Synthesis of 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine, a highly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors

Abstract

This paper reports the synthesis of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine and its radiolabeling with fluorine-18 ([18F]FK-K222) by nucleophilic aromatic nitro-to-fluoro substitution in DMSO by conventional heating at 150°C for 20 min or by microwave activation at 100 Watt for 1 min. This fluoro compound is a closely related analog of the high affinity nicotinic ligand A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine). This compound is the lead compound of a novel 3-pyridyl ether series of new nAChR ligands recently published, and possesses not only subnanomolar affinity, comparable to that of epibatidine, for the α4β2 subtype, but also a weaker affinity for the other subtypes of nAChRs. 110–140 mCi (4.1–5.2 GBq) of pure 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380) could be obtained in less than 2 hours, with specific radioactivities of 3–5 Ci/μmol (111–185 GBq/μmol) calculated for End of Bombardment (or 1.5–2.5 Ci/μmol (55.5–92.5 GBq/μmol) at End of Synthesis) for a 20 μA, 30 min (36000 μC) irradiation of a 95% enriched [18O]water target with a 16 MeV proton beam [18O(p,n)18F]. Yields (with respect to [18F]fluoride ion): decay-corrected 49–64%; non-decay-corrected 25–33%. Total synthesis time from EOB: 105–110 min (this includes the recovery of the [18F]fluoride ion from the target and the [18F]FK-K222-complex preparation). Preliminary results in rats showed a substantial uptake of the ligand in the thalamus (1% I.D./g tissue at 30 min) while the cerebellar uptake was 2-fold lower. Thalamic uptake was reduced by 75–85% following a pre-treatment with nicotine, cytisine, epibatidine or fluoro-A-85380. The full pharmacological profile and the potential for eventual clinical applications of this ligand as a tracer for PET experiments are currently under investigation. © 1998 John Wiley & Sons, Ltd.