Positron emission tomographic analysis of dose-dependent NAD-299 binding to 5-hydroxytryptamine-1A receptors in the human brain.

Rationale: The serotonin 5-HT(1A) receptor has been ascribed a putative role in the pathophysiology and drug treatment of depression. NAD-299 (generic name robalzotan) is a new potential antidepressant with high affinity and selectivity for the 5-HT(1A) receptor.

Objectives: The aim of this positron emission tomography (PET) study was to examine the extent and time-course of 5-HT(1A) occupancy by NAD-299 in the human brain, in relation to plasma concentration after escalating single oral doses.

Methods: Five healthy male subjects received one or more single oral doses of NAD-299 (0.5, 2.5 and 10 mg) in aqueous solution under fasting conditions. Total and unbound (after ultrafiltration) plasma concentrations of NAD-299 were determined by liquid chromatography-mass spectrometry (LC-MC), over a tentative dosage interval of 8 h. Regional 5-HT(1A) receptor occupancy in brain was calculated by the simplified reference tissue model using the radioligand [ carbonyl-(11)C]WAY-100635.

Results: After the 10 mg dose, occupancy was high in the raphe (62-85%) and neocortical regions (68-75%) at time for C(max), but had declined considerably (17-44%) at 7 h after dose intake.

Conclusions: This study confirmed that the new selective 5-HT(1A) antagonist NAD-299 occupies 5-HT(1A) receptors in the living human brain in a dose-dependent manner following oral dosage. The curvilinear relationship between NAD-299 drug concentration and 5-HT(1A) receptor occupancy was established and can be used for dose selection in subsequent clinical patient studies.