Comparison of the in vivo rat brain regional pharmacokinetics of [3H]QNB, (R,S)-[125I]-4IQNB, and (R,R)-[125I]-4IQNB binding to the muscarinic acetylcholine receptor in relationship to the regional subtype composition.

Abstract

We have used the dissection of selected rat brain regions to compare the in vivo pharmacokinetics of [3H]QNB, (R,S)-[125I]-4IQNB, and (R,R)-[125I]-4IQNB binding to the muscarinic acetylcholine receptor (mAChR). [3H]IQNB is distributed in accordance with the m2 subtype concentration, (R,S)-[125I]-4IQNB is distributed in accordance with the total mAChR concentration, and (R,R)-[125I]-4IQNB is distributed in accordance with the m1/m4 subtype concentration. Although the cerebellum is relatively poor in mAChR (composed almost exclusively of the m2 subtype), the [3H]QNB concentration in the cerebellum is nearly equal to that in the other brain regions and is predominantly composed of specific binding. In contrast, the (R,S)-[125I]-4IQNB and (R,R)-[125I]-4IQNB concentrations in the cerebellum are relatively low and are predominantly or exclusively composed of nonspecific binding. These results dramatically demonstrate the in vivo m2 selectivity of [3H]QNB. All three radioligands exhibit large population standard deviations, with a substantial reduction of the between-animal variability resulting from normalization to each individual animal's corpus striatum value. Thus, the large population standard deviations arise from variability in radioligand delivery (variations in global cerebral blood flow, radioligand binding to serum proteins, loss of parent radioligand through conversion to metabolites, and blood-brain barrier transport.