[H-3] QNB DISPLAYS IN-VIVO SELECTIVITY FOR THE M2 SUBTYPE

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of th e human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-s elective radioligand which can penetrate the blood-brain barrier. [H-3 ](R)-3-quinuclidinylbenzilate ([H-3]QNB) is commonly used for performi ng in vitro studies of the muscarinic acetylcholine receptor (mAChR), either with membrane homogenates or with autoradiographic slices, in w hich [H-3]QNB is nonsubtype-selective. We report here the results of i n vivo studies, using both carrier-free and low specific activity [H-3 ]QNB, which show that [H-3]QNB exhibits a substantial in vivo m2-selec tivity. Previously reported in vivo (R)-3-quinuclidinyl (R)-4-iodobenz ilate ((R,R)-[I-125]IQNB) binding appears to be nonsubtype-selective. Apparently the bulky iodine substitution in the 4 position reduces the subtype selectivity of QNB. it is possible that a less bulky fluorine substitution might permit retention of the selectivity exhibited by Q NB itself. We conclude that a suitably radiolabeled derivative of QNB, possibly labeled with F-18, may be of potential use in positron emiss ion tomographic (PET) study of the loss of m2 receptors in AD.