In Vivo Differences between Two Optical Isomers of Radioiodinated o-iodo-trans-decalinvesamicol for Use as a Radioligand for the Vesicular Acetylcholine Transporter

PURPOSE: To develop a superior VAChT imaging probe for SPECT, radiolabeled (-)-OIDV and (+)-OIDV were isolated and investigated for differences in their binding affinity and selectivity to VAChT, as well as their in vivo activities. PROCEDURES: Radioiodinated o-iodo-trans-decalinvesamicol ([(125)I]OIDV) has a high binding affinity for vesicular acetylcholine transporter (VAChT) both in vitro and in vivo. Racemic [(125)I]OIDV was separated into its two optical isomers (-)-[(125)I]OIDV and (+)-[(125)I]OIDV by HPLC. To investigate VAChT binding affinity (Ki) of two OIDV isomers, in vitro binding assays were performed. In vivo biodistribution study of each [(125)I]OIDV isomer in blood, brain regions and major organs of rats was performed at 2,30 and 60 min post-injection. In vivo blocking study were performed to reveal the binding selectivity of two [(125)I]OIDV isomers to VAChT in vivo. Ex vivo autoradiography were performed to reveal the regional brain distribution of two [(125)I]OIDV isomers and (-)-[(123)I]OIDV for SPECT at 60 min postinjection. RESULTS: VAChT binding affinity (Ki) of (-)-[(125)I]OIDV and (+)-[(125)I]OIDV was 22.1 nM and 79.0 nM, respectively. At 2 min post-injection, accumulation of (-)-[(125)I]OIDV was the same as that of (+)-[(125)I]OIDV. However, (+)-[(125)I]OIDV clearance from the brain was faster than (-)-[(125)I]OIDV. At 30 min post-injection, accumulation of (-)-[(125)I]OIDV (0.62 ± 0.10%ID/g) was higher than (+)-[(125)I]OIDV (0.46 ± 0.07%ID/g) in the cortex. Inhibition of OIDV binding showed that (-)-[(125)I]OIDV was selectively accumulated in regions known to express VAChT in the rat brain, and ex vivo autoradiography further confirmed these results showing similar accumulation of (-)-[(125)I]OIDV in these regions. Furthermore, (-)-[(123)I]OIDV for SPECT showed the same regional brain distribution as (-)-[(125)I]OIDV. CONCLUSION: These results suggest that radioiodinated (-)-OIDV may be a potentially useful tool for studying presynaptic cholinergic neurons in the brain.