A Positron Emission Tomography Study to Assess Binding of Lecozotan, a Novel 5-Hydroxytryptamine-1A Silent Antagonist, to Brain 5-HT1A Receptors in Healthy Young and Elderly Subjects, and in Patients With Alzheimer's Disease

Abstract

This positron emission tomography (PET) study was conducted to assess binding of lecozotan, a new potent and silent 5-hydroxytryptamine-1A (5-HT1A) antagonist being developed for the treatment of Alzheimer's disease (AD), to 5-HT1A receptors in the human brain using 11C-labeled WAY-100635. Lecozotan was administered as a single dose of 0.5, 1, or 5 mg to young subjects and 5 mg to elderly subjects and AD patients. PET measurements were performed at 3-4 time points over a 25-h period. Mean peak 5-HT1A receptor occupancy (RO) in young subjects (seen at 1 h) was 10%, 18%, and 44% for the three doses, respectively. Mean peak RO was slightly higher in elderly (63%) and AD patients (55%). An Emax pharmacokinetic/pharmacodynamic model adequately described the lecozotan plasma concentration-RO relationship. Steady-state peak RO is predicted to be approximately 70% for 5 mg q12 h (twice-daily). Results demonstrate that lecozotan binds to the human brain 5-HT1A receptors and has a maximum observed RO of 50-60% following a single dose of 5 mg in elderly subjects/AD patients.