Synthesis and initial in vitro characterization of 6-[18
F]fluoro-3-(2(S)-azetidinylmethoxy)puridine, a high-affinity radioligand for central nicotinic acetylcholine receptors
6-[18F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine ([18F]1), a novel analogue of the high-affinity nicotinic acetylcholine receptor ligand, A-85380, was prepared by a two-step procedure from an appropriate nitro precursor. In the first step, a Kryptofix 222-assisted 18F nucleophilic heteroaromatic substitution in 6-nitro-3-((1-tert-butoxycarbonyl-2(S)-azetidinyl)methoxy)pyridine provided a radiofluorinated Boc-protected intermediate. Subsequent acidic deprotection of the intermediate gave [18F]1 with an overall radiochemical yield of 8 to 12% (non-decay-corrected). The typical synthesis time was ca. 110 min. Specific radioactivity of the final product ranged from 1000 to 4500 mCi/μmol, as calculated at the end-of-synthesis. In vitro studies demonstrated that the novel radioligand bound to a single population of sites in rat brain membranes, presumably, to the α4β2 subtype of nicotinic acetylcholine receptor. This binding was characterized by a K(d) value of 28 pM, consistent with the K(i) value of 25 pM, derived previously for unlabeled 1 in competition assays with (±)-[3H]epibatidine.
Koren, AO; Horti, AG; Mukhin, AG; Gündisch, D; Dannals, RF; London, ED
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