Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine:: A new positron emission tomography ligand for nicotinic receptors

The lead compound of a new series of 3-pyridyl ethers, the azetidine derivative A-85380 (3-[(S)-2-azetidinylmethoxy]pyridine), is a potent and selective ligand for the human alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR) subtype. In vitro, the fluoro derivative of A-85380 (2-fluoro-3-[(S)-2-azetidinylmethoxy]pyridine or F-A-85380) competitively displaced [H-3]cytisine or [H-3]epibatidine with K-i values of 48 and 46 pM, respectively. F-A-85380 has been labeled with the positron emitter fluorine-18 (t(1/2) (half-life) = 110 min) by no-carrier-added nucleophilic aromatic substitution by K[F-18]F-K-222 complex with (3-[2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridin-2-yl)trimethylammonium trifluoromethanesulfonate as a highly efficient labeling precursor, followed by TFA removal of the Boc protective group. The total synthesis time was 50-53 min from the end of cyclotron fluorine-18 production (EOB). Radiochemical yields, with respect to initial [F-18]fluoride ion radioactivity, were 68-72% (decay-corrected) and 49-52% (non-decay-corrected), and the specific radioactivities at EOB were 4-7 Ci/mu mol (148-259 GBq/mu mol). In vivo characterization of [F-18]F-A-85380 showed promising properties for PET imaging of central nAChRs. This compound does not bind in vivo to alpha 7 nicotinic or 5HT(3) receptors. Moreover, its cerebral uptake can be modulated by the synaptic concentration of the endogenous ligand acetylcholine. The preliminary PET experiments in baboons with [F-18]F-A-85380 show an accumulation of the radiotracer in the brain within 60 min. In the thalamus, a nAChR-rich area, uptake of radioactivity reached a maximum at 60 min (4% I.D./100 mL of tissue). [F-18]F-A-85380 appears to be a suitable radioligand for brain imaging nAChRs with PET.