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Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia.

ABSTRACT: Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60?mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N?=?10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60?mg ITI-007 occurring 1?h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.

SUBMITTER: Vanover KE

PROVIDER: S-EPMC6333832 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia.

Vanover Kimberly E KE Davis Robert E RE Zhou Yun Y Ye Weiguo W Brašić James R JR Gapasin Lorena L Saillard Jelena J Weingart Michal M Litman Robert E RE Mates Sharon S Wong Dean F DF

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20181026 3

Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the ...[more]

PMID: 30449883

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Project description:Dopamine D2 receptors (D2R) are expressed in the human retina and play an important role in the modulation of neural responses to light-adaptation. However, it is unknown whether dopamine D3 receptors (D3R) are expressed in the human retina. Using positron emission tomography (PET), we have observed significant uptake of the D3R-preferring agonist radiotracer [11C]-(+)-PHNO into the retina of humans in vivo. This led us to examine whether [11C]-(+)-PHNO binding in the retina was quantifiable using reference tissue methods and if D3R are expressed in human post-mortem retinal tissue. [11C]-(+)-PHNO data from 49 healthy controls (mean age: 39.96 ± 14.36; 16 female) and 12 antipsychotic-naïve patients with schizophrenia (mean age: 25.75 ± 6.25; 4 female) were analyzed. We observed no differences in [11C]-(+)-PHNO binding in the retina between first-episode, drug-naïve patients with schizophrenia and healthy controls. Post-mortem retinal tissues from four healthy persons (mean age: 59.75 ± 9.11; 2 female) and four patients with schizophrenia (mean age: 54 ± 17.11; 2 female) were analyzed using a targeted mass spectrometry technique: parallel reaction monitoring (PRM) analysis. Using targeted mass spectrometry, we confirmed that D3R are expressed in human retinal tissue ex vivo. Notably, there was far greater expression of D2R relative to D3R in the healthy human retina (?12:1). Moreover, PRM analysis revealed reduced D2R, but not D3R, expression in the retinas of non-first episode patients with schizophrenia compared to healthy controls. We confirm that D3R are expressed in the human retina. Future studies are needed to determine what proportion of the [11C]-(+)-PHNO signal in the human retina in vivo is due to binding to D3R versus D2R. Knowledge that both D2R and D3R are expressed in the human retina, and potentially quantifiable in vivo using [11C]-(+)-PHNO, poses new research avenues for better understanding the role of retinal dopamine in human vision. This work may have important implications for elucidating pathophysiological and antipsychotic induced visual deficits in schizophrenia.

Dataset Information

Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia.

Publications

Dopamine D<sub>2</sub> receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia.

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