Abstract
1050
Introduction: Radiolabeled sigma receptors targeted compounds can determine the expression level of the receptors. They will be useful for diagnoses of various diseases and companion diagnosis of therapeutic agents targeting the sigma receptors. Moreover, they may be applied to the receptor radionuclide therapy. Purpose of this study is developing radiolabeled compounds, which have high affinity for sigma receptor and show higher specific accumulation in tumor. Previously, we synthesized aza-vesamicol homologous. In this study, we also synthesized homologues, which contain a cyclopentane ring instead of a cyclohexane ring, and evaluated them because it was reported that the cyclopentane ring could increase the selectivity of sigma-1 receptor.
Methods: Iodine introduced compounds were synthesized from the corresponding bromine compounds. 125I-labeled compounds were prepared using iododestannylation of the corresponding trimethylstannyl precursor with in high radiochemical yields (65-78%) and purities (>99%). Sigma receptor binding assays, cell uptake studies, and biodistribution experiments were performed. Results: 2-{4-[2-(3-iodophenyl)ethyl]piperazin-1-yl}cyclopentane-1-ol (1) and 2-{4-[3-(3-iodophenyl)propyl]piperazin-1-yl}cyclopentane-1-ol (2) showed high affinity for sigma-1 receptor (Ki = 7.9 and 10.9 nM, respectively) in aza-vesamicol homologous. 2 showed high affinity for sigma-2 receptor also (Ki = 9.9 nM). [125I]1 and [125I]2 showed high uptake in the sigma-1 receptor expressed DU-145 in the cell uptake study. The uptakes were significantly inhibited by haloperidol as a blocking agent. In biodistribution study, [125I]1 and [125I]2 showed higher tumor/background ratios than previous our tracers. Conclusion: The results indicates that radiohalogen labeled 1 and 2 are promising agent for not only sigma receptor imaging but also receptor radionuclide therapy.