In vitro and in vivo m2 muscarinic subtype selectivity of some dibenzodiazepinones and pyridobenzodiazepinones

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not mi, subtype receptors in cortical and hippocampal regions of the human brain. Emission tomographic study of the loss of m2 receptors in AD has been limited by the absence of available m2-selective radioligands, which can penetrate the blood-brain barrier. We now report on the in vitro and in vivo m2 muscarinic subtype selectivity of a series of dibenzodiazepinones and pyridobenzodiazepinones determined by competition studies against (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[I-125]IQNB) or [H-3]QNB. Of the compounds examined, three of the 5-[[4-[(4-dialkylamino)butyl]-1-piperidinyl]acetyl]- 10,11-dihydro-5-H-dibenzo[b, e][1,4]diazepin-11-ones (including DIBA) and three of the 11-[[4-[4-(dialkylamino)butyl]-1-phenyl]acetyl]-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-ones (including PBID) exhibited both high binding affinity for the m2 subtype (less than or equal to 5 nM) and high m(2)/ml selectivity (greater than or equal to 10). In vive rat brain dissection studies of the competition of PBID or DIED against (R,S)[I-125]IQNB or [H-3]QNB exhibited a dose-dependent preferential decrease in the binding of the radiotracer in brain regions that are enriched in the m2 muscarinic subtype. In vivo rat brain autoradiographic studies of the competition of PBID, BIBN 99, or DIBD against (R,S)[I-125]IQNB exhibited an insignificant effect of BIBN 99 and confirmed the effect of PBID and DIED in decreasing the binding of (R,S)[I-125]IQNB in brain regions that are enriched in the m2 muscarinic subtype. We conclude that PBID and DIED are potentially useful parent compounds from which in vive m2 selective derivatives may be prepared for potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD. (C) 2000 Published by Elsevier Science B.V. All rights reserved.