Syntheses and evaluation of a homologous series of aza-vesamicol as improved radioiodine-labeled probes for sigma-1 receptor imaging.

Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol (5) (K = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5. The radioiodine labeled probe [I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([I]10) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both in vitro and in vivo. Co-injection of [I]10 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo, indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes.