Kishore K Gangangari1,2,3, András Váradi4, Susruta Majumdar4,5, Steven M Larson1,4,6, Gavril W Pasternak4, NagaVara Kishore Pillarsetty7,8. 1. Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA. 2. Department of Chemistry, Hunter College, City University of New York, New York, NY, USA. 3. Ph.D Program in Chemistry, The Graduate Center, City University of New York, New York, NY, USA. 4. Molecular Pharmacology and Chemistry Program, Department of Neurology, MSKCC, New York, NY, USA. 5. Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. 6. Molecular Imaging and Therapy Service, Department of Radiology, MSKCC, New York, NY, USA. 7. Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA. pillarsn@mskcc.org. 8. Department of Radiology, Weill Cornell Medical College, New York, NY, USA. pillarsn@mskcc.org.
Abstract
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. PROCEDURES: [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. RESULTS: [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. CONCLUSIONS: [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.
PURPOSE: Sigma-1 receptors (S1Rs) are overexpressed in almost all humancancers, 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. PROCEDURES: [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. RESULTS: [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. CONCLUSIONS: [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.
Entities:
Keywords:
Biodistribution studies; Breast cancer; Iodine-124; PET imaging; Prostate cancer; Sigma-1 receptor; [124I]IPAG; [131I]IPAG
Authors: Michelle L James; Bin Shen; Cristina L Zavaleta; Carsten H Nielsen; Christophe Mesangeau; Pradeep K Vuppala; Carmel Chan; Bonnie A Avery; James A Fishback; Rae R Matsumoto; Sanjiv S Gambhir; Christopher R McCurdy; Frederick T Chin Journal: J Med Chem Date: 2012-09-20 Impact factor: 7.446
Authors: Giacomo Pirovano; Alvaro A Ordonez; Sanjay K Jain; Thomas Reiner; Laurence S Carroll; Naga Vara Kishore Pillarsetty Journal: Nucl Med Biol Date: 2021-05-25 Impact factor: 2.947