT techniques (rotating gamma cameras, multi-hole collimators, and filtered backprojection reconstruction) for imaging astatine-211 distributions. Since 211At emits alpha particles, this nuclide has potential for use in radiotherapy. The capability of imaging this nuclide would allow in vivo evaluation of the distribution and stability of potential 211At-labelled radiotherapeutic agents. 211At decay yields x-rays in the 77-92 keV range in addition to 500-900 keV gamma rays. This study evaluates the feasibility of SPECT imaging using the x-ray emissions of 211At. We have evaluated several collimators, with the determination that the medium-energy collimators we used are suitable, with 7% penetration (uncollimated counts versus collimated counts). Several phantoms were imaged and attenuation coefficients were measured (narrow-beam mu = 0.182 cm-1 for 77-80 keV x-rays in water). Reconstructed images demonstrate qualitative capabilities and a simple quantitative study demonstrates good correction for attenuation and scatter (approximately 10% error), at low count densities, at least for the phantom geometries used in this study.

Authors
Turkington, TG; Zalutsky, MR; Jaszczak, RJ; Garg, PK; Vaidyanathan, G; Coleman, RE
MLA Citation
Turkington, TG, Zalutsky, MR, Jaszczak, RJ, Garg, PK, Vaidyanathan, G, and Coleman, RE. "Measuring astatine-211 distributions with SPECT." Phys Med Biol 38.8 (August 1993): 1121-1130.
PMID
8367523
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
38
Issue
8
Publish Date
1993
Start Page
1121
End Page
1130

MEASURING ASTATINE-211 DISTRIBUTIONS WITH SPECT

Authors
TURKINGTON, TG; ZALUTSKY, MR; JASZCZAK, RJ; GARG, P; VAIDYANATHAN, G; COLEMAN, RE
MLA Citation
TURKINGTON, TG, ZALUTSKY, MR, JASZCZAK, RJ, GARG, P, VAIDYANATHAN, G, and COLEMAN, RE. "MEASURING ASTATINE-211 DISTRIBUTIONS WITH SPECT." JOURNAL OF NUCLEAR MEDICINE 34.5 (May 1993): P191-P191.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
34
Issue
5
Publish Date
1993
Start Page
P191
End Page
P191

INVITRO CYTOTOXICITY OF M-[AT-211]ASTATOBENZYLGUANIDINE (MABG)

Authors
VAIDYANATHAN, G; HARRISON, C; WELSH, P; AFFLECK, D; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, HARRISON, C, WELSH, P, AFFLECK, D, and ZALUTSKY, MR. "INVITRO CYTOTOXICITY OF M-[AT-211]ASTATOBENZYLGUANIDINE (MABG)." JOURNAL OF NUCLEAR MEDICINE 34.5 (May 1993): P218-P218.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
34
Issue
5
Publish Date
1993
Start Page
P218
End Page
P218

No-carrier-added synthesis of meta-[131I]iodobenzylguanidine.

No-carrier-added meta-[131I]iodobenzylguanidine ([131I]MIBG) was prepared starting with two different metallated precursors. Attempted preparation of 3-(tri-n-butylstannyl)benzylguanidine was not successful. An alternate two-step strategy using 3-(tri-n-butylstannyl)benzylamine could be used to prepare radio-iodinated [131I]MIBG in an overall radiochemical yield of 30-33%. Synthesis of [131I]MIBG via the radioiododesilylation of 3-trimethylsilylbenzylguanidine was also investigated. Yields were dependent on temperature, precursor concentration, solvent and nature of the oxidant. Radiochemical yields of 90% were obtained in 5 min at room temperature using either N-chlorosuccinimide or hydrogen peroxide in trifluoroacetic acid as oxidants. The percentage of specific binding in vitro of no-carrier-added MIBG to SK-N-SH neuroblastoma cells remained constant over a 2 log activity range, while the binding of MIBG prepared by isotopic exchange dropped by a factor of seven. In normal mice, heart and adrenal uptake of no-carrier-added [131I]MIBG was found to be higher than that of [131I]MIBG prepared by isotopic exchange.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "No-carrier-added synthesis of meta-[131I]iodobenzylguanidine." Appl Radiat Isot 44.3 (March 1993): 621-628.
PMID
8472027
Source
pubmed
Published In
Applied Radiation and Isotopes
Volume
44
Issue
3
Publish Date
1993
Start Page
621
End Page
628

Radioiodination of proteins using N-succinimidyl 4-hydroxy-3-iodobenzoate.

N-Succinimidyl 4-hydroxy-3-[131I]iodobenzoate ([131I]SHIB) was synthesized from 4-hydroxybenzoic acid in two steps. The overall radiochemical yield was 40-56%. A monoclonal antibody (mAb) was labeled in 10-15% yield by reaction with [131I]SHIB. The specific binding of [131I]SHIB mAb to tumor homogenates in vivo was 78 +/- 3%, compared to 84 +/- 3% for the same mAb labeled using N-succinimidyl 3-[125I]iodobenzoate ([125I]SIB). Paired-label studies in normal mice demonstrated similar tissue distributions of 131I and 125I except in thyroid. In thyroid, uptake of the two isotopes was similar on day 1; however, 131I levels increased gradually to 2-3 times those of 125I by day 6. Our results indicate that loss of label in vivo from mAbs labeled using SHIB is somewhat higher than seen with SIB but significantly lower than that observed when direct iodination methods are used.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "Radioiodination of proteins using N-succinimidyl 4-hydroxy-3-iodobenzoate." Bioconjug Chem 4.1 (January 1993): 78-84.
PMID
8431515
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
4
Issue
1
Publish Date
1993
Start Page
78
End Page
84

1-(m-[211At]astatobenzyl)guanidine: synthesis via astato demetalation and preliminary in vitro and in vivo evaluation.

No-carrier-added 1-(m-[211At]astatobenzyl)guanidine ([211At]MABG) was synthesized by astato demetalation using two different routes. The overall yield for the two-step approach from 3-(tri-n-butylstannyl)benzylamine was 13%. N-Chlorosuccinimide-mediated astato desilylation of 1-[3-(trimethylsilyl)benzyl]guanidine in acetic acid gave poor yields. In trifluoroacetic acid, the reaction worked well. The radiochemical yield was independent of reaction time and the amount of precursor used; however, the temperature of the reaction had a marked effect. Yields of 85% were obtained in 5 min at 70 degrees C using 0.5 mumol of the precursor. The percentage specific binding in vitro of [211At]MABG was nearly constant over a 2-log activity range and was comparable to that of no-carrier-added [131]MIBG. The accumulation of [211At]MABG in the heart and adrenals of normal mice was similar to that observed for no-carrier-added [131]MIBG.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "1-(m-[211At]astatobenzyl)guanidine: synthesis via astato demetalation and preliminary in vitro and in vivo evaluation." Bioconjug Chem 3.6 (November 1992): 499-503.
PMID
1463779
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
3
Issue
6
Publish Date
1992
Start Page
499
End Page
503

Fluorine-18-labeled monoclonal antibody fragments: a potential approach for combining radioimmunoscintigraphy and positron emission tomography.

Monoclonal antibody fragments labeled with 18F could be useful for PET if selective tumor uptake could be achieved within a few half-lives of this nuclide. To evaluate this possibility, the F(ab')2 fragment of Mel-14, an antibody reactive with gliomas and other tumors, was labeled by reaction with N-succinimidyl-4-[18F]fluorobenzoate. The in-vitro binding properties of 18F-labeled Mel-14 F(ab')2 were nearly identical to those observed when this F(ab')2 was labeled by reaction with N-succinimidyl-4-[125I]iodobenzoate (18F, affinity constant = (6.7 +/- 1.1) x 10(8) M-1; 125I, affinity constant = (8.8 +/- 0.6) x 10(8) M-1). The tissue distribution of the two labeled fragments was compared in paired-label studies performed in athymic mice with subcutaneous D-54 MG human glioma xenografts. Uptake of both nuclides in tumor was rapid with levels as high as 18.7% +/- 1.1% injected dose/g for 18F and 19.4% +/- 1.0% injected dose/g for 125I observed by 4 hr after injection. Tumor-to-normal tissue ratios for 18F-labeled Mel-14 F(ab')2 at 4 hr ranged between 0.8:1 for kidneys to 40:1 for brain. These results suggest that it may be feasible to use 18F-labeled antibody fragments for imaging tumors with PET.

Authors
Vaidyanathan, G; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Bigner, DD, and Zalutsky, MR. "Fluorine-18-labeled monoclonal antibody fragments: a potential approach for combining radioimmunoscintigraphy and positron emission tomography." J Nucl Med 33.8 (August 1992): 1535-1541.
PMID
1634947
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
33
Issue
8
Publish Date
1992
Start Page
1535
End Page
1541

Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate.

Two methods were investigated for the no-carrier-added synthesis of N-succinimidyl 4-[18F]fluorobenzoate (S[18F]FB). The first, an attempted nucleophilic aromatic substitution by [18F]fluoride on N-succinimidyl 4-nitrobenzoate was unsuccessful. The second method involved three steps; [18F]fluoride for trimethylammonium substitution on 4-formyl-N,N,N-trimethylanilinium triflate, oxidation to 4-[18F]fluorobenzoic acid, followed by reaction with N-hydroxysuccinimide and dicyclohexylcarbodiimide to form S[18F]FB. Total synthesis and purification time was 100 min and the overall radiochemical yield was 25% (decay corrected). A monoclonal antibody F(ab')2 fragment could be labeled in 40-60% yield by reaction with S[18F]FB for 15-20 min. The tissue distribution in normal mice and in vitro tumor binding of the antibody F(ab')2 labeled by reaction with S[18F]FB were comparable to those observed for the fragment after radioiodination using N-succinimidyl 4-[125I]iodobenzoate.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate." Int J Rad Appl Instrum B 19.3 (April 1992): 275-281.
PMID
1629016
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
19
Issue
3
Publish Date
1992
Start Page
275
End Page
281

1-(m-[211At]astatobenzyl)guanidine: Synthesis via astato demetalation and preliminary in vitro and in vivo evaluation

No-carrier-added 1-(m-[211At]astatobenzyl)guanidine ([211At]MABG) was synthesized by astato demetalation using two different routes. The overall yield for the two-step approach from 3-(tri-n-butylstannyl)benzylamine was 13%. N-Chlorosuccinimide-mediated astato desilylation of 1-[3-(trimethylsilyl)benzyl]guanidine in acetic acid gave poor yields. In trifluoroacetic acid, the reaction worked well. The radiochemical yield was independent of reaction time and the amount of precursor used; however, the temperature of the reaction had a marked effect. Yields of 85% were obtained in 5 min at 70°C using 0.5 μmol of the precursor. The percentage specific binding in vitro of [211At]MABG was nearly constant over a 2-log activity range and was comparable to that of no-carrier-added [131I]MIBG. The accumulation of [211At]MABG in the heart and adrenals of normal mice was similar to that observed for no-carrier-added [131I]MIBG. © 1992 American Chemical Society.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "1-(m-[211At]astatobenzyl)guanidine: Synthesis via astato demetalation and preliminary in vitro and in vivo evaluation." Bioconjugate Chemistry 3.6 (1992): 499-503.
Source
scival
Published In
Bioconjugate Chemistry
Volume
3
Issue
6
Publish Date
1992
Start Page
499
End Page
503

Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate

Two methods were investigated for the no-carrier-added synthesis of N-succinimidyl 4-[18F]fluorobenzoate (S[18F]FB). The first, an attempted nucleophilic aromatic substitution by [18F]fluoride on N-succinimidyl 4-nitrobenzoate was unsuccessful. The second method involved three steps; [18F]fluoride for trimethylammonium substitution on 4-formyl-N,N,N-trimethylanilinium triflate, oxidation to 4-[18F]fluorobenzoic acid, followed by reaction with N-hydroxysuccinimide and dicyclohexylcarbodiimide to form S[18F]FB. Total synthesis and purification time was 100 min and the overall radiochemical yield was 25% (decay corrected). A monoclonal antibody F(ab')2 fragment could be labeled in 40-60% yield by reaction with S[18F]FB for 15-20 min. The tissue distribution in normal mice and in vitro tumor binding of the antibody F(ab')2 labeled by reaction with S[18F]FB were comparable to those observed for the fragment after radioiodination using N-succinimidyl 4-[125I]iodobenzoate.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate." Nuclear Medicine and Biology 19.3 (1992): 275-281.
Source
scival
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
19
Issue
3
Publish Date
1992
Start Page
275
End Page
281
DOI
10.1016/0883-2897(92)90111-B

1-(M-[AT-211]ASTATOBENZYL)GUANIDINE - SYNTHESIS VIA ASTATO DEMETALATION AND PRELIMINARY INVITRO AND INVIVO EVALUATION

Authors
VAIDYANATHAN, G; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, and ZALUTSKY, MR. "1-(M-[AT-211]ASTATOBENZYL)GUANIDINE - SYNTHESIS VIA ASTATO DEMETALATION AND PRELIMINARY INVITRO AND INVIVO EVALUATION." BIOCONJUGATE CHEMISTRY 3.6 (1992): 499-503.
Source
wos-lite
Published In
Bioconjugate Chemistry
Volume
3
Issue
6
Publish Date
1992
Start Page
499
End Page
503
DOI
10.1021/bc00018a006

Aromatic acylation reagents for use in the radioiodination of proteins

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "Aromatic acylation reagents for use in the radioiodination of proteins." Journal of Labelled Compounds and Radiopharmaceuticals 30 (1991): 209-210.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
30
Publish Date
1991
Start Page
209
End Page
210

Scintigraphic evaluation of the ocular disposition of 18F-imirestat in rabbits.

Authors
Vaidyanathan, G; Jay, M; Bera, RK; Mayer, PR; Brazzell, RK
MLA Citation
Vaidyanathan, G, Jay, M, Bera, RK, Mayer, PR, and Brazzell, RK. "Scintigraphic evaluation of the ocular disposition of 18F-imirestat in rabbits." Pharm Res 7.11 (November 1990): 1198-1200.
PMID
2127314
Source
pubmed
Published In
Pharmaceutical Research
Volume
7
Issue
11
Publish Date
1990
Start Page
1198
End Page
1200

Radioiodination of antibodies via N-succinimidyl 2,4-dimethoxy-3-(trialkylstannyl)benzoates.

We have previously shown that use of N-succinimidyl 3-iodobenzoate (SIB) for radioiodination of monoclonal antibodies (MAbs) decreases the loss of radioiodine in vivo compared to MAbs labeled by using conventional methods. Herein, the synthesis of N-succinimidyl 2,4-dimethoxy-3-(trialkylstannyl)benzoates (alkyl = Me, Bu) are described as is their use as precursors for the radiosynthesis of N-succinimidyl 2,4-dimethoxy-3-iodobenzoate (SDMIB). A MAb F(ab')2 fragment labeled with SDMIB retained its ability to bind specifically to tumor homogenates. Paired-label tissue distribution studies indicate that the thyroid uptake (an indicator of deiodination) of hydrolyzed SDMIB was about 20 times that of hydrolyzed SIB. In contrast, thyroid uptake for SDMIB, when conjugated to a MAb, was only 1.4-2.8 times that for SIB and was considerably lower than levels reported in the literature for MAbs labeled by using direct, electrophilic iodination methods. Although MAbs labeled with SDMIB are significantly more inert to dehalogenation than those labeled by conventional methods, compared to the original SIB reagent, addition of two methoxy groups decreased retention of label in vivo.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Radioiodination of antibodies via N-succinimidyl 2,4-dimethoxy-3-(trialkylstannyl)benzoates." Bioconjug Chem 1.6 (November 1990): 387-393.
PMID
2099187
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
1
Issue
6
Publish Date
1990
Start Page
387
End Page
393

Protein radiohalogenation: observations on the design of N-succinimidyl ester acylation agents.

In previous studies we have demonstrated that antibodies radioiodinated with N-succinimidyl 3-iodobenzoate (SIB) are less susceptible to loss of radioiodine in vivo than antibodies iodinated directly by electrophilic substitution on their tyrosine residues with Iodogen. Since the Bolton-Hunter reagent, N-succinimidyl 3-(4-hydroxy-3-iodophenyl)propionate, is identical with SIB except that it contains a hydroxyl group on the aromatic ring and a two-methylene spacer, a comparison of their coupling chemistry and in vivo behavior was performed to better understand the structural requirements for a useful iodinated acylation agent. Protein concentration and pH had a significant effect on the coupling efficiency of both SIB and the Bolton-Hunter reagent; however, protein-labeling yields with SIB were generally higher by a factor of 2. Paired-label biodistribution studies in mice demonstrated that thyroid uptake (a monitor of dehalogenation) of antibody labeled by the Bolton-Hunter method was twice that of antibody labeled with SIB but only 7% of that observed for antibody labeled with Iodogen. These results suggest that even minor differences in iodination site can profoundly alter the retention of label on a protein in vivo.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Protein radiohalogenation: observations on the design of N-succinimidyl ester acylation agents." Bioconjug Chem 1.4 (July 1990): 269-273.
PMID
2096920
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
1
Issue
4
Publish Date
1990
Start Page
269
End Page
273

RADIOIODINATION AND ASTATINATION OF MONOCLONAL-ANTIBODIES

Authors
GARG, PK; VAIDYANATHAN, G; GARG, S; ZALUTSKY, MR
MLA Citation
GARG, PK, VAIDYANATHAN, G, GARG, S, and ZALUTSKY, MR. "RADIOIODINATION AND ASTATINATION OF MONOCLONAL-ANTIBODIES." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 199 (April 22, 1990): 16-NUCL.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
199
Publish Date
1990
Start Page
16
End Page
NUCL

Reaction of cyclopropanamines with hypochlorite

Ethylene was formed in 65% yield when 1-(1-piperidino)cyclopropanol, 6, was treated with hypochlorite. This observation raised the possibility that 1-aminocyclopropanecarboxylic acids (ACCs) could yield ethylene by a mechanism that involves (1) decarboxylation to a 1-aminocyclopropanol, followed by (2) a fragmentation of the carbinolamine to ethylene induced by a hypochlorite equivalent. Although this mechanism could be ruled out only for 1e, no evidence could be found for it in the reactions of other ACCs, 1a-f, with hypochlorite. The fact that 1b-cis-2,3-d2 yielded only ethylene-cis-1,2-d2 is consistent with either the mechanism described above or a nitrenium ion mechanism. In the reaction of cyclopropanamines with neutral hypochlorite, ethylene is not the major product. From the primary and secondary amino acids 1a-c, a 3-hydroxypropanenitrile or propanamide, 2a-c, probably the product of a nucleophilic ring-opening step followed by decarboxylation, is formed. Similar products are formed from other cyclopropanamines: 2a from 1g, 2d from 1h, 2e and 2f from 1i, and lactone 5 from 1j. © 1989 American Chemical Society.

Authors
Vaidyanathan, G; Wilson, JW
MLA Citation
Vaidyanathan, G, and Wilson, JW. "Reaction of cyclopropanamines with hypochlorite." Journal of Organic Chemistry 54.8 (1989): 1815-1820.
Source
scival
Published In
The Journal of Organic Chemistry
Volume
54
Issue
8
Publish Date
1989
Start Page
1815
End Page
1820

Decarboxylation of 1-aminocyclopropanecarboxylic acid and its derivatives

The question of whether the title compounds could be decarboxylated to cyclopropanone derivatives was answered in the affirmative by the following observations. (1) Compound 11a was decarboxylated by 1,2,3-indantrione in acetonitrile, benzene, or methanol. The initially formed intermediate could be trapped by N-phenylmaleimide (to form 3), by diethyl azodicarboxylate (to form an unstable adduct), by ninhydrin itself (to form 5) or by a proton (in methanol, to form 8). (2) Compound 11d was decarboxylated by phenylbis(trifluoroacetato-O)iodine to yield carbinolamine 12d. cis-2,3-Dideuterio-11d yielded cis-2,3-dideuterio-12d under the same conditions. (3) ACC was decarboxylated by phenanthroquinone to yield oxazole 9, probably by way of oxazoline 10. © 1989 American Chemical Society.

Authors
Vaidyanathan, G; Wilson, JW
MLA Citation
Vaidyanathan, G, and Wilson, JW. "Decarboxylation of 1-aminocyclopropanecarboxylic acid and its derivatives." Journal of Organic Chemistry 54.8 (1989): 1810-1815.
Source
scival
Published In
The Journal of Organic Chemistry
Volume
54
Issue
8
Publish Date
1989
Start Page
1810
End Page
1815
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