High 5HT_2A receptor occupancy in M100907-treated schizophrenic patients

Abstract 

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 ¹¹C-labeled M100907, was performed prestudy and under steady state conditions. Clinical ratings were performed weekly. Results: Clinical treatment with M100907, 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.