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 σ ₁ and σ ₂ receptors, namely (4-(4-fluorobenzoyl)-4′-hydroxy- [1,3′-bipiperidin]-1′-yl)(3-methylthiophen-2-yl)methanone oxalate (9g) (K _i-VAChT = 11.4 nM, VAChT/σ ₁ = 1063, VAChT/σ ₂ = 370), (1′-benzoyl-4′-hydroxy-[1, 3′-bipiperidin]-4-yl)(4-methoxyphenyl)methanone oxalate (10c) (K _i-VAChT = 15.4 nM, VAChT/σ ₁ = 374, VAChT/σ 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/σ ₁ = 1787, VAChT/σ ₂ = 335), and (4′-hydroxy-1′-(3- methylthiophene-2-carbonyl)-[1,3′-bipiperidin]-4-yl)(4-methoxyphenyl) methanone oxalate (10g) (K _i-VAChT = 10.2 nM, VAChT/σ ₁ = 1500, VAChT/σ 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.