Description:
<jats:title>Abstract</jats:title><jats:p>Nicotinic acetylcholine receptors (nAChRs) play an important role in many central nervous system disorders such as Alzheimer’s and Parkinson’s diseases, schizophrenia, and mood disorders. The α<jats:sub>4</jats:sub>β<jats:sub>2</jats:sub> subtype has emerged as an important target for the early diagnosis and amelioration of Alzheimer’s disease symptoms. Herein we report a new class of α<jats:sub>4</jats:sub>β<jats:sub>2</jats:sub> receptor ligands characterized by a basic pyrrolidine nucleus, the basicity of which was properly decreased through the insertion of a fluorine atom at the 3‐position, and a pyridine ring carrying at the 3‐position substituents known to positively affect affinity and selectivity toward the α<jats:sub>4</jats:sub>β<jats:sub>2</jats:sub> subtype. Derivatives 3‐(((2<jats:italic>S</jats:italic>,4<jats:italic>R</jats:italic>)‐4‐fluoropyrrolidin‐2‐yl)methoxy)‐5‐(phenylethynyl)pyridine (<jats:bold>11</jats:bold>) and 3‐((4‐fluorophenyl)ethynyl)‐5‐(((2<jats:italic>S</jats:italic>,4<jats:italic>R</jats:italic>)‐4‐fluoropyrrolidin‐2‐yl)methoxy)pyridine (<jats:bold>12</jats:bold>) were found to be the most promising ligands identified in this study, showing good affinity and selectivity for the α<jats:sub>4</jats:sub>β<jats:sub>2</jats:sub> subtype and physicochemical properties predictive of a relevant central nervous system penetration.</jats:p>