5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography

摘要: Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and lipophilicity (log D) ranging from −1.6 to +1.5 have been synthesized. Most members of series, which are derivatives 5-substituted-6-halogeno-A-85380, exhibited a higher binding α4β2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role orientation additional heterocyclic ring on nAChRs. The existing pharmacophore models do not accommodate this finding. Two compounds 6-[18F]fluoro-5-(pyridin-3-yl)-A-85380 ([18F]31) 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[18F]fluoropyridin-5-yl)pyridine) ([18F]35), were radiolabeled 18F. Comparison PET data for [18F]31 2-[18F]FA shows influence potential. Our recent studies [18F]35 demonstrated that its potential values in Rhesus monk...