PET imaging of muscarinic receptors

Abstract

We have successfully developed a novel PET ligand for muscarinic acetylcholine receptors (mAChR), (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB), and evaluated this in the brain of conscious monkeys using high-resolution positron emission tomography (PET). (+)3-MPB had relatively low selectivity to the subtype of mAChR, showing K i values of 1.3, 1.1, 2.8, 1.7, and 5.9 nM for M1, M2, M3, M4, and M5, respectively, of the human receptors. The regional cortical distribution of [11C](+)3-MPB was found to be consistent with mAChR density in the monkey brain as reported in vitro. Time-activity curves of [11C](+)3-MPB peaked in all brain regions, suggesting that this PET probe bound reversibly to the mAChR. Administration of scopolamine, a mAChR antagonist, reduced the radioactivity of [11C](+)3-MPB in all regions except the cerebellum, and the reduction of [11C](+)3-MPB uptake was well correlated with the degree of impairment of working memory performance (R 2 = 0.55 and 0.84 in hippocampus and brainstem, respectively) assessed in conscious monkeys. Based on these preclinical studies, we recently demonstrated in clinical study that chronic fatigue syndrome (CFS) patients with positive serum autoantibody against mAChR showed significantly lower [11C](+)3-MPB binding than negative patients and normal controls. These results demonstrated that PET imaging with [11C](+)3-MPB could be useful for diagnosis of neurological diseases associated with impaired mAChR function and cognitive function.