Synthesis and evaluation of N-[11C]methylated analogues of epibatidine as tracers for positron emission tomographic studies of nicotinic acetylcholine receptors

Andrew G. Horti, Ursula Scheffel, Alane S. Kimes, John L. Musachio, Hayden T. Ravert, William B. Mathews, Yougen Zhan, Paige A. Finley, Edythe D. London, Robert F. Dannals

Research output: Contribution to journalArticle

Abstract

Four halogen-substituted analogues of N-methylepibatidine, a nicotinic acetylcholine receptor (nAChR) ligand, were synthesized. They were (±)-exo- N-methyl-2-(2-halogeno-5-pyridyl)-7-azabicyclo[2.2.1]heptanes, where halogeno = F (1a), C1 (2a), Br (3a), I (4a). (±)-N-Ethylepibatidine (2b) also was synthesized. The compounds 1a, 2a, 3a, and 4a and their corresponding normethyl analogues 1, 2, 3, and 4 inhibited the in vitro binding of [3H]epibatidine to nAChRs to a similar degree, with affinities in the 27-50 pM range. The binding affinity of N-ethylepibatidine (2b), however, was substantially lower. The N-[11C]methyl derivatives of 1, 2, and 3 were synthesized from high-specific radioactivity [11C]methyl iodide using a high' temperature/high-pressure technique. The corresponding radiolabeled compounds [11C]1a, [11C]2a, and [11C]3a were administrated to mice intravenously. The pattern of regional distribution of the three tracers in the mouse brain following intravenous administration matched those of [3H]epibatidine, [3H]norchloroepibatidine, and (±)-exo-2-(2-[18F]fluoro- 5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), which are highly specific nAChR probes. The initial brain uptake of the 13C analogues and the acute toxicity of the corresponding authentic nonlabeled compounds appeared to be related to their lipophilicity.

Original languageEnglish (US)
Pages (from-to)4199-4206
Number of pages8
JournalJournal of medicinal chemistry
Volume41
Issue number22
DOIs
StatePublished - Oct 23 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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