SYNTHESIS OF [F-18]FLUORO-3-[2(S)-2-AZETIDINYLMETHOXY]PYRIDINE, A HIGHLY POTENT RADIOLIGAND FOR IN-VIVO IMAGING CENTRAL NICOTINIC ACETYLCHOLINE-RECEPTORS

This paper reports the synthesis of 2-fluoro-3-[2(S)-2-azetidinylmetho xyl] and its radiolabeling with fluorine-18 ([F-18]FK-K-222) by nucleo philic aromatic nitro-to-fluoro substitution in DMSO by conventional h eating at 150 degrees C for 20 min or by microwave activation at 100 W att For 1 min. This fluoro compound is a closely related analog of the high affinity nicotinic ligand A-85380 (3-[2(S)-2-azetidinylmethoxy]p yridine) This compound is the lead compound of a novel 3-pyridyl ether series sf new nAChR ligands recently published, and possesses not onl y subnanomolar affinity, comparable to that of epibatidine, for the al pha 4 beta 2 subtype, but also a weaker affinity for the other subtype s of nAChRs. 110-140 mCi (4. -5.2 GBq) of pure -[F-18]fluoro-3-[2(S)-2 -azetidinylmethoxy]pyridine ([F-18]fluoro-A-85380) could be obtained i n less than 2 !lours, with specific radioactivities of 3-5 Ci/mu mol ( 111-185 GBq/mu mol) calculated for End of Bombardment (or 1.5-2.5 Ci/m u mol (55.5-92.5 GBq/mu mol) at End of Synthesis) for a 20 mu A, 30 mi n (36000 mu C) irradiation of a 95% enriched [O-18]water target with a 16 MeV proton beam [O-18(p,n)F-18]. Yields (with respect to [F-18]flu oride ion) : decay-corrected 49-64%; non-decay-corrected 25-33%. Total synthesis rime from EOB : 105-110 min (this includes the recovery of the [F-18]fluoride ion from the target and the [F-18]FK-K-222-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 c erebellar uptake was 2-fold lower. Thalamic uptake was reduced by 75-8 5% following a pretreatment with nicotine, cytisine, epibatidine or fl uoro-A-85380. The full pharmacological profile and the potential for e ventual clinical applications of this ligand as a tracer for PET exper iments are currently under investigation.