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 brai n. Emission tomographic study of the loss of m2 receptors in AD has been li mited by the absence of available m2-selective radioligands, which can pene trate the blood-brain barrier. We now report on the in vitro and in vivo m2 muscarinic subtype selectivity of a series of dibenzodiazepinones and pyri dobenzodiazepinones determined by competition studies against (R)-3-quinucl idinyl (S)-4-iodobenzilate ((R,S)-[I-125]IQNB) or [H-3]QNB. Of the compound s 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) an d 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 d issection studies of the competition of PBID or DIED against (R,S)[I-125]IQ NB or [H-3]QNB exhibited a dose-dependent preferential decrease in the bind ing of the radiotracer in brain regions that are enriched in the m2 muscari nic subtype. In vivo rat brain autoradiographic studies of the competition of PBID, BIBN 99, or DIBD against (R,S)[I-125]IQNB exhibited an insignifica nt effect of BIBN 99 and confirmed the effect of PBID and DIED in decreasin g 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 usef ul parent compounds from which in vive m2 selective derivatives may be prep ared 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.