AUTORADIOGRAPHIC EVIDENCE THAT (R)-3-QUINUCLIDINYL (S)-4-FLUOROMETHYLBENZILATE ((R,S)-FMEQNB) DISPLAYS IN-VIVO SELECTIVITY FOR THE MUSCARINIC M2 SUBTYPE

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in cortical and hippocampal regions of the human brain. Until recently, emission tomographic study of the lo ss of m2 receptors in AD has been limited by the absence of available m2 selective radioligands that can penetrate the blood brain barrier. We now demonstrate the in vivo m2 selectivity of a fluorinated derivat ive of QNB, (R)-3-quinuclidinyl (S)-4-fluoromethylbenzilate ((R,S)-FMe QNB), by studying autoradiographically the in vivo inhibition of radio iodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[I-125]IQNB) binding by unlabelled (R,S)-FMeQNB. In the absence of (R,S)-FMeQNB, (R ,S)-[I-125]IQNB labels brain regions in proportion to the total muscar inic receptor concentration; in the presence of 75 nmol of (R,S)-FMeQN B, (R,S)-[I-125]IQNB labelling in those brain regions containing predo minantly m2 subtype is reduced to background levels. We conclude that (R,S)-FMeQNB is m2 selective in vivo, and that (R,S)-[F-18]FMeQNB may be of potential use in positron emission tomographic (PET) study of th e loss of m2 receptors in AD. Copyright (C) Elsevier Science Inc.