Longitudinal Pet Imaging Of Antipsychotic Binding To The Dopamine-3 Receptor In Schizophrenia

Aside from the recently approved muscarinic agonist xanomeline, all treatments for schizophrenia (SCZ) have been assumed to function by blocking dopamine-2 receptors (D2Rs) based on their in vitro binding profiles. Interest in the dopamine-3 receptor (D3R) was encouraged by findings, in preclinical models, that D3R antagonists reverse cognitive impairment and enhance locomotor activity of habituated rats, suggesting potential for improving negative symptoms. However, while numerous preclinical studies have demonstrated that the D3R is relevant to both the neurobiology and treatment of SCZ, in vivo studies initially and surprisingly reported that, after several weeks of administration, antipsychotic medications may not bind to the D3R but may paradoxically increase levels of the D3R. These findings were discrepant with our own findings in non- human primates and individuals with SCZ demonstrating that acute doses of antipsychotic medications bind to the D3R and D2R in ratios predicted by their in vitro binding profiles. In a later study conducted by our group, 10 days of chronic dosing of brexpiprazole (BREX) also led to increased levels of the D3R at 1mg and negligible binding at 4mg. Finally, in a study of the D3R-preferring antipsychotic medication cariprazine (CAR), there was robust binding to the D3R and D2R after both acute and subchronic dosing. These seemingly discrepant findings may be related to methodological differences, difference in the binding profiles of D2R- vs. D3R-preferring antipsychotic medications, or to homeostatic responses to chronic antipsychotic treatment (i.e., upregulation). The goals of this proposal are to elucidate the contribution of D3R binding to antipsychotic action, both acutely (SA1) and subchronically (SA2), in the same patients. We will also investigate the relationship between occupancy, upregulation, and therapeutic response (SA3, EA). To accomplish these goals, we will recruit 40 antipsychotic-free patients with SCZ. After screening and baseline procedures (e.g., MRI, PANSS, MATRICS, CAINS), subjects will be randomized to multiple doses of CAR or BREX and receive a total of three PET scans with [11C]-(+)-PHNO: one at baseline (baseline scan) followed by a second scan after one dose of their antipsychotic medication to measure acute occupancy (acute scan), and a third scan after 2 weeks of stable treatment. Our aims are to: 1) measure the acute binding of CAR/BREX to the D3R; 2) measure D3R availability for evidence of upregulation following subchronic administration of CAR/BREX in the same set of patients; and 3) explore relationships between acute and subchronic binding of CAR/BREX to, and upregulation of, the D3R vs. D2R and changes in positive and negative symptoms, cognitive deficits, and extrapyramidal side effects. By elucidating the contribution of D3R binding and upregulation to antipsychotic action the field may be able to develop more selective antipsychotic agents that improve upon current medications by demonstrating less side effects or greater efficacy against a range of symptoms. Project Number: 1R01MH139651-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Ragy Girgis (+1 co-PI) | Institution: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC, NEW YORK, NY | Award Amount: $843,322 | Activity Code: R01 | Study Section: Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section[NPAS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296445