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 σ receptors (σ-1, σ-2) were evaluated by in vitro binding assays using rat cerebral or liver membranes. OIDV and OBDV showed greater binding affinity to VAChT (Ki = 20.5 ± 5.6 and 13.8 ± 1.2 nM, respectively) than did vesamicol (Ki = 33.9 ± 18.1 nM) with low affinity to σ receptors. A saturation binding assay in rat cerebral membranes revealed that [125I]OIDV had a single high affinity binding site with a Kd value of 1.73 nM and a Bmax value of 164.4 fmol/mg protein. [125I]OIDV revealed little competition with inhibitors, which possessed specific affinity to each σ (σ-1 and σ-2), serotonin (5-HT1A and 5-HT2A), noradrenaline, and muscarinic acetylcholine receptors. In addition, BBB penetration of [125I]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.

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