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

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.