Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter

Junfeng Li, Xiang Zhang, Zhanbin Zhang, Prashanth K. Padakanti, Hongjun Jin, Jinquan Cui, Aixiao Li, Dexing Zeng, Nigam P. Rath, Hubert Flores, Joel S. Perlmutter, Stanley M. Parsons, Zhude Tu

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)6216-6233
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number15
StatePublished - Aug 8 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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