Synthesis and evaluation of a novel series of 2-chloro-5-((1-methyl-2-(S)-pyrrolidinyl)methoxy)- 3-(2-(4-pyridinyl)vinyl)pyridine analogues as potential positron emission tomography imaging agents for nicotinic acetylcholine receptors

La Verne L. Brown, Santosh Kulkarni, Olga A. Pavlova, Andrei O. Koren, Alexey G. Mukhin, Amy H. Newman, Andrew G. Horti

Research output: Contribution to journalArticle

Abstract

Reportedly, 2-[18F]fluoro-A-85380, 1, a promising radiotracer for imaging the nicotinic acetylcholine receptor (nAChR) by positron emission tomography (PET) in humans, exhibits slow penetration through the blood-brain barrier (BBB) due to its low lipophilicity. A ligand for nAChRs with greater lipophilicity than that of 1 would be potentially more favorable for PET imaging of nAChR due to its faster penetration through the BBB. Herein, a novel series of compounds has been developed based on the high affinity ligand for nAChRs, 2-chloro-5-((1-methyl-2-(S)-pyrrolidinyl)methoxy)- 3-(2-(4-pyridinyl)vinyl)pyridine, 3b. The in vitro binding affinities for the new series were found to be in the range of Ki = 9-331 pM. A molecular modeling study showed differences in the comformational profiles and the electronic properties of these compounds, which provides further insight into the structure-activity relationships at nAChR. Lipophilicities of the compounds 3b-6b have been found to be substantially higher than that of 1. As a result, compounds 3b-6b might exhibit a faster penetration through the BBB than the less lipophilic 1. The N-methyl derivatives 3b and 6b demonstrated very high affinities at nAChRs (Ki = 28 and 23 pM, respectively) and will be targets for development of 11CH3-labeled derivatives as radiotracers for PET imaging of nAChRs.

Original languageEnglish (US)
Pages (from-to)2841-2849
Number of pages9
JournalJournal of medicinal chemistry
Volume45
Issue number13
DOIs
StatePublished - Jun 20 2002
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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