Syntheses and in vitro evaluation of decalinvesamicol analogues as potential imaging probes for vesicular acetylcholine transporter (VAChT)

A series of vesamicol analogues, o-iodo-trans-decalinvesamicol (OIDV) or o-bromo-trans-decalinvesamicol (OBDV), were synthesized and their affinities to vesicular acetylcholine transporter (VAChT) and sigma receptors (sigma-1, sigma-2) were evaluated by in vitro binding assays using rat cerebral or liver membranes. OIDV and OBDV showed greater binding affinity to VAChT (K-i = 20.5 +/- 5.6 and 13.8 +/- 1.2 nM, respectively) than did vesamicol (K-i = 33.9 +/- 18.1 nM) with low affinity to r receptors. A saturation binding assay in rat cerebral membranes revealed that [I-125]OIDV had a single high affinity binding site with a K-d value of 1.73 nM and a B-max value of 164.4 fmol/mg protein. [I-125]OIDV revealed little competition with inhibitors, which possessed specific affinity to each sigma (sigma-1 and sigma-2), serotonin (5-HT1A and 5-HT2A), noradrenaline, and muscarinic acetylcholine receptors. In addition, BBB penetration of [I-125]OIDV was verified in in vivo. The results of the binding studies indicated that OIDV and OBDV had great potential to be VAChT imaging probes with high affinity and selectivity. (C) 2012 Elsevier Ltd. All rights reserved.