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Chitneni, Satish K.

Positions:

Assistant Professor of Radiology

Radiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2007

Ph.D. — Katholieke Universiteit Leuven (Belgium)

Grants:

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

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

EGFRvIII-targeted Bispecific T cell Engagers for brain tumors

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Research Associate
Start Date
September 30, 2013
End Date
May 31, 2018

Novel Approach to Quantify Nicotinic Receptor Upregulation in Smokers

Administered By
Psychiatry & Behavioral Sciences, Addictions
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2014
End Date
August 31, 2017

Imaging IDH1 Mutations in Glioma and Other Malignancies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2014
End Date
December 31, 2016
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Publications:

Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs.

Malignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET).A small library of nonradioactive analogs were designed and synthesized based on the chemical structure of reported butyl-phenyl sulfonamide inhibitors of mutant IDH1. Enzyme inhibition assays were conducted using purified mutant IDH1 enzyme, IDH1-R132H, to determine the IC50 and the maximal inhibitory efficiency of the synthesized compounds. Selected compounds, 1 and 4, were labeled with radioiodine ((125)I) and/or (18)F using bromo- and phenol precursors, respectively. In vivo behavior of the labeled inhibitors was studied by conducting tissue distribution studies with [(125)I]1 in normal mice. Cell uptake studies were conducted using an isogenic astrocytoma cell line that carried a native IDH1-R132H mutation to evaluate the potential uptake of the labeled inhibitors in IDH1-mutated tumor cells.Enzyme inhibition assays showed good inhibitory potency for compounds that have iodine or a fluoroethoxy substituent at the ortho position of the phenyl ring in compounds 1 and 4 with IC50 values of 1.7 μM and 2.3 μM, respectively. Compounds 1 and 4 inhibited mutant IDH1 activity and decreased the production of 2-HG in an IDH1-mutated astrocytoma cell line. Radiolabeling of 1 and 4 was achieved with an average radiochemical yield of 56.6 ± 20.1% for [(125)I]1 (n = 4) and 67.5 ± 6.6% for [(18)F]4 (n = 3). [(125)I]1 exhibited favorable biodistribution characteristics in normal mice, with rapid clearance from the blood and elimination via the hepatobiliary system by 4 h after injection. The uptake of [(125)I]1 in tumor cells positive for IDH1-R132H was significantly higher compared to isogenic WT-IDH1 controls, with a maximal uptake ratio of 1.67 at 3 h post injection. Co-incubation of the labeled inhibitors with the corresponding nonradioactive analogs, and decreasing the normal concentrations of FBS (10%) in the incubation media substantially increased the uptake of the labeled inhibitors in both the IDH1-mutant and WT-IDH1 tumor cell lines, suggesting significant non-specific binding of the synthesized labeled butyl-phenyl sulfonamide inhibitors.These data demonstrate the feasibility of developing radiolabeled probes for the mutant IDH1 enzyme based on enzyme inhibitors. Further optimization of the labeled inhibitors by modifying the chemical structure to decrease the lipophilicity and to increase potency may yield compounds with improved characteristics as probes for imaging mutant IDH1 expression in tumors.

Authors
Chitneni, SK; Reitman, ZJ; Gooden, DM; Yan, H; Zalutsky, MR
MLA Citation
Chitneni, SK, Reitman, ZJ, Gooden, DM, Yan, H, and Zalutsky, MR. "Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs." European journal of medicinal chemistry 119 (August 2016): 218-230.
Website
http://hdl.handle.net/10161/12001
PMID
27163884
Source
epmc
Published In
European Journal of Medicinal Chemistry
Volume
119
Publish Date
2016
Start Page
218
End Page
230
DOI
10.1016/j.ejmech.2016.04.066

IDH1 Mutations in Glioma: Considerations for Radiotracer Development.

Authors
Chitneni, SK
MLA Citation
Chitneni, SK. "IDH1 Mutations in Glioma: Considerations for Radiotracer Development." SM radiology journal 2.1 (January 2016).
Website
http://hdl.handle.net/10161/12002
PMID
27158682
Source
epmc
Published In
SM radiology journal
Volume
2
Issue
1
Publish Date
2016

Reply: Pharmacokinetic and Pharmacodynamic Modifiers of EF5 Uptake and Binding.

Authors
Chitneni, SK; Bida, GT; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Zalutsky, MR, and Dewhirst, MW. "Reply: Pharmacokinetic and Pharmacodynamic Modifiers of EF5 Uptake and Binding." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 56.4 (April 2015): 653-654. (Letter)
PMID
25745087
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
56
Issue
4
Publish Date
2015
Start Page
653
End Page
654
DOI
10.2967/jnumed.115.154054

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

Copper signaling axis as a target for prostate cancer therapeutics.

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.

Authors
Safi, R; Nelson, ER; Chitneni, SK; Franz, KJ; George, DJ; Zalutsky, MR; McDonnell, DP
MLA Citation
Safi, R, Nelson, ER, Chitneni, SK, Franz, KJ, George, DJ, Zalutsky, MR, and McDonnell, DP. "Copper signaling axis as a target for prostate cancer therapeutics." Cancer research 74.20 (October 2014): 5819-5831.
Website
http://hdl.handle.net/10161/9192
PMID
25320179
Source
epmc
Published In
Cancer Research
Volume
74
Issue
20
Publish Date
2014
Start Page
5819
End Page
5831
DOI
10.1158/0008-5472.can-13-3527

Comparison of the Hypoxia PET Tracer (18)F-EF5 to Immunohistochemical Marker EF5 in 3 Different Human Tumor Xenograft Models.

The availability of (18)F-labeled and unlabeled 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) allows for a comparative assessment of tumor hypoxia by PET and immunohistochemistry; however, the combined use of these 2 approaches has not been fully assessed in vivo. The aim of this study was to evaluate (18)F-EF5 tumor uptake versus EF5 binding and hypoxia as determined from immunohistochemistry at both macroscopic and microregional levels.Three tumor models-PC3, HCT116, and H460-were evaluated. Tumor-bearing animals were coinjected with (18)F-EF5 and EF5 (30 mg/kg), and PET imaging was performed at 2.5 h after injection. After PET imaging and 2 min after Hoechst 33342 injection, the tumors were excised and evaluated for (18)F-EF5 distribution by autoradiography and EF5 binding by immunohistochemistry. Additionally, the effects of nonradioactive EF5 (30 mg/kg) on the hypoxia-imaging characteristics of (18)F-EF5 were evaluated by comparing the PET data for H460 tumors with those from animals injected with (18)F-EF5 alone.The uptake of (18)F-EF5 in hypoxic tumor regions and the spatial relationship between (18)F-EF5 uptake and EF5 binding varied among tumors. H460 tumors showed higher tumor-to-muscle contrast in PET imaging; however, the distribution and uptake of the tracer was less specific for hypoxia in H460 than in HCT116 and PC3 tumors. Correlation analyses revealed that the highest spatial correlation between (18)F-EF5 uptake and EF5 binding was in PC3 tumors (r = 0.73 ± 0.02) followed by HCT116 (r = 0.60 ± 0.06) and H460 (r = 0.53 ± 0.10). Uptake and binding of (18)F-EF5 and EF5 correlated negatively with Hoechst 33342 perfusion marker distribution in the 3 tumor models. Image contrast and heterogeneous uptake of (18)F-EF5 in H460 tumors was significantly higher when the radiotracer was used alone versus in combination with unlabeled EF5 (tumor-to-muscle ratio of 2.51 ± 0.33 vs. 1.71 ± 0.17, P < 0.001).The uptake and hypoxia selectivity of (18)F-EF5 varied among tumor models when animals also received nonradioactive EF5. Combined use of radioactive and nonradioactive EF5 for independent assessment of tumor hypoxia by PET and immunohistochemistry methods is promising; however, the EF5 drug concentrations that are required for immunohistochemistry assays may affect the uptake of (18)F-EF5 in hypoxic cells in certain tumor types as observed in H460 in this study.

Authors
Chitneni, SK; Bida, GT; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Zalutsky, MR, and Dewhirst, MW. "Comparison of the Hypoxia PET Tracer (18)F-EF5 to Immunohistochemical Marker EF5 in 3 Different Human Tumor Xenograft Models." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 55.7 (July 2014): 1192-1197.
PMID
24854792
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
55
Issue
7
Publish Date
2014
Start Page
1192
End Page
1197
DOI
10.2967/jnumed.114.137448

Radioiodinated AGI-5198 for in vivo imaging of isocitrate dehydrogenase 1 (IDH1) mutation in gliomas

Authors
Chitneni, S; Reitman, Z; Yan, H; Zalutsky, M
MLA Citation
Chitneni, S, Reitman, Z, Yan, H, and Zalutsky, M. "Radioiodinated AGI-5198 for in vivo imaging of isocitrate dehydrogenase 1 (IDH1) mutation in gliomas." May 2014.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
55
Publish Date
2014

Development and biological evaluation of ⁹⁹mTc-sulfonamide derivatives for in vivo visualization of CA IX as surrogate tumor hypoxia markers.

In vivo visualization of tumor hypoxia related markers, such as the endogenous transmembrane protein CA IX may lead to novel therapeutic and diagnostic applications in the management of solid tumors. In this study 4-(2-aminoethyl)benzene sulfonamide (AEBS, K(i) = 33 nM for CA IX) has been conjugated with bis(aminoethanethiol) (BAT) and mercaptoacetyldiglycine (MAG2) tetradendate ligands and the conjugates radiolabelled with (99m)Tc, to obtain anionic and neutral (99m)Tc-labeled sulfonamide derivatives, respectively. The corresponding rhenium analogues were also prepared and showed good inhibitory activities against hCA IX (K(i) = 59-66 nM). In addition, a second generation bis AEBS was conjugated with MAG2 and labeled with (99m)Tc, and the obtained diastereomers were also evaluated in targeting CA IX. Biodistribution studies in mice bearing HT-29 colorectal xenografts revealed a maximum tumor uptake of <0.5% ID/g at 0.5 h p.i for all the tracers. In vivo radiometabolite analysis indicated that at 1 h p.i. MAG₂ tetradendate ligands were more stable in plasma (>50% intact) compared to the neutral complex (28% intact). This preliminary data suggest that negatively charged (99m)Tc-labeled sulfonamide derivatives with modest lipophilicity and longer circulation time could be promising markers to target CA IX.

Authors
Akurathi, V; Dubois, L; Celen, S; Lieuwes, NG; Chitneni, SK; Cleynhens, BJ; Innocenti, A; Supuran, CT; Verbruggen, AM; Lambin, P; Bormans, GM
MLA Citation
Akurathi, V, Dubois, L, Celen, S, Lieuwes, NG, Chitneni, SK, Cleynhens, BJ, Innocenti, A, Supuran, CT, Verbruggen, AM, Lambin, P, and Bormans, GM. "Development and biological evaluation of ⁹⁹mTc-sulfonamide derivatives for in vivo visualization of CA IX as surrogate tumor hypoxia markers." Eur J Med Chem 71 (January 2014): 374-384.
PMID
24378650
Source
pubmed
Published In
European Journal of Medicinal Chemistry
Volume
71
Publish Date
2014
Start Page
374
End Page
384
DOI
10.1016/j.ejmech.2013.10.027

18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model.

UNLABELLED: Hypoxia is a significant therapeutic problem for solid tumors because hypoxic cells are treatment-resistant and more aggressive. Hypoxia-activated prodrugs such as SN30000 use a mechanism of activation in hypoxic cells similar to that of 2-nitroimidazole hypoxia PET tracers. Therefore, we have evaluated the usefulness of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-(18)F-pentafluoropropyl)-acetamide ((18)F-EF5) PET to monitor and predict tumor response to SN30000 plus radiation treatment (RT). METHODS: Human non-small cell lung cancer xenografts (H460) in athymic rats were imaged with (18)F-EF5 PET before and after treatment with SN30000 (90 mg/kg), with or without 15-Gy RT. The feasibility of imaging early changes in hypoxia in response to SN30000 was examined 24 h after treatment, followed by ex vivo γ-counting and immunohistochemical examination to study drug-induced apoptosis. Subsequently, the therapeutic effects of SN30000 with or without RT were evaluated in tumor growth delay studies and compared with early treatment-induced changes observed by (18)F-EF5 PET. Changes in tumor hemoglobin oxygen saturation as a function of time after treatment measured by optical spectroscopy were compared with PET data. RESULTS: The uptake of (18)F-EF5 was significantly lower in SN30000-treated tumors than in saline controls 24 h after treatment (mean standardized uptake value, 0.44 ± 0.08 vs. 0.56 ± 0.08 for control group; P < 0.05). Apoptosis was significantly higher in SN30000-treated tumors than in controls. Early treatment-induced changes in (18)F-EF5 uptake were indicative of tumor response in growth delay studies at the group level. SN30000 plus RT significantly decreased (18)F-EF5 uptake relative to baseline and resulted in complete tumor remission in 5 of 7 animals. SN30000 alone decreased (18)F-EF5 uptake, generally in tumors with high initial standardized uptake values, and showed a minor tumor growth delay effect. The changes induced by SN30000 with or without RT in (18)F-EF5 uptake correlated with baseline hypoxia levels. RT caused significant increases in tumor oxygen concentration and hemoglobin oxygen saturation. CONCLUSION: A hypoxia PET imaging agent can measure changes in tumor hypoxic fraction in response to SN30000. These results suggest the utility of (18)F-EF5 PET for monitoring early response to tumor treatment with SN30000 plus RT in the clinical development of this novel hypoxia-activated prodrug.

Authors
Chitneni, SK; Bida, GT; Yuan, H; Palmer, GM; Hay, MP; Melcher, T; Wilson, WR; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Yuan, H, Palmer, GM, Hay, MP, Melcher, T, Wilson, WR, Zalutsky, MR, and Dewhirst, MW. "18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model." J Nucl Med 54.8 (August 2013): 1339-1346.
PMID
23740105
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
54
Issue
8
Publish Date
2013
Start Page
1339
End Page
1346
DOI
10.2967/jnumed.112.116293

Preliminary validation of varicella zoster virus thymidine kinase as a novel reporter gene for PET.

INTRODUCTION: Imaging of gene expression with positron emission tomography (PET) has emerged as a powerful tool for biomedical research during the last decade. The prototypical herpes simplex virus type 1 thymidine kinase (HSV1-TK) PET reporter gene (PRG) is widely used and many other PRGs have also been validated. We investigated varicella zoster virus thymidine kinase (VZV-tk) as new PRG with radiolabeled bicyclic nucleoside analogues (BCNAs) as PET tracers. METHODS: The uptake and washout of four different radiolabeled BCNAs was evaluated in cells expressing VZV-tk after lentiviral vector (LV) transduction and in control cells. Metabolism of the tracers was assayed by high pressure liquid chromatography (HPLC). Mice bearing VZV-TK expressing xenografts were imaged with PET. RESULTS: High uptake in VZV-tk expressing cells was seen for 3 of the 4 tracers tested. The uptake of the tracers could be blocked by the presence of excess thymidine in the incubation solution. Cellular retention was variable, with one tracer showing an acceptable half-life of ~1 hour. The amount of intracellular tracer correlated with the titer of LV used to transduce the cells. VZV-TK dependent conversion into metabolites was shown by HPLC. No specific accumulation was observed in cells expressing a fusion protein containing an HSV1-TK moiety. VZV-tk expression in xenografts resulted in a 60% increase in uptake in vivo as measured with PET. CONCLUSIONS: We have validated the combination of VZV-tk and radiolabeled BCNAs as new PRG/PRP system. Further optimization of the PRPs and the PRG are warranted to increase the signal.

Authors
Deroose, CM; Chitneni, SK; Gijsbers, R; Vermaelen, P; Ibrahimi, A; Balzarini, J; Baekelandt, V; Verbruggen, A; Nuyts, J; Debyser, Z; Bormans, GM; Mortelmans, L
MLA Citation
Deroose, CM, Chitneni, SK, Gijsbers, R, Vermaelen, P, Ibrahimi, A, Balzarini, J, Baekelandt, V, Verbruggen, A, Nuyts, J, Debyser, Z, Bormans, GM, and Mortelmans, L. "Preliminary validation of varicella zoster virus thymidine kinase as a novel reporter gene for PET." Nucl Med Biol 39.8 (November 2012): 1266-1274.
PMID
22981986
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
39
Issue
8
Publish Date
2012
Start Page
1266
End Page
1274
DOI
10.1016/j.nucmedbio.2012.06.014

A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([18F]EF5).

INTRODUCTION: [(18)F]EF5 is a validated marker for PET imaging of tumor hypoxia. It is prepared by reacting a trifluoroallyl precursor with carrier-added [(18)F]F(2) gas in trifluoroacetic acid (TFA) solvent. We report here an improved radiosynthesis and purification of [(18)F]EF5 by utilizing an electroformed nickel (Ni) target for [(18)F]F(2) production, and Oasis® HLB cartridges for on-line solid phase extraction of [(18)F]EF5 prior to HPLC purification. METHODS: [(18)F]F(2) was produced by deuteron bombardment of neon plus F(2) in an Ni target, and bubbled through the radiolabelling precursor solution. Purification was achieved by extracting the contents of the crude reaction mixture onto Oasis HLB cartridges, and subsequently eluted onto a semi-preparative HPLC column for further separation. Purified [(18)F]EF5 was evaluated in small animal PET studies using HCT116 tumor xenografts in nude mice. RESULTS: The electroformed Ni target enabled recovery of >75% of the radioactivity from the cyclotron target, resulting in 16.2 ± 2.2 GBq (438 ± 58 mCi) of [(18)F]F(2) available for the synthesis. Use of Oasis cartridges yielded a less complex mixture for purification. On average, 1140 ± 200 MBq (30.8 ± 5.4 mCi) of [(18)F]EF5 were collected at EOS. Small animal PET imaging studies showed specific retention of [(18)F]EF5 in tumors, with tumor-to-muscle ratios of 2.7 ± 0.3 at about 160 min after injection. CONCLUSION: A simple procedure has been developed for the routine synthesis of [(18)F]EF5 in amounts and purity required for clinical studies. This new method avoids the need for TFA evaporation and also enables facile automation of the synthesis using commercially available radiosynthesis modules.

Authors
Chitneni, SK; Bida, GT; Dewhirst, MW; Zalutsky, MR
MLA Citation
Chitneni, SK, Bida, GT, Dewhirst, MW, and Zalutsky, MR. "A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([18F]EF5)." Nucl Med Biol 39.7 (October 2012): 1012-1018.
PMID
22727821
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
39
Issue
7
Publish Date
2012
Start Page
1012
End Page
1018
DOI
10.1016/j.nucmedbio.2012.05.006

Abstract 5306: 18 F-EF5 microPET imaging of treatment response from a novel, hypoxia-selective cytotoxin SN30000 in a human lung cancer xenograft model

Authors
Chitneni, SK; Bida, GT; Hay, MP; Zalutsky, MR; Melcher, T; Wilson, WR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Hay, MP, Zalutsky, MR, Melcher, T, Wilson, WR, and Dewhirst, MW. "Abstract 5306: 18 F-EF5 microPET imaging of treatment response from a novel, hypoxia-selective cytotoxin SN30000 in a human lung cancer xenograft model." Cancer Research 71.8 Supplement (April 15, 2011): 5306-5306.
Source
crossref
Published In
Cancer Research
Volume
71
Issue
8 Supplement
Publish Date
2011
Start Page
5306
End Page
5306
DOI
10.1158/1538-7445.AM2011-5306

Molecular imaging of hypoxia.

A wide variety of imaging approaches have been developed in the past few decades for monitoring tumor oxygenation and hypoxia in vivo. In particular, nuclear medicine has seen the development of several radiolabeled hypoxia markers and is the preferred method for imaging of tumor hypoxia. Hypoxia imaging is increasingly being used in the clinical setting and is progressing from a mere detection method to application in individualization of chemoradiotherapy.

Authors
Chitneni, SK; Palmer, GM; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Palmer, GM, Zalutsky, MR, and Dewhirst, MW. "Molecular imaging of hypoxia." J Nucl Med 52.2 (February 2011): 165-168. (Review)
PMID
21233176
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
52
Issue
2
Publish Date
2011
Start Page
165
End Page
168
DOI
10.2967/jnumed.110.075663

Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain.

UNLABELLED: Phosphodiesterases are enzymes that inactivate the intracellular second messengers 3',5'-cyclic adenosine-monophosphate and/or cyclic guanosine-monophosphate. Of all 11 known phosphodiesterase families, phosphodiesterase-10A (PDE10A) has the most restricted distribution, with high expression in the striatum. PDE10A inhibitors are pursued as drugs for treatment of neuropsychiatric disorders. We have synthesized and evaluated (18)F-JNJ41510417 as a selective and high-affinity radioligand for in vivo brain imaging of PDE10A using PET. METHODS: The biodistribution of (18)F-JNJ41510417 was evaluated in rats. Rat plasma and perfused brain homogenates were analyzed by high-performance liquid chromatography to quantify radiometabolites. Dynamic small-animal PET was performed in rats and in wild-type and PDE10A knock-out mice and compared with ex vivo autoradiography. Blocking and displacement experiments were performed using the nonradioactive analog and other selective PDE10A inhibitors. RESULTS: Tissue distribution studies showed predominant hepatobiliary excretion, sufficient brain uptake (0.56 ± 0.00 percentage injected dose at 2 min after tracer injection), and continuous accumulation of the tracer in the striatum over time; rapid washout of nonspecific binding from other brain regions was observed. Polar radiometabolites were detected in plasma and brain tissue. Dynamic small-animal PET showed continuous tracer accumulation in the striatum, with rapid decline in the cortex and cerebellum. Pretreatment and chase experiments with PDE10A inhibitors showed that the tracer binding to PDE10A was specific and reversible. Imaging in PDE10A knock-out and wild-type mice further confirmed that binding in the striatum was specific for PDE10A. CONCLUSION: Experiments in rats and PDE10A knock-out mice indicate that (18)F-JNJ41510417 binds specifically and reversibly to PDE10A in the striatum, suggesting that this new fluorinated quinoline derivative is a promising candidate for in vivo imaging of PDE10A using PET.

Authors
Celen, S; Koole, M; De Angelis, M; Sannen, I; Chitneni, SK; Alcazar, J; Dedeurwaerdere, S; Moechars, D; Schmidt, M; Verbruggen, A; Langlois, X; Van Laere, K; Andrés, JI; Bormans, G
MLA Citation
Celen, S, Koole, M, De Angelis, M, Sannen, I, Chitneni, SK, Alcazar, J, Dedeurwaerdere, S, Moechars, D, Schmidt, M, Verbruggen, A, Langlois, X, Van Laere, K, Andrés, JI, and Bormans, G. "Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain." J Nucl Med 51.10 (October 2010): 1584-1591.
PMID
20847170
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
51
Issue
10
Publish Date
2010
Start Page
1584
End Page
1591
DOI
10.2967/jnumed.110.077040

[18F]JNJ41510417 a potential PET radioligand for imaging phosphodiesterase-10A in the brain

Authors
Celen, S; Koole, M; De Angelis, M; Sannen, I; Chitneni, SK; Alcazar, J; Dedeurwaerdere, S; Moechars, D; Schmidt, M; Verbruggen, A; Xavier, L; Van Laere, K; Ignacio Andres, J; Bormans, G
MLA Citation
Celen, S, Koole, M, De Angelis, M, Sannen, I, Chitneni, SK, Alcazar, J, Dedeurwaerdere, S, Moechars, D, Schmidt, M, Verbruggen, A, Xavier, L, Van Laere, K, Ignacio Andres, J, and Bormans, G. "[18F]JNJ41510417 a potential PET radioligand for imaging phosphodiesterase-10A in the brain." August 2010.
Source
wos-lite
Published In
NeuroImage
Volume
52
Publish Date
2010
Start Page
S15
End Page
S15
DOI
10.1016/j.neuroimage.2010.04.200

Synthesis and biological evaluation of a 99mTc-labelled sulfonamide conjugate for in vivo visualization of carbonic anhydrase IX expression in tumor hypoxia.

INTRODUCTION: Carbonic anhydrase (CA) IX is a transmembrane protein overexpressed in many frequently occurring tumors associated with tumor hypoxia. Sulfonamides and their bioisosteres are known to inhibit CA IX activity. In this study, 4-(2-aminoethyl)benzenesulfonamide was conjugated to a tridentate ligand, N-2-picolyl-N-acetic acid and labeled with a (99m)Tc(I)-tricarbonyl moiety resulting in [(99m)Tc(CO)(3) (L)] (L=N-(pyridin-2-yl-methyl)-N[2-(4-sulfamoylphenyl)-ethyl]aminoethyl acetate) complex, [(99m)Tc]-5. Similarly the corresponding rhenium congener (Re-4) was synthesized. The in vitro CA IX affinity and inhibitory activity of Re-4 were determined and [(99m)Tc]-5 was evaluated as a tracer for in vivo visualisation of CA IX expression. METHODS: Evaluation of the in vitro affinity (inhibition constant, K(i)) of Re-4 for CA isozymes I, II, IX and XII was carried out by assaying the CA catalyzed CO(2) hydration activity and efficacy studies were performed in HT 29 cell lines expressing CA IX under normoxia or hypoxia. Biodistribution studies of [(99m)Tc]-5 were performed in xenograft mice bearing CA IX expressing tumors. RESULTS: The in vitro affinity of Re-4 for CA IX was 58 nM and CA IX induced acidification of extracellular medium was efficiently reduced (P<.05) in the presence of 1 mM Re-4. Biodistribution studies indicated a maximal tumor uptake of [(99m)Tc]-5 of 0.1% ID/g at 30 min post injection. CONCLUSION: [(99m)Tc]-5 and its rhenium congener were synthesized and characterized. In vitro studies showed that the rhenium compound has a high affinity for CA IX and effectively inhibits CA IX activity. In vivo studies revealed a limited tracer accumulation in a CA IX expressing tumor but with increasing tumor-to-blood activity ratios as a function of time.

Authors
Akurathi, V; Dubois, L; Lieuwes, NG; Chitneni, SK; Cleynhens, BJ; Vullo, D; Supuran, CT; Verbruggen, AM; Lambin, P; Bormans, GM
MLA Citation
Akurathi, V, Dubois, L, Lieuwes, NG, Chitneni, SK, Cleynhens, BJ, Vullo, D, Supuran, CT, Verbruggen, AM, Lambin, P, and Bormans, GM. "Synthesis and biological evaluation of a 99mTc-labelled sulfonamide conjugate for in vivo visualization of carbonic anhydrase IX expression in tumor hypoxia." Nucl Med Biol 37.5 (July 2010): 557-564.
PMID
20610160
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
37
Issue
5
Publish Date
2010
Start Page
557
End Page
564
DOI
10.1016/j.nucmedbio.2010.02.006

Synthesis and preliminary biological evaluation of [F-18]JNJ41510417as a radioligand for positron emission tomography imaging of phosphodiesterase-10A in the brain

Authors
Celen, S; De Angelis, M; Chitneni, SK; Alcazar, J; Koole, M; Dedeurwaerdere, S; Steckler, T; Schmidt, M; Van Laere, K; Verbruggen, A; Langlois, X; Andres, JI; Bormans, G
MLA Citation
Celen, S, De Angelis, M, Chitneni, SK, Alcazar, J, Koole, M, Dedeurwaerdere, S, Steckler, T, Schmidt, M, Van Laere, K, Verbruggen, A, Langlois, X, Andres, JI, and Bormans, G. "Synthesis and preliminary biological evaluation of [F-18]JNJ41510417as a radioligand for positron emission tomography imaging of phosphodiesterase-10A in the brain." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 36 (September 2009): S236-S236.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
36
Publish Date
2009
Start Page
S236
End Page
S236

Synthesis and Biological Evaluation of 99mTc-Labelled Aminoethylbenzenesulfonamide Conjugate for In vivo Visualisation of Carbonic Anhydrase IX (CAIX) Expression in Tumor Hypoxia

Authors
Akurathi, V; Dubois, L; Lieuwes, NG; Chitneni, SK; Cleynhens, BJ; Verbruggen, AM; Lambin, P; Bormans, G
MLA Citation
Akurathi, V, Dubois, L, Lieuwes, NG, Chitneni, SK, Cleynhens, BJ, Verbruggen, AM, Lambin, P, and Bormans, G. "Synthesis and Biological Evaluation of 99mTc-Labelled Aminoethylbenzenesulfonamide Conjugate for In vivo Visualisation of Carbonic Anhydrase IX (CAIX) Expression in Tumor Hypoxia." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 36 (September 2009): S309-S309.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
36
Publish Date
2009
Start Page
S309
End Page
S309

DEVELOPMENT AND PRELIMINARY EVALUATION OF A 11C LABELED SULFONAMIDE DERIVATES AS POTENTIAL PET TRACER FOR BLOOD POOL IMAGING

Authors
Akurathi, V; Chitneni, S; Cleynhens, B; Verbruggen, A; Bormans, G
MLA Citation
Akurathi, V, Chitneni, S, Cleynhens, B, Verbruggen, A, and Bormans, G. "DEVELOPMENT AND PRELIMINARY EVALUATION OF A 11C LABELED SULFONAMIDE DERIVATES AS POTENTIAL PET TRACER FOR BLOOD POOL IMAGING." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 52 (2009): S341-S341.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
52
Publish Date
2009
Start Page
S341
End Page
S341

SYNTHESIS AND BIOLOGICAL EVALUATION OF A NEGATIVELY CHARGED 99mTc-LABELLED AMINOETHYLBENZENE SULFONAMIDE CONJUGATE FOR IN VIVO VISUALISATION OF CARBONIC ANHYDRASE IX (CA IX) EXPRESSION AS A SURROGATE MARKER OF TUMOR HYPOXIA

Authors
Akurathi, V; Dubois, L; Lieuwes, N; Chitneni, SK; Cleynhens, B; Verbruggen, A; Lambin, P; Bormans, G
MLA Citation
Akurathi, V, Dubois, L, Lieuwes, N, Chitneni, SK, Cleynhens, B, Verbruggen, A, Lambin, P, and Bormans, G. "SYNTHESIS AND BIOLOGICAL EVALUATION OF A NEGATIVELY CHARGED 99mTc-LABELLED AMINOETHYLBENZENE SULFONAMIDE CONJUGATE FOR IN VIVO VISUALISATION OF CARBONIC ANHYDRASE IX (CA IX) EXPRESSION AS A SURROGATE MARKER OF TUMOR HYPOXIA." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 52 (2009): S135-S135.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
52
Publish Date
2009
Start Page
S135
End Page
S135

Efficient purification and metabolite analysis of radiotracers using high-performance liquid chromatography and on-line solid-phase extraction.

This study describes an efficient method using on-line solid-phase extraction (SPE) (Oasis HLB) for preparative HPLC purification of short-lived radiotracers for positron emission tomography (PET) and for HPLC analysis of radiotracers and their metabolites in cell homogenates, plasma and urine samples. The radiochemical purity of tracers (fluorine-18 labeled) purified using this method (Oasis column) was >99% compared to 90% when no Oasis column was used. Radiometabolites of several fluorine-18 and carbon-11-labeled tracers and one technetium-99m tracer were quantified in cell homogenates, plasma and urine samples. Samples were analyzed using Oasis column and analytical HPLC system without prior precipitation of proteins or removal of other biological matrices. The metabolites observed for the evaluated tracers were all polar relative to the unchanged tracer. The extraction repeatability was found to be good (RSD 2.2%) and recoveries of Oasis column/HPLC-injected radioactivity (plasma) were found to be high (mean recovery >91%). The same Oasis column was used for several times without back pressure build-up or decrease of the HPLC separation characteristics.

Authors
Chitneni, SK; Serdons, K; Evens, N; Fonge, H; Celen, S; Deroose, CM; Debyser, Z; Mortelmans, L; Verbruggen, AM; Bormans, GM
MLA Citation
Chitneni, SK, Serdons, K, Evens, N, Fonge, H, Celen, S, Deroose, CM, Debyser, Z, Mortelmans, L, Verbruggen, AM, and Bormans, GM. "Efficient purification and metabolite analysis of radiotracers using high-performance liquid chromatography and on-line solid-phase extraction." J Chromatogr A 1189.1-2 (May 2, 2008): 323-331.
PMID
18045609
Source
pubmed
Published In
Journal of Chromatography A
Volume
1189
Issue
1-2
Publish Date
2008
Start Page
323
End Page
331
DOI
10.1016/j.chroma.2007.10.084

Synthesis and evaluation of 18F- and 11C-labeled phenyl-galactopyranosides as potential probes for in vivo visualization of LacZ gene expression using positron emission tomography.

3-Hydroxy-2-nitrophenyl 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranoside, a derivative of the chromogenic beta-galactosidase (beta-gal) substrate o-nitrophenyl beta-D-galactopyranoside (ONPG) was synthesized using a Koenigs-Knorr glycosylation reaction. It was alkylated with 2-[(18)F]fluoroethyl triflate or [(11)C]methyl triflate, followed by deacetylation of the sugar hydroxyl groups to obtain radiolabeled 3-(2'-[(18)F]fluoroethoxy)-2-nitrophenyl beta-D-galactopyranoside ([(18)F]-2c) and 3-[(11)C]methoxy-2-nitrophenyl beta- d-galactopyranoside ([(11)C]-3c), which were evaluated as potential reporter probes for in vivo visualization of LacZ gene expression with positron emission tomography (PET). In vitro, [(18)F]- 2c and [(11)C]-3c were good substrates of beta-gal and showed, respectively, a 7.5- and 2.5-fold higher uptake into beta-gal expressing cells (LacZ cells) compared to control cells. However, reversed-phase HPLC analysis of the LacZ cell lysate and supernatant showed that labeled 3-(2'-[(18)F]fluoroethoxy)-2-nitrophenol, the hydrolysis product formed by beta-gal-mediated cleavage of [(18)F]-2c, substantially leaked out of the cells, which would lead to loss of PET signal. In a microPET study of [(18)F]-2c in a mouse with a beta-gal expressing tumor, high retention was observed in liver and kidneys, but only negligible accumulation was seen in the tumor. As a general conclusion, it can be stated that the synthesized PET tracers [ (18)F]-2c and [(11)C]-3c are not suitable for use as LacZ reporter probes. Further structural modifications to improve the diffusion over the tumor cell membrane and to increase retention in beta-gal expressing cells may lead to more favorable in vivo imaging probes.

Authors
Celen, S; Deroose, C; de Groot, T; Chitneni, SK; Gijsbers, R; Debyser, Z; Mortelmans, L; Verbruggen, A; Bormans, G
MLA Citation
Celen, S, Deroose, C, de Groot, T, Chitneni, SK, Gijsbers, R, Debyser, Z, Mortelmans, L, Verbruggen, A, and Bormans, G. "Synthesis and evaluation of 18F- and 11C-labeled phenyl-galactopyranosides as potential probes for in vivo visualization of LacZ gene expression using positron emission tomography." Bioconjug Chem 19.2 (February 2008): 441-449.
PMID
18179161
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
19
Issue
2
Publish Date
2008
Start Page
441
End Page
449
DOI
10.1021/bc700216d

Improved synthesis and metabolic stability analysis of the dopamine transporter ligand [(18)F]FECT.

INTRODUCTION: [2'-[(18)F]Fluoroethyl (lR-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]-octane-2-carboxylate] ([(18)F]FECT) is a positron emission tomography (PET) tracer for imaging the dopamine transporter (DAT) in vivo. We report an improved radiosynthesis procedure and affinity data and have analyzed both brain tissue and plasma samples for the presence of radiometabolites as a function of time post intravenous injection of [(18)F]FECT to rats. METHODS: The radiosynthesis of [(18)F]FECT was carried out using [(18)F]fluoroethyltriflate ([(18)F]FEtOTf) as a labeling agent. The affinity of FECT for DAT was determined in vitro by binding experiments on rat striatal membranes. Three rats were injected with [(18)F]FECT and blood samples were collected at 1 or 3 h post injection (p.i.). Plasma was separated and analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC). Similarly, cerebrum and cerebellum were isolated after sacrifice of the animals at 3 h p.i. of the tracer and homogenized. HPLC analysis was performed on extracts of both samples to examine the presence of metabolites. RESULTS: The radiochemical yield for [(18)F]FECT was 85% relative to the starting activity of [(18)F]FEtOTf. The inhibitory constant (K(i)) of FECT for DAT was found to be 6 nM. The fraction of radioactivity corresponding to intact [(18)F]FECT was 93% in plasma at both 1 and 3 h p.i. and 96% in cerebrum as well as cerebellum samples at 3 h p.i. CONCLUSIONS: FECT has a high affinity for the dopamine transporter. [(18)F]FECT was found to be stable in vivo and the amount of radiolabeled metabolites in plasma and brain at 3 h p.i. is negligible. Hence, [(18)F]FECT can be used for the in vivo quantification of DAT using PET.

Authors
Chitneni, SK; Garreau, L; Cleynhens, B; Evens, N; Bex, M; Vermaelen, P; Chalon, S; Busson, R; Guilloteau, D; Van Laere, K; Verbruggen, A; Bormans, G
MLA Citation
Chitneni, SK, Garreau, L, Cleynhens, B, Evens, N, Bex, M, Vermaelen, P, Chalon, S, Busson, R, Guilloteau, D, Van Laere, K, Verbruggen, A, and Bormans, G. "Improved synthesis and metabolic stability analysis of the dopamine transporter ligand [(18)F]FECT." Nucl Med Biol 35.1 (January 2008): 75-82.
PMID
18158946
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
35
Issue
1
Publish Date
2008
Start Page
75
End Page
82
DOI
10.1016/j.nucmedbio.2007.09.001

Synthesis and biological evaluation of carbon-11-labeled acyclic and furo[2,3-d]pyrimidine derivatives of bicyclic nucleoside analogues (BCNAs) for structure-brain uptake relationship study of BCNA tracers

We reported earlier on radiolabeled alkoxyphenyl bicyclic nucleoside analogues (BCNAs) as potential positron emission tomography (PET) reporter probes for imaging of varicella zoster virus thymidine kinase (VZV-tk) gene in vivo. Despite their favorable physicochemical properties, these tracers are not taken up in the brain in mice. In order to probe the role of the deoxyribose sugar moiety in blood-brain barrier (BBB) penetration of these molecules, we have synthesized and evaluated a carbon-11-labeled acyclic bicyclic nucleoside derivative ([11C]-10) where the 2′-deoxyribose sugar is replaced with a (2-hydroxyethoxy)methyl group and [11C]-12, which has no sugar moiety but a [11C]methyl group on the N-3 position of the pyrimidine ring. Methylation was achieved on the phenol ([11C]-10) or the N-3 position ([11C]-12) using [11C]methyl triflate (radiosynthesis). The (non-radioactive) acyclic O-methyl derivative 10 has rather poor affinity for the enzyme VZV-TK in vitro (IC50: 430 μM), compared with the moderate affinity of the BCNA-base N-methyl derivative 12 (IC50: 79 μM). In normal mice, none of the two tracers ([ 11C]-10 or [11C]-12) showed significant uptake in the brain, suggesting that compounds containing a furo[2,3-d]pyrimidine system do not cross the BBB. Copyright © 2008 John Wiley & Sons, Ltd.

Authors
Chitneni, SK; Balzarini, J; Celen, S; Dyubankova, N; Verbruggen, AM; Bormans, GM
MLA Citation
Chitneni, SK, Balzarini, J, Celen, S, Dyubankova, N, Verbruggen, AM, and Bormans, GM. "Synthesis and biological evaluation of carbon-11-labeled acyclic and furo[2,3-d]pyrimidine derivatives of bicyclic nucleoside analogues (BCNAs) for structure-brain uptake relationship study of BCNA tracers." Journal of Labelled Compounds and Radiopharmaceuticals 51.3 (2008): 159-166.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
51
Issue
3
Publish Date
2008
Start Page
159
End Page
166
DOI
10.1002/jlcr.1494

A p-[18F]fluoroethoxyphenyl bicyclic nucleoside analogue as a potential positron emission tomography imaging agent for varicella-zoster virus thymidine kinase gene expression.

We recently reported a new positron emission tomography (PET) reporter gene, namely, varicella-zoster virus thymidine kinase (VZV-tk) in combination, with carbon-11 or fluorine-18 labeled m-alkoxyphenyl bicyclic nucleoside analogues (BCNAs) as PET reporter probes. We now report the synthesis and evaluation of p-alkoxyphenyl-BCNA tracers ([11C]-4 and [18F]-5), which are found to be superior to the m-alkoxyphenyl-BCNA tracers. In particular, the fluorine-18 labeled tracer ([18F]-5, IC50 of 5 is 4.2 microM) shows a higher accumulation in VZV-tk expressing cells than the previously reported m-methoxyphenyl BCNA. [11C]-4 and [18F]-5 were synthesized by heating the phenol precursor 3 with 11CH 3I and 18FCH 2CH 2Br, respectively, as alkylating agents. In vitro evaluation of [11C]-4 and [18F]-5 in 293T cells showed about 14- and 54-fold higher uptake, respectively, into VZV-tk gene-transduced cells compared to control cells. LC-MS analysis confirmed the formation of monophosphate derivative of 5 upon catalysis by VZV TK. In vivo studies of this new reporter gene/probe system are in progress.

Authors
Chitneni, SK; Deroose, CM; Balzarini, J; Gijsbers, R; Celen, S; Debyser, Z; Mortelmans, L; Verbruggen, AM; Bormans, GM
MLA Citation
Chitneni, SK, Deroose, CM, Balzarini, J, Gijsbers, R, Celen, S, Debyser, Z, Mortelmans, L, Verbruggen, AM, and Bormans, GM. "A p-[18F]fluoroethoxyphenyl bicyclic nucleoside analogue as a potential positron emission tomography imaging agent for varicella-zoster virus thymidine kinase gene expression." J Med Chem 50.26 (December 27, 2007): 6627-6637.
PMID
18047266
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
50
Issue
26
Publish Date
2007
Start Page
6627
End Page
6637
DOI
10.1021/jm700971p

Necrosis avidity of (99m)Tc(CO)3-labeled pamoic acid derivatives: synthesis and preliminary biological evaluation in animal models of necrosis.

In a search for an infarct avid tracer agent with improved properties, we have observed that bis-DTPA derivatives of pamoic acid have a high avidity for necrotic tissue. Here, we report the synthesis, radiolabeling, and preliminary evaluation in normal mice and rats with hepatic infarction of the (99m)Tc-tricarbonyl complexes of N, N'-bis(diethylenetriaminopentaacetato)-4,4'-methylene bis(2-hydroxy-3-naphthoic hydrazide) ( (99m)Tc(CO) 3-bis-DTPA-pamoate) and [ N-(5-aminopentyl)pyridin-2-yl-methylamino]methylacetato-4,4'-methylene-2-hydroxy-3-napthalenecarboxamide-(2'-hydroxy-3'-naphthoic acid methyl ester) ( (99m)Tc(CO) 3 -12). Radiolabeling with (99m)Tc(CO) 3 (+) was achieved with a radiochemical yield of over 95% for both tracer agents. In normal mice, the polar (99m)Tc(CO) 3-bis-DTPA-pamoate was cleared from plasma via both the liver and the kidneys, while the more lipophilic (99m)Tc(CO) 3 -12 was rapidly cleared via the liver. Blood clearance in mice was faster for (99m)Tc(CO) 3 -12 (0.1% injected dose per gram at 4 h postinjection) than for (99m)Tc(CO) 3-bis-DTPA-pamoate (9.3% injected dose per gram at 4 h postinjection). Affinity and specificity of the tracers for necrotic tissue was studied in rats with hepatic infarction and ethanol-induced necrosis of the liver or muscles. Activity ratios of infarct to viable liver tissue of (99m)Tc(CO) 3-bis-DTPA-pamoate quantified by autoradiography of tissue slices ranged from 4 to 18, depending on the necrosis model and time postinjection of the tracer. Infarcts were also visualized in vivo by (99m)Tc(CO) 3-bis-DTPA-pamoate planar gamma imaging. After injection of (99m)Tc(CO) 3-bis-DTPA-pamoate, in vivo and ex vivo images correlated well with histochemical staining with triphenyltetrazolium chloride and hematoxylin and eosin. (99m)Tc(CO) 3 -12 on the other hand showed no uptake in necrotic tissue. Stability of the tracers was determined in vitro after storage at room temperature and by histidine challenge experiments, and in vivo in mouse plasma and in urine (for (99m)Tc(CO) 3-bis-DTPA-pamoate). (99m)Tc(CO) 3-bis-DTPA-pamoate was unstable in vitro to histidine challenge, while (99m)Tc(CO) 3 -12 was 98% stable in vitro in the same conditions. Both tracers showed good in vivo stability. (99m)Tc(CO) 3-bis-DTPA-pamoate shows high specificity for necrotic tissue and merits further evaluation as a necrosis avid imaging agent. (99m)Tc(CO) 3 -12 is not useful for visualization of necrotic tissue.

Authors
Fonge, H; Chitneni, SK; Lixin, J; Vunckx, K; Prinsen, K; Nuyts, J; Mortelmans, L; Bormans, G; Ni, Y; Verbruggen, A
MLA Citation
Fonge, H, Chitneni, SK, Lixin, J, Vunckx, K, Prinsen, K, Nuyts, J, Mortelmans, L, Bormans, G, Ni, Y, and Verbruggen, A. "Necrosis avidity of (99m)Tc(CO)3-labeled pamoic acid derivatives: synthesis and preliminary biological evaluation in animal models of necrosis." Bioconjug Chem 18.6 (November 2007): 1924-1934.
PMID
17929883
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
18
Issue
6
Publish Date
2007
Start Page
1924
End Page
1934
DOI
10.1021/bc700236j

Synthesis and biological evaluation of C-11-labeled acyclic- and furo[2,3-d] pyrimidine derivative of bicyclic nucleoside analogs (BCNAs) for structure-brain uptake relationship study of BCNA tracers

Authors
Chitneni, SK; Balzarini, J; Verbruggen, A; Bormans, G
MLA Citation
Chitneni, SK, Balzarini, J, Verbruggen, A, and Bormans, G. "Synthesis and biological evaluation of C-11-labeled acyclic- and furo[2,3-d] pyrimidine derivative of bicyclic nucleoside analogs (BCNAs) for structure-brain uptake relationship study of BCNA tracers." October 2007.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
34
Publish Date
2007
Start Page
S331
End Page
S332

Synthesis and biological evaluation of an 123I-labeled bicyclic nucleoside analogue (BCNA) as potential SPECT tracer for VZV-tk reporter gene imaging.

An iodine-123 labeled bicyclic nucleoside analogue ([(123)I]-4) has been synthesized and evaluated as a potential single photon emission tomography (SPECT) reporter probe for the non-invasive imaging of expression of the varicella zoster virus thymidine kinase (VZV-tk) reporter gene. In vitro enzymatic assays revealed that the non-radioactive mono-iodo derivative 4 has good affinity for VZV-TK (IC(50): 4.2 microM). Biodistribution of [(123)I]-4 was examined in normal mice. Evaluation of [(123)I]-4 in HEK-293T cells showed 1.74-fold higher accumulation in VZV-TK-expressing cells compared to control cells.

Authors
Chitneni, SK; Deroose, CM; Fonge, H; Gijsbers, R; Dyubankova, N; Balzarini, J; Debyser, Z; Mortelmans, L; Verbruggen, AM; Bormans, GM
MLA Citation
Chitneni, SK, Deroose, CM, Fonge, H, Gijsbers, R, Dyubankova, N, Balzarini, J, Debyser, Z, Mortelmans, L, Verbruggen, AM, and Bormans, GM. "Synthesis and biological evaluation of an 123I-labeled bicyclic nucleoside analogue (BCNA) as potential SPECT tracer for VZV-tk reporter gene imaging." Bioorg Med Chem Lett 17.12 (June 15, 2007): 3458-3462.
PMID
17446073
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
17
Issue
12
Publish Date
2007
Start Page
3458
End Page
3462
DOI
10.1016/j.bmcl.2007.03.081

Fetal gene transfer with lentiviral vectors: long-term in vivo follow-up evaluation in a rat model.

OBJECTIVE: The purpose of this study was to evaluate the long-term expression of a transgene and subsequent immune response after the injection of lentiviral vectors in a fetal rats. STUDY DESIGN: Fetal rats were injected in the liver, peritoneal cavity, or lung at E19 (term, E21) with a lentiviral vector expressing enhanced green fluorescent protein and luciferase. Controls received saline solution. After birth, full body bioluminescence was done at weeks 1, 4, 10, and 30 of life; seroconversion for the transgene was assessed. RESULTS: All surviving fetuses that had been injected in the liver (8/9 fetuses), peritoneum (3/3 fetuses), or lung (9/10 fetuses) showed a signal on bioluminescence imaging scan up to 30 weeks. None of the survivors displayed seroconversion against the transgene. CONCLUSION: In the rat model, the administration of lentiviral vectors into the fetal lung and liver resulted in long-term transgene expression without detectable humoral immune response.

Authors
Toelen, J; Deroose, CM; Gijsbers, R; Reumers, V; Sbragia, LN; Vets, S; Chitneni, SK; Bormans, G; Mortelmans, L; Deprest, JA; Debyser, Z
MLA Citation
Toelen, J, Deroose, CM, Gijsbers, R, Reumers, V, Sbragia, LN, Vets, S, Chitneni, SK, Bormans, G, Mortelmans, L, Deprest, JA, and Debyser, Z. "Fetal gene transfer with lentiviral vectors: long-term in vivo follow-up evaluation in a rat model." Am J Obstet Gynecol 196.4 (April 2007): 352.e1-352.e6.
PMID
17403419
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
196
Issue
4
Publish Date
2007
Start Page
352.e1
End Page
352.e6
DOI
10.1016/j.ajog.2007.01.038

Synthesis and preliminary evaluation of 18F- or 11C-labeled bicyclic nucleoside analogues as potential probes for imaging varicella-zoster virus thymidine kinase gene expression using positron emission tomography.

Two radiolabeled bicyclic nucleoside analogues (BCNAs) were synthesized, namely 3-(2'-deoxy-beta-d-ribofuranosyl)-6-(3-[18F]fluoroethoxyphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one ([18F]-2) and 3-(2'-deoxy-beta-d-ribofuranosyl)-6-(3-[11C]methoxyphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one ([11C]-3), and evaluated as PET reporter probes for varicella-zoster virus thymidine kinase (VZV-tk) gene expression imaging in brain. [18F]-2 and [11C]-3 were synthesized starting from phenol precursor 1. The phenol precursor 1 was converted to stable as well as to radiolabeled compounds 2 and 3 using (19/18)FCH(2)CH(2)Br or (12/11)CH(3)I as alkylating agent. In vitro evaluation of [18F]-2 and [11C]-3 in 293T cells showed a 4.5 and 53-fold higher uptake, respectively, into VZV-tk gene-transduced cells compared to control cells. However, biodistribution studies in mice demonstrated low uptake of these tracers in the brain. RP-HPLC analysis of plasma and urine samples of mice injected with [11C]-3 revealed that this tracer is very stable in vivo. These data warrant further evaluation of these tracers as noninvasive imaging agents for VZV infection and VZV-tk reporter gene expression in vivo.

Authors
Chitneni, SK; Deroose, CM; Balzarini, J; Gijsbers, R; Celen, SJL; de Groot, TJ; Debyser, Z; Mortelmans, L; Verbruggen, AM; Bormans, GM
MLA Citation
Chitneni, SK, Deroose, CM, Balzarini, J, Gijsbers, R, Celen, SJL, de Groot, TJ, Debyser, Z, Mortelmans, L, Verbruggen, AM, and Bormans, GM. "Synthesis and preliminary evaluation of 18F- or 11C-labeled bicyclic nucleoside analogues as potential probes for imaging varicella-zoster virus thymidine kinase gene expression using positron emission tomography." J Med Chem 50.5 (March 8, 2007): 1041-1049.
PMID
17298046
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
50
Issue
5
Publish Date
2007
Start Page
1041
End Page
1049
DOI
10.1021/jm060964m

Synthesis and biological evaluation of a lipophilic, fluorine-18-labeled 5-ethynyl-2′-deoxyuridine derivative

The synthesis and preliminary biological evaluation of a lipophilic, fluorine-18-labeled 5-ethynyl-2′-deoxyuridine derivative [ 18F]-3 is described. Initially, 5-ethynyl-2′-deoxyuridine 5 was synthesized by coupling trimethylsilyl protected acetylene to 5-iodo-2′-deoxyuridine 4, followed by deprotection in alkaline conditions. Compound 5 was then reacted with 4-(4′-iodophenyl)phenol to give 5-[4(4′-hydroxyphenyl)phenyl]ethynyl-2′-deoxyuridine 6. Compound 6 was reacted with BrCH2CH219/18F as alkylating agent to give stable or radiolabeled 3. The crude products were purified using reversed phase-high performance liquid chromatography to obtain compound 3 and [18F]-3 in 33 and 7.4% yield (decay corrected), respectively. The synthesis time to obtain pure [18F]-3 was about 60min (starting from BrCH2CH218F). The specific radioactivity of the tracer was between 74 and 222 GBq/μmol. The log P7.4 of [ 18F]-3 was found to be 2.4. However, biodistribution study in normal mice showed low uptake of the tracer in the brain. The affinity of compounds 6 and 3 for varicella-zoster virus thymidine kinase enzyme (VZV-TK) was examined in vitro and the results revealed that the fluorinated analog 3 has a poor affinity for the enzyme in contrast to the phenol precursor 6. Copyright © 2007 John Wiley & Sons, Ltd.

Authors
Chitneni, SK; Ruymaeker, TD; Balzarini, J; Verbruggen, AM; Bormans, GM
MLA Citation
Chitneni, SK, Ruymaeker, TD, Balzarini, J, Verbruggen, AM, and Bormans, GM. "Synthesis and biological evaluation of a lipophilic, fluorine-18-labeled 5-ethynyl-2′-deoxyuridine derivative." Journal of Labelled Compounds and Radiopharmaceuticals 50.7 (2007): 649-655.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
50
Issue
7
Publish Date
2007
Start Page
649
End Page
655
DOI
10.1002/jlcr.1312

Synthesis and preliminary evaluation of F-18 and C-11 labeled bi-cyclic nucleoside analogues (BCNAs) as potential PET reporter probes for imaging varicella-zoster virus thymidine kinase (VZV-tk) gene expression

Authors
Chitneni, S; Deroose, C; Balzarini, J; Verbruggen, A; Bormans, G
MLA Citation
Chitneni, S, Deroose, C, Balzarini, J, Verbruggen, A, and Bormans, G. "Synthesis and preliminary evaluation of F-18 and C-11 labeled bi-cyclic nucleoside analogues (BCNAs) as potential PET reporter probes for imaging varicella-zoster virus thymidine kinase (VZV-tk) gene expression." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S175-S175.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S175
End Page
S175

A New Precursor for a High Yield Synthesis of[F-18]FHBG

Authors
Chitneni, S; Cleynhens, B; de Groot, T; Verbruggen, A; Bormans, G
MLA Citation
Chitneni, S, Cleynhens, B, de Groot, T, Verbruggen, A, and Bormans, G. "A New Precursor for a High Yield Synthesis of[F-18]FHBG." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 32 (September 2005): S268-S269.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
32
Publish Date
2005
Start Page
S268
End Page
S269

Identification of impurities in erythromycin by liquid chromatography-mass spectrometric detection

Authors
Chitneni, SK; Govaerts, C; Adams, E; Van Schepdael, A; Hoogmartens, J
MLA Citation
Chitneni, SK, Govaerts, C, Adams, E, Van Schepdael, A, and Hoogmartens, J. "Identification of impurities in erythromycin by liquid chromatography-mass spectrometric detection." November 12, 2004.
PMID
15595540
Source
wos-lite
Published In
Journal of Chromatography A
Volume
1056
Issue
1-2
Publish Date
2004
Start Page
111
End Page
120
DOI
10.1016/j.chroma.2004.07.091
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Research Areas:

  • Animals
  • Anoxia
  • Antigens, Neoplasm
  • Benzimidazoles
  • Bicyclo Compounds
  • Bicyclo Compounds, Heterocyclic
  • Biological Transport
  • Brain
  • Carbon Radioisotopes
  • Carbonic Anhydrases
  • Carboxylic Acids
  • Cell Line
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Chemistry Techniques, Synthetic
  • Chromatography, High Pressure Liquid
  • Cocaine
  • Cyclic N-Oxides
  • Disease Models, Animal
  • Dopamine Plasma Membrane Transport Proteins
  • Drug Evaluation, Preclinical
  • Esters
  • Female
  • Fetus
  • Fluorine Radioisotopes
  • Follow-Up Studies
  • Gene Expression
  • Gene Transfer Techniques
  • Genes, Reporter
  • Genetic Therapy
  • Genetic Vectors
  • HEK293 Cells
  • Herpesvirus 3, Human
  • Homeostasis
  • Humans
  • Immunohistochemistry
  • Intracellular Space
  • Isotope Labeling
  • Kidney
  • Kinetics
  • Lac Operon
  • Lentivirus
  • Ligands
  • Liver
  • Lung
  • Lung Neoplasms
  • Magnetic Resonance Spectroscopy
  • Male
  • Metabolic Clearance Rate
  • Mice
  • Misonidazole
  • Models, Chemical
  • Molecular Imaging
  • Molecular Structure
  • Molecular Targeted Therapy
  • Necrosis
  • Neoplasms
  • Neovascularization, Pathologic
  • Nitroimidazoles
  • Nucleosides
  • Nucleotides, Cyclic
  • Oligopeptides
  • Organ Specificity
  • Organotechnetium Compounds
  • Phosphoric Diester Hydrolases
  • Phosphorylation
  • Positron-Emission Tomography
  • Pregnancy
  • Pregnancy, Animal
  • Prodrugs
  • Prostatic Neoplasms
  • Pyrans
  • Pyrazoles
  • Pyrimidine Nucleosides
  • Quinolines
  • Radioisotopes
  • Radiopharmaceuticals
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species
  • Reproducibility of Results
  • Rhenium
  • Sensitivity and Specificity
  • Signal Transduction
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship
  • Sulfonamides
  • Thymidine Kinase
  • Time Factors
  • Tissue Distribution
  • Transduction, Genetic
  • Treatment Outcome
  • Triazines
  • Tumor Markers, Biological
  • Viral Load
  • Xenograft Model Antitumor Assays