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

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.