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Autoradiography helps to determine the distribution and density of muscarinic receptor (MR) binding sites in the brain. However, it relies on the selectivity of radioligands toward their target.  3 H-Pirenzepine is commonly believed to label predominantly M 1 MR,  3 H-AFDX-384 is considered as M 2 MR selective ligand. Here we performed series of autoradiographies with  3 H-AFDX-384 (2 nM), and  3 H-pirenzepine (5 nM) in WT, M 1 KO, M 2 KO, and M 4 KO mice to address the ligand selectivity. Labeling with  3 H-pirenzepine using M 1 KO, M 2 KO, and M 4 KO brain sections showed the high selectivity toward M 1 MR. Selectivity of  3 H-AFDX-384 toward M 2 MR varies among brain regions and depends on individual MR subtype proportion. All binding sites in the medulla oblongata and pons, correspond to M 2 MR. In caudate putamen, nucleus accumbens and olfactory tubercle, 77.7, 74.2, and 74.6% of  3 H-AFDX-384 binding sites, respectively, are represented by M 4 MR and M 2 MR constitute only a minor portion. In cortex and hippocampus,  3 H-AFDX-384 labels almost similar amounts of M 2 MR and M 4 MR alongside significant amounts of non-M 2 /non-M 4 MR. In cortex, the proportion of  3 H-AFDX-384 binding sites attributable to M 2 MR can be increased by blocking M 4 MR with MT3 toxin without affecting non-M 4 MR. PD102807, which is considered as a highly selective M 4 MR antagonist failed to improve the discrimination of M 2 MR. Autoradiography with  3 H-QNB showed genotype specific loss of binding sites. In conclusion: while  3 H-pirenzepine showed the high selectivity toward M 1 MR,  3 H-AFDX-384 binding sites represent different populations of MR subtypes in a brain-region-specific manner. This finding has to be taken into account when interpreting the binding data.

Autoradiography of 3H-pirenzepine and 3H-AFDX-384 in Mouse Brain Regions: Possible Insights into M1, M2, and M4 Muscarinic Receptors Distribution