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

Article abstract of DOI:10.1002/(SICI)1099-1344(199805)41:5<451::AID-JLCR111>3.0.CO;2-R

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 comparable to that of epibatidine, for the α4β2 subtype, but also a weaker affinity for the other subtypes or nAChRs. 110-140 mCl (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]. Yield (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.