Evaluation of 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(S)- pyrrolidinylmethoxy)pyridine and its analogues as PET radioligands for imaging nicotinic acetylcholine receptors

La Verne Brown, Svetlana Chefer, Olga Pavlova, D. Bruce Vaupel, Andrei O. Koren, Alane S. Kimes, Andrew G. Horti, Alexey G. Mukhin

Research output: Contribution to journalArticlepeer-review

Abstract

A novel series of compounds derived from the high-affinity nicotinic acetylcholine receptor (nAChR) ligand, 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-((1- methyl-2-(S)-pyrrolidinyl)methoxy)pyridine (Me-p-PVC), originally developed by Abbott Laboratories, was characterized in vitro in nAChR binding assays at 37°C to show Ki values in the range of 9-611 pM. Several compounds of this series were radiolabeled with 11C and evaluated in vivo in mice and monkeys as potential candidates for PET imaging of nAChRs. [11C]Me-p-PVC (Ki = 56 pM at 37°C; logD = 1.6) was identified as a radioligand suitable for the in vivo imaging of the α4β2* nAChR subtype. Compared with 2-[18F]FA, a PET radioligand that has been successfully used in humans and is characterized by a slow kinetic of brain distribution, [11C]Me-p-PVC is more lipophilic. As a result, [11C]Me-p-PVC accumulated in the brain more rapidly than 2-[18F]FA. Pharmacological evaluation of Me-p-PVC in mice demonstrated that the toxicity of this compound was comparable with or lower than that of 2-FA. Taken together, these results suggest that [ 11C]Me-p-PVC is a promising PET radioligand for studying nAChR occupancy by endogenous and exogenous ligands in the brain in vivo.

Original languageEnglish (US)
Pages (from-to)600-612
Number of pages13
JournalJournal of Neurochemistry
Volume91
Issue number3
DOIs
StatePublished - Nov 2004
Externally publishedYes

Keywords

  • Nicotinic acetylcholine receptor
  • Positron emission tomography
  • Receptor binding

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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