AUTORADIOGRAPHIC EVIDENCE THAT QUINUCLIDINYL 4-(BROMOPHENYL)-2-THIENYLGLYCOLATE (QBPTG) 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. Emission tomographic study of the loss of m2 recepto rs in AD is limited by the fact that there is currently no available m 2-selective radioligand which can penetrate the blood-brain barrier. W e now demonstrate the in vivo m2 selectivity of an analogue of QNB, 4- (bromophenyl)-2-thienylglycolate (QBPTG), by studying autoradiographic ally the in vivo inhibition of radioiodinated (R)-3-quinuclidinyl (S)- 4-iodobenzilate ((R,S)-[I-125]IQNB) binding by unlabeled QBPTG in rat brain. In the absence of QBPTG, (R,S)-[(125)]IQNB labels brain regions in proportion to the total muscarinic receptor concentration; in the presence of 37.5 nmol of racemic QBPTG, (R,S)-[(125)]IQNB labeling in those brain regions containing predominantly the m2 subtype is reduced to background levels. We conclude that QBPTG is m2-selective in vivo and that [Br-76]QBPTG, or a radiofluorinated analogue, may be of poten tial use in positron emission tomographic study of the loss of m2 rece ptors in AD. In addition, a radioiodinated analogue may be of potentia l use in single photon emission tomographic studies. (C) 1995 Academic Press, Inc.