High 5HT2A receptor occupancy in M100907-treated schizophrenic patients

Rationale: Selective drugs are required to test the hypothesis whether antipsychotic effects may be induced or modulated by 5HT(2A) receptor antagonism. M100907 (previously known as MDL 100,907) is a highly selective 5HT(2A) antagonist in clinical development. Objective: To test if the suggested clinical dose of 20 mg M100907 daily induces high 5HT(2A) receptor occupancy in patients with schizophrenia Methods: The 5HT(2A) receptor occupancy was determined in two patients with schizophrenia treated with M100907, 20 mg once a day. Positron emission tomography (PET) with C-11-labeled M100907, was performed prestudy and under steady state conditions. Clinical ratings were performed weekly. Results: Clinical treatment with M100307.20 mg daily induced a very high 5HT(2A) receptor occupancy in the frontal cortex of both patients (>90%). M100907 was well tolerated. One patient improved minimally and one patient became minimally worse during treatment. Conclusions: The results confirm that an oral dose of 20 mg per day ensures adequate 5HT(2A) receptor occupancy for clinical proof of concept. The sample is too small to allow conclusions about the clinical effect.