Lower Muscarinic M1 Receptor Availability in Schizophrenia: In Vivo Positron Emission Tomography Evidence

Background There is growing interest in the contributions of brain muscarinic M1 receptors to the neurobiology of schizophrenia (SZ). Postmortem evidence strongly indicates M1 deficits in SZ patients. Recently, the FDA approved COBENFY TM , which contains M1/M4 agonist xanomeline, as the first non-dopaminergic medication for SZ. The development of the PET ligand 11 C-LSN3172176 enables in vivo quantification of brain M1 availability in SZ and its relationship to clinical features . Methods M1 availability in SZ patients ( n =16) was compared to age/sex-matched healthy controls (HC) ( n =16) using 11 C-LSN3172176 and the High-Resolution Research Tomograph. Distribution volume ratio relative to the centrum semiovale ( DVR CS ) and distribution volume ( V T ) were measured. Regional variation in percent gray matter fraction (%GM) was included as a covariate to account for potential atrophy. Results Compared to HCs, patients with SZ showed significantly lower M1 availability across several cortical and subcortical regions, with large effect sizes: frontal ( DVR CS : -13%), temporal ( DVR CS : -15%; V T : -12%), parietal ( DVR CS : -14%; V T : -11%), occipital ( DVR CS : -16%; V T : -13%), caudate ( DVR CS : -19%; V T : -15%), putamen ( DVR CS : -19%; V T : -17%), hippocampus ( DVR CS : -13%), amygdala ( DVR CS : -19%; V T : -16%). A subgroup of patients ( DVR CS : 44%; V T : 27%) showed larger whole-brain M1 deficits (>20% from the mean of HCs). Exploratory analyses suggested associations between M1 availability and selected clinical measures. Conclusions These in vivo findings together with postmortem data warrant further characterization of M1 deficits in SZ and highlight M1 as a therapeutic target and potential biomarker for muscarinic-based treatments.