COMPARISON OF THE IN-VIVO RAT-BRAIN REGIONAL PHARMACOKINETICS OF [H-3] QNB, (R,S)-[I-125]-4IQNB, AND (R,R)-[I-125]-4IQNB BINDING TO THE MUSCARINIC ACETYLCHOLINE-RECEPTOR IN RELATIONSHIP TO THE REGIONAL SUBTYPECOMPOSITION

We have used the dissection of selected rat brain regions to compare t he in vivo pharmacokinetics of [H-3]QNB, (R,S)-[I-125]-4IQNB, and (R,R )-[I-125]-4IQNB binding to the muscarinic acetylcholine receptor (mACh R). [H-3]IQNB is distributed in accordance with the m2 subtype concent ration, (R,S)-[I-125]-4IQNB is distributed in accordance with the tota l mAChR concentration, and (R,R)-[I-125]-4IQNB is distributed in accor dance with the m1/m4 subtype concentration. Although the cerebellum is relatively poor in mAChR (composed almost exclusively of the m2 subty pe), the [3H]QNB concentration in the cerebellum is nearly equal to th at in the other brain regions and is predominantly composed of specifi c binding. Ln contrast, the (R,S)-[I-125]-4IQNB and (R,R)-[(125)]-4IQN B concentrations in the cerebellum are relatively low and are predomin antly or exclusively composed of nonspecific binding. These results dr amatically demonstrate the in vivo m2 selectivity of [H-3]QNB. AU thre e radioligands exhibit large population standard deviations, with a su bstantial reduction of the between-animal variability resulting from n ormalization to each individual animal's corpus striatum value. Thus, the large population standard deviations arise from variability in rad ioligand delivery (variations in global cerebral blood flow, radioliga nd binding to serum proteins, loss of parent radioligand through conve rsion to metabolites, and blood-brain barrier transport).