Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for the cholinergic system. A potent and selective VAChT inhibitor containing fluorine atom can be radiolabeled with [18F]/F-, and potentially serves as a PET probe for imaging the cholinergic system in vivo. We report the design, syntheses of fluorine containing VAChT ligands, and in vitro binding affinities of these ligands toward VAChT and their selectivity for VAChT over sigma receptors.Fifteen novel benzovesamicol derivatives were synthesized and fully characterized. Structural-activity relationship (SAR) study suggested: a) 5-Substitution on the A-moiety increases VAChT potency, with 5-fluoroethoxy > 5-hydroxy > 5-amino > unsubstituted; b) PEGylation on the C-ring lead to higher selectivity to sigma receptors; c) VAChT binding is stereoselective, with the (-)-isomer having a higher potency than the (+)-counterpart. Utilizing in vitro screening, 6 compounds were identified possessing high potency for VAChT ( 500-fold). These 6 compounds can be radiolabeled with F-18 to be evaluated as PET probes for imaging VAChT in vivo.

Syntheses and in vitro evaluation of fluorine-containing inhibitors for vesicular acetylcholine transporter

248th National Meeting (2014)

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