Synthesis and evaluation of in vitro bioactivity for vesicular acetylcholine transporter inhibitors containing two carbonyl groups

To identify selective high-affinity ligands for the vesicular acetylcholine transporter (VAChT), we have incorporated a carbonyl group into the structures of trozamicol and prezamicol scaffolds, and also converted the secondary amines of the piperidines of trozamicols and prezamicols into amides. Of 18 new racemic compounds, 4 compounds displayed high affinity for VAChT (K-i = 10-20 nM) and greater than 300-fold selectivity for VAChT over sigma(1) and sigma(2) receptors, namely (4-(4-fluorobenzoyl)-4'-hydroxy-[1,3'-bipiperidin]-1'-yl)(3-methylthiophen-2-yl) methanone oxalate (9g) (Ki-VAChT = 11.4 nM, VAChT/sigma(1) = 1063, VAChT/sigma(2) = 370), (1'-benzoyl-4'-hydroxy-[1,3'-bipiperidin]-4-yl)(4-methoxyphenyl) methanone oxalate (10c) (Ki-VAChT = 15.4 nM, VAChT/sigma(1) = 374, VAChT/sigma(2) = 315), (4'-hydroxy-1'-(thiophene-2-carbonyl)-[1,3'-bipiperidin]-4-yl)(4-methoxyphenyl) methanone oxalate (10e) (K-i-(VAChT) = 19.0 nM, VAChT/sigma(1) = 1787, VAChT/sigma(2) = 335), and (4'-hydroxy-1'-(3-methylthiophene-2-carbonyl)-[1,3'-bipiperidin]- 4-yl)(4-methoxyphenyl) methanone oxalate (10g) (Ki-VAChT = 10.2 nM, VAChT/sigma(1) = 1500, VAChT/sigma(2) = 2030). These four compounds can be radiosynthesized with C-11 or F-18 to validate their possibilities of serving as PET probes for quantifying the levels of VAChT in vivo. (C) 2012 Elsevier Ltd. All rights reserved.