Syntheses and biological properties of chiral fluoroalkyl quinuclidinyl benzilates

Article abstract of DOI:10.1021/jm00010a016

Previously, (R)-quinuclidinyl (R)-4-iodobenzilate ((R,R)-IQNB), a muscarinic receptor antagonist, has been labeled with ¹²³I and ¹²⁵I for use in in vitro and in vivo studies in animals and humans. We have prepared fluoroalkyl analogs of QNB, which are amenable to labeling with ¹⁸F, for potential imaging applications with positron emission tomography. The enantiomers of (fluoroalkyl)benzilic acids were prepared via an enantioselective Grignard addition reaction. Subsequent coupling of the enantiomeric (fluoroalkyl)benzilic acid with a selected enantiomer of quinuclidinol provides fluorinated analogs of QNB with known stereochemistry at each of the stereogenic centers. These compounds exhibit different affinities for the muscarinic receptor tissue subtypes in vitro. (R,R)-4- (Fluoromethyl)-QNB, (R,R)-IQNB, and (R,R)-4-(fluoroethyl)-QNB exhibit selectivity for the M1 subtype, and (R,S)-4-(fluoromethyl)-QNB exhibits selectivity for the M2 subtype.