ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

Abstract

RationaleCentral modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. ObjectivesThe purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT 2A receptors, dopamine D 2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. MethodsCarbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT 2A receptors, D 2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. ResultsOral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT 2A receptors and low occupancy of striatal D 2 receptors (~12 %). D 2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2 = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D 2 receptors and 33 % of striatal serotonin transporters. ConclusionsThe results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial

“…Individuals randomized to 120 mg ITI-007 or risperidone received a single day dose titration (60 mg to 120 mg ITI-007 on day 2; 2 mg to 4 mg risperidone on day 2); 60 mg ITI-007 required no dose titration. Doses of 60 mg and 120 mg ITI-007 were selected based on estimated striatal D 2 receptor occupancy of approximately 50% and 70%, respectively, modeled from the D 2 receptor occupancies determined in a positron emission tomography study at lower doses in healthy volunteers (14). A dose of risperidone of 4 mg was selected as a positive control for assay sensitivity based on its mean modal effective dose determined by the Clinical Antipsychotic Trials of Intervention Effectiveness (15) and its well-characterized efficacy and safety profile as one of the most prescribed antipsychotics in the United States.…”

Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates

“…4). Clinical studies in healthy volunteers using positron emission tomography revealed that lumateperone displayed high occupancy of the 5-HT 2A R in the cortex and negligible occupancy of the D 2 striatal receptors [118], suggesting that it is less likely to induce extrapyramidal side effects. Lumateperone has a unique mechanism of action, modulating synergistically multiple neurotransmitter systems, and has been suggested as a potential treatment for a range of neuropsychiatric disorders [73].…”

Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future

“…Clozapine is an exception with relatively low striatal D 2 receptor occupancy (<60%) at antipsychotic doses and a low liability for parkinsonism, akathisia, and hyperprolactinemia [152, 174, 183, 185, 186]. At a low single dose of 10 mg in healthy volunteers, ITI-007 demonstrated low (~12%) striatal D 2 receptor occupancy and high (>80%) cortical 5-HT 2A receptor occupancy [156]. ITI-007 demonstrated an average of 29% (peak of 39%) D 2 occupancy at the highest evaluated dose in healthy volunteers.…”

“…These clinical observations suggest that ITI-007 is not associated with the usual side effects of existing medications for schizophrenia. An effective dose of 60 mg ITI-007 is associated with approximately 40% striatal D 2 receptor occupancy, substantially lower than that required by other antipsychotic drugs [125, 156]. This sparing of D 2 receptor occupancy likely contributes to ITI-007’s reduced liability for motor side effects and hyperprolactinemia.…”