1. ¹Wyeth Research, Early Development and Clinical Pharmacology, Collegeville, Pennsylvania, USA
2. ²Biotrial, Rennes, France
3. ³Wyeth Research, Early Development and Clinical Pharmacology, Paris, France
4. ⁴Wyeth, Neuroscience Discovery Research, Princeton, New Jersey, USA
5. ⁵Uppsala Imanet (formerly Uppsala University PET Center), Uppsala, Sweden

Correspondence: S Raje, (rajes@wyeth.com)

Received 22 November 2006; Accepted 5 April 2007; Published online 16 May 2007.

Abstract

This positron emission tomography (PET) study was conducted to assess binding of lecozotan, a new potent and silent 5-hydroxytryptamine-1A (5-HT_1A) antagonist being developed for the treatment of Alzheimer's disease (AD), to 5-HT_1A 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-HT_1A 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 E_max 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-HT_1A receptors and has a maximum observed RO of 50–60% following a single dose of 5 mg in elderly subjects/AD patients.