209530-92-7Relevant academic research and scientific papers
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
Dollé, Frédéric,Dolci, Lilian,Valette, Héric,Hinnen, Fran?oise,Vaufrey, Fran?oise,Guenther, Ilonka,Fuseau, Chantal,Coulon, Christine,Bottlaender, Michel,Crouzel, Christian
, p. 2251 - 2259 (2007/10/03)
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 α4β2 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 [3H]cytisine or [3H]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[18F]F-K222 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 [18F]fluoride ion radioactivity, were 68- 72% (decay-corrected) and 49-52% (non-decay-corrected), and the specific radioactivities at EOB were 4-7 Ci/μmol (148-259 GBq/μmol). In vivo characterization of [18F]F-A-85380 showed promising properties for PET imaging of central nAChRs. This compound does not bind in vivo to α7 nicotinic or 5HT3 receptors. Moreover, its cerebral uptake can be modulated by the synaptic concentration of the endogenous ligand acetylcholine. The preliminary PET experiments in baboons with [18F]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). [18F]F-A-85380 appears to be a suitable radioligand for brain imaging nAChRs with PET.
Synthesis of 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine, a highly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors
Dolle, Frederic,Valette, Heric,Bottlaender, Michel,Hinnen, Francoise,Vaufrey, Francoise,Guenther, Ilonka,Crouzel, Christian
, p. 451 - 463 (2007/10/03)
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.
