To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[11C]24b (Ki = 0.78 nM for VAChT, 1200-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[11C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.