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Nagavarakishore Pillarsetty - One of the best experts on this subject based on the ideXlab platform.
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imaging sigma 1 receptor s1r expression using Iodine 124 labeled 1 4 iodophenyl 3 2 adamantyl guanidine 124 i ipag
Molecular Imaging and Biology, 2020Co-Authors: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, Nagavarakishore PillarsettyAbstract:Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of Iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors. [124I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 107 cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [124I]IPAG to image tumors was evaluated in LNCaP tumor–bearing mice as well. [124I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [124I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor–bearing mice reveal that [124I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [124I]IPAG could be competitively inhibited by excess of IPAG and haloperidol. [124I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [124I]IPAG. [124I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers.
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Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG).
Molecular Imaging and Biology, 2019Co-Authors: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, Nagavarakishore PillarsettyAbstract:Purpose Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of Iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors.
Steven M. Larson - One of the best experts on this subject based on the ideXlab platform.
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imaging sigma 1 receptor s1r expression using Iodine 124 labeled 1 4 iodophenyl 3 2 adamantyl guanidine 124 i ipag
Molecular Imaging and Biology, 2020Co-Authors: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, Nagavarakishore PillarsettyAbstract:Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of Iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors. [124I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 107 cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [124I]IPAG to image tumors was evaluated in LNCaP tumor–bearing mice as well. [124I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [124I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor–bearing mice reveal that [124I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [124I]IPAG could be competitively inhibited by excess of IPAG and haloperidol. [124I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [124I]IPAG. [124I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers.
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Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG).
Molecular Imaging and Biology, 2019Co-Authors: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, Nagavarakishore PillarsettyAbstract:Purpose Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of Iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors.
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vemurafenib redifferentiation of braf mutant rai refractory thyroid cancers
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Steven M. Larson, Ravinder K. Grewal, Lara Dunn, E Sherman, Shrujal S Baxi, Vatche Tchekmedyian, Keith S. PentlowAbstract:Context BRAFV600E mutant thyroid cancers are often refractory to radioIodine (RAI). Objectives To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). Design This was a pilot trial that enrolled from June 2014 to January 2016. Setting Academic cancer center. Patients Patients with RAIR, BRAF mutant thyroid cancer. Intervention Patients underwent thyrotropin-stimulated Iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with Iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. Main outcome measure The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. Results Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). Conclusions Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.
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Redifferentiating Thyroid Cancer: Selumetinib-enhanced RadioIodine Uptake in Thyroid Cancer.
Molecular Imaging and Radionuclide Therapy, 2017Co-Authors: Steven M. Larson, Ravinder K. Grewal, Joseph R. Osborne, R. Michael TuttleAbstract:In a recent article, we reported a restorative therapeutic intervention that turned individual thyroid cancer lesions into more efficient tissues for taking up radioactive Iodine (RAI), resulting in clinically significant and durable responses. A group of Iodine-131 refractory thyroid cancer patients were treated with the MEK tyrosine kinase inhibitor (TKI) selumetinib, and RAI uptake was restored in a subset of patients. We employed Iodine-124 positron emission tomography to measure radiation absorbed dose, on a lesion by lesion basis. The process can be thought of as a re-differentiation of the cancer toward a more nearly normal state most like the tissue from which the cancer arose. Remarkably, in its own way, a change was detected within a few weeks of treatment, restoring uptake with therapeutically effective levels of RAI and in some patients, previously completely refractory to radioIodine treatment. In this article, we summarize the basic work that led to this seminal study, and make the case for lesional dosimetry in thyroid cancer with Iodine-124 as a new optimal radiotracer for precision medicine in patients with well differentiated thyroid cancer.
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Radiosynthesis of the Iodine-124 labeled Hsp90 inhibitor PU-H71.
Journal of Labelled Compounds and Radiopharmaceuticals, 2016Co-Authors: Tony Taldone, Pat Zanzonico, Danuta Zatorska, Stefan O. Ochiana, Peter Smith-jones, Jacek Koziorowski, Mark Dunphy, Alexander Bolaender, Steven M. LarsonAbstract:Heat shock protein 90 (Hsp90) is an ATP dependent molecular chaperone protein whose function is critical for maintaining several key proteins involved in survival and proliferation of cancer cells. PU-H71 (1), is a potent purine-scaffold based ATP pocket binding Hsp90 inhibitor which has been shown to have potent activity in a broad range of in vivo cancer models and is currently in Phase I clinical trials in patients with advanced solid malignancies, lymphomas, and myeloproliferative neoplasms. In this report, we describe the radiosynthesis of [(124)I]-PU-H71(5); this was synthesized from the corresponding Boc-protected stannane precursor 3 by iododestannylation with [(124)I]-NaI using chloramine-T as an oxidant for 2 min, followed by Boc deprotection with 6 N HCl at 50 °C for 30 min to yield the final compound. The final product 5 was purified using HPLC and was isolated with an overall yield of 55 ± 6% (n = 6, isolated) from 3, and >98% purity and an average specific activity of 980 mCi/µmol. Our report sets the stage for the introduction of [(124)I]-PU-H71 as a potential non-invasive probe for understanding biodistribution and pharmacokinetics of PU-H71 in living subjects using positron emission tomography imaging.
Kishore K. Gangangari - One of the best experts on this subject based on the ideXlab platform.
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imaging sigma 1 receptor s1r expression using Iodine 124 labeled 1 4 iodophenyl 3 2 adamantyl guanidine 124 i ipag
Molecular Imaging and Biology, 2020Co-Authors: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, Nagavarakishore PillarsettyAbstract:Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of Iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors. [124I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 107 cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [124I]IPAG to image tumors was evaluated in LNCaP tumor–bearing mice as well. [124I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [124I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor–bearing mice reveal that [124I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [124I]IPAG could be competitively inhibited by excess of IPAG and haloperidol. [124I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [124I]IPAG. [124I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers.
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Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG).
Molecular Imaging and Biology, 2019Co-Authors: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, Nagavarakishore PillarsettyAbstract:Purpose Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of Iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors.
Susruta Majumdar - One of the best experts on this subject based on the ideXlab platform.
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imaging sigma 1 receptor s1r expression using Iodine 124 labeled 1 4 iodophenyl 3 2 adamantyl guanidine 124 i ipag
Molecular Imaging and Biology, 2020Co-Authors: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, Nagavarakishore PillarsettyAbstract:Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of Iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors. [124I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 107 cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [124I]IPAG to image tumors was evaluated in LNCaP tumor–bearing mice as well. [124I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [124I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor–bearing mice reveal that [124I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [124I]IPAG could be competitively inhibited by excess of IPAG and haloperidol. [124I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [124I]IPAG. [124I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers.
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Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG).
Molecular Imaging and Biology, 2019Co-Authors: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, Nagavarakishore PillarsettyAbstract:Purpose Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of Iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors.
Jurgen Seidel - One of the best experts on this subject based on the ideXlab platform.
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ectopic expression of the sodium iodide symporter enables imaging of transplanted cardiac stem cells in vivo by single photon emission computed tomography or positron emission tomography
Journal of the American College of Cardiology, 2008Co-Authors: John Terrovitis, Keng Fai Kwok, Riikka Lautamaki, James M Engles, Andreas S Barth, Eddy Kizana, Junichiro Miake, Michelle K Leppo, James Fox, Jurgen SeidelAbstract:Objectives: We examined the sodium-iodide symporter (NIS), which promotes in vivo cellular uptake of technetium 99m (99mTc) or Iodine 124 (124I), as a reporter gene for cell tracking by single-phot...
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ectopic expression of the sodium iodide symporter enables imaging of transplanted cardiac stem cells in vivo by single photon emission computed tomography or positron emission tomography
Journal of the American College of Cardiology, 2008Co-Authors: John Terrovitis, Keng Fai Kwok, Riikka Lautamaki, James M Engles, Andreas S Barth, Eddy Kizana, Junichiro Miake, Michelle K Leppo, James Fox, Jurgen SeidelAbstract:Objectives We examined the sodium-iodide symporter (NIS), which promotes in vivo cellular uptake of technetium 99m ( 99m Tc) or Iodine 124 ( 124 I), as a reporter gene for cell tracking by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Background Stem cells offer the promise of cardiac repair. Stem cell labeling is a prerequisite to tracking cell fate in vivo. Methods The human NIS complementary deoxyribonucleic acid was transduced into rat cardiac-derived stem cells (rCDCs) using lentiviral vectors. Rats were injected intramyocardially with up to 4 million NIS + -rCDCs immediately after left anterior descending coronary artery ligation. Dual isotope SPECT (or PET) imaging was performed, using 99m Tc (or 124 I) for cell detection and thallium 201 (or ammonia 13) for myocardial delineation. In a subset of animals, high resolution ex vivo SPECT scans of explanted hearts were obtained to confirm that in vivo signals were derived from the cell injection site. Results NIS expression in rCDCs did not affect cell viability and proliferation. NIS activity was verified in isolated transduced cells by measuring 99m Tc uptake. NIS + rCDCs were visualized in vivo as regions of 99m Tc or 124 I uptake within a perfusion deficit in the SPECT and PET images, respectively. Cells could be visualized by SPECT up to 6 days post-injection. Ex vivo SPECT confirmed that in vivo 99m Tc signals were localized to the cell injection sites. Conclusions Ectopic NIS expression allows noninvasive in vivo stem cell tracking in the myocardium, using either SPECT or PET. The general approach shows significant promise in tracking the fate of transplanted cells participating in cardiac regeneration, given its ability to observe living cells using clinically applicable imaging modalities.
