Synthesis and evaluation of 6-[F-18]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 nic otinic acetylcholine receptors (nAChR) but do not elicit the pronounced tox icity of epibatidine. 6-[F-18]Fluoro-3-(2(S)-azetidinylmethoxy) (6-[F-18]fl uoro-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 aro matic substitution reactions has proven to be a versatile and efficient str ategy, and offers several advantages over other leaving groups. Here, we re port the synthetic strategy for the preparation of a precursor, as a trimet hylammonium iodide salt, and its use in the radiosynthesis to 6-[F-18]fluor o-A-85380. Preliminary compartative PET studies of 6-[F-18]fluoro-A-85380 a nd 2-[F-18]fluoro-A-85380 were carried out in baboon to examine their suita bility as tracers for studying nAChR system. NUCL MED BIOL 27;4: 381-389, 2 000. (C) 2000 Elsevier Science Inc. All rights reserved.