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Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG)

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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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The authors thank Integrative Graduate Education and Research Traineeship (IGERT 0965983 at Hunter College) by the National Science Foundation for their generous support. Technical services provided by the MSKCC Small-Animal Imaging Core Facility, supported in part by NIH Cancer Center Support Grant No. 2 P30 CA008748-48 and Radiochemistry and Molecular Imaging Probes Core Facility (RMIP) are gratefully acknowledged. Additional support was obtained from the National Institute on Drug Abuse (DA06241) and from Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center to GWP.

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Correspondence to NagaVara Kishore Pillarsetty.

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Conflict of Interest

S.M. Larson reports receiving commercial research grants from Genentech, Inc., Wilex AG, Telix Pharmaceuticals Ltd., and Regeneron Pharmaceuticals Inc., has ownership interest (including stock, patents, etc.) in Imaginab, Inc., Samus Therapeutics Inc., Elucida Oncology Inc., Voreyda Theranostics Inc., and YMABS Therapeutic Inc., is a consultant/advisory board member for Cynvec LLC, Eli Lilly, Prescient Therapeutics Limited, Advanced Therapeutic Partners, Gerson Lehman Group, Progenics, and Janssen Pharmaceuticals Inc., and has received other remuneration from Fonde de Research Sante, Quebec. All are outside the scope of current work. G. W. Pasternak. reports personal fees and/or other fees from Novartis, Collegium, Nektar, Confo, Endo, outside the current work; He is a co-founder of Sparionbio. S. Majumdar reports other interests from Palion Therapeutics, outside the submitted work; He is a co-founder of Sparionbio. N Pillarsetty reports that he is an inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics, Inc., which are outside the scope of current work.

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All applicable institutional and/or national guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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This manuscript is dedicated to our colleague, mentor, and, co-author, late Dr. Gavril Pasternak.

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Gangangari, K.K., Váradi, A., Majumdar, S. et al. Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG). Mol Imaging Biol (2019). https://doi.org/10.1007/s11307-019-01369-8

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Key Words

  • Sigma-1 receptor
  • [124I]IPAG
  • [131I]IPAG
  • Iodine-124
  • Breast cancer
  • Prostate cancer
  • PET imaging
  • Biodistribution studies