PET Imaging Confirms Lower Muscarinic M1 Receptor Availability in Schizophrenia

For decades, evidence implicating the muscarinic acetylcholine M1 receptor in the pathophysiology of schizophrenia came almost entirely from postmortem tissue, leaving it unclear whether these abnormalities were present in living patients or how they related to clinical symptoms. A new study in Biological Psychiatry provides the first in vivo positron emission tomography (PET) evidence of widespread M1 receptor deficits in patients with schizophrenia, using a novel radiotracer developed specifically for this receptor.¹

Investigators compared M1 receptor availability in 16 patients with schizophrenia and 16 age- and sex-matched healthy controls using the PET radiotracer 11C-LSN3172176 and a High-Resolution Research Tomograph. Patients with schizophrenia showed significantly lower M1 receptor availability, approximately 13% to 19% lower, across multiple brain regions compared with controls. These regions are involved in cognition, learning, memory, and executive function.

"The development of a novel PET radiotracer for the M1 receptor provided a unique opportunity to directly measure M1 receptor availability in the living brain," said co-lead investigator Deepak C. D'Souza, MBBS, MD, Department of Psychiatry, Yale University School of Medicine. "Although receptor availability is not identical to receptor density, it is widely accepted as a useful proxy for the brain's functional M1 receptor system. This allowed us, for the first time, to confirm that muscarinic dysfunction is a feature of schizophrenia in living patients."

The findings were robust across multiple methods of PET quantification and remained significant after accounting for potential confounding factors, including gray matter differences and partial-volume effects, according to co-first author Tommaso Volpi, MD, PhD, associate research scientist in Radiology and Biomedical Imaging at Yale University School of Medicine.

M1 receptor availability was more strongly associated with measures of cognition than with the severity of psychotic symptoms, according to the investigators, suggesting M1 dysfunction may be particularly relevant to the cognitive impairments that are among the most disabling aspects of schizophrenia.

Pharmacological treatment of schizophrenia has long been dominated by dopamine D2 receptor antagonists and partial agonists, commonly referred to as antipsychotics. Their limited efficacy for negative and cognitive symptoms, along with significant side effects, has driven interest in drugs with alternative mechanisms. M1 receptors are G-protein-coupled receptors present throughout the cortex and subcortical regions and are increasingly considered a target for both treatment and biomarker development in schizophrenia.

"This study is particularly interesting in light of the emergence of M1 and M4 muscarinic agonist drugs as pharmacotherapies in schizophrenia," said John Krystal, MD, editor of Biological Psychiatry. "These findings are particularly timely given the recent approval of xanomeline-trospium (Cobenfy), the first antipsychotic medication in more than 70 years to treat schizophrenia through a primarily non-dopaminergic mechanism of action."

The study did not evaluate treatment response. "It strengthens the biological rationale for developing muscarinic-based therapies and raises the possibility that M1 receptor imaging could eventually help identify biologically distinct subgroups of patients and inform future precision medicine approaches," said co-lead investigator Rajiv Radhakrishnan, MBBS, MD, Department of Radiology and Biomedical Engineering and Department of Psychiatry, Yale University School of Medicine.

The study was funded by the National Institute of Mental Health, the National Center for Homelessness Among Veterans, and the Schizophrenia Neuropharmacology Research Group at Yale.

References

1. Volpi T, Radhakrishnan R, Hird R, et al. Lower muscarinic M1 receptor availability in schizophrenia: in vivo PET evidence. Biol Psychiatry. 2026:S0006-3223(26)01316-8.

2. Brain imaging now reveals muscarinic dysfunction in living patients with schizophrenia. News release. Elsevier. July 16, 2026. Accessed July 24, 2026. https://www.eurekalert.org/news-releases/1136426