[3H]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 the 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-selective radioligand which can penetrate the blood-brain barrier. [3H](R)-3-quinuclidinylbenzilate ([3H]QNB) is commonly used for performing in vitro studies of the muscarinic acetylcholine receptor (mAChR), either with membrane homogenates or with autoradiographic slices, in which [3H]QNB is nonsubtype-selective. We report here the results of in vivo studies, using both carrier-free and low specific activity [3H]QNB, which show that [3H]QNB exhibits a substantial in vivo m2-selectivity. Previously reported in vivo (R)-3-quinuclidinyl (R)-4-iodobenzilate ((R,R)-[125I]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 QNB itself. We conclude that a suitably radiolabeled derivative of QNB, possibly labeled with 18F, may be of potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD.
Department of Radiology, George Washington University Medical Center, Washington, D.C.
M S
MS
Gitler
R
R
De la Cruz
B R
BR
Zeeberg
R C
RC
Reba
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D008432:Mathematical Computing; D008954:Models, Biological; D011813:Quinuclidinyl Benzilate / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000145:classification* / Q000378:metabolism*; D014316:Tritium
D011976:Receptors, Muscarinic; D014316:Tritium; D011813:Quinuclidinyl Benzilate