SYNTHESES AND BIOLOGICAL PROPERTIES OF CHIRAL FLUOROALKYL QUINUCLIDINYL BENZILATES

Previously, (R)-quinuclidinyl (R)-4-iodobenzilate ((R,R)-IQNB), a musc arinic receptor antagonist, has been labeled with I-123 and I-125 for use in in vitro and in vivo studies in animals and humans. We have pre pared fluoroalkyl analogs of QNB, which are amenable to labeling with F-18, for potential imaging applications with positron emission tomogr aphy. The enantiomers of (fluoroalkyl)benzilic acids were prepared via an enantioselective Grignard addition reaction. Subsequent coupling o f the enantiomeric (fluoroalkyl)benzilic acid with a selected enantiom er of quinuclidinol provides fluorinated analogs of QNB with known ste reochemistry at each of the stereogenic centers. These compounds exhib it different affinities for the muscarinic receptor tissue subtypes in vitro. (R,R)-4-(Fluoromethyl)-QNB, (R,R)-IQNB, and (R,R)-4-(fluoroeth yl)-QNB exhibit selectivity for the M1 subtype, and (R,S)-4-(fluoromet hyl)-QNB exhibits selectivity for the M2 subtype.