Synthesis and evaluation of 6-[¹⁸F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine as a PET tracer for nicotinic acetylcholine receptors

Both ABT-594 ((R)-2-chloro-5-(2-azetidinylmethoxy)pyridine) and A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine), novel nicotinic agonists that possess potent non-opioid analgesic properties, have high affinity for neuronal nicotinic acetylcholine receptors (nAChR) but do not elicit the pronounced toxicity of epibatidine. 6-[¹⁸F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[¹⁸F]fluoro-A-85380), a F-18 labeled analogue of these two compounds, is therefore a promising radioligand for positron emission tomography (PET) studies in humans. The use of trimethylammonium as a leaving group in nucleophilic aromatic substitution reactions has proven to be a versatile and efficient strategy, and offers several advantages over other leaving groups. Here, we report the synthetic strategy for the preparation of a precursor, as a trimethylammonium iodide salt, and its use in the radiosynthesis to 6-[¹⁸F]fluoro-A-85380. Preliminary compartative PET studies of 6-[¹⁸F]fluoro-A-85380 and 2-[¹⁸F]fluoro-A-85380 were carried out in baboon to examine their suitability as tracers for studying nAChR system. (C) 2000 Elsevier Science Inc.