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.

• Authors: S Raje, A A Patat, V Parks, L Schechter, A Plotka, J Paul, B Langstrom
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 83 Issue 1 Pg. 86-96 (Jan 2008) ISSN: 1532-6535 [Electronic] United States
• PMID: 17507923 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Carbon Radioisotopes
• Dioxanes
• Piperazines
• Pyridines
• Radiopharmaceuticals
• Serotonin 5-HT1 Receptor Antagonists
• Serotonin Antagonists
• Receptor, Serotonin, 5-HT1A
• lecozotan
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Aging (metabolism)
• Alzheimer Disease (diagnostic imaging, metabolism)
• Brain (diagnostic imaging, drug effects, metabolism)
• Carbon Radioisotopes
• Computer Simulation
• Dioxanes (administration & dosage, adverse effects, metabolism, pharmacokinetics)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• Models, Biological
• Piperazines (administration & dosage, adverse effects, metabolism, pharmacokinetics)
• Positron-Emission Tomography
• Protein Binding
• Pyridines
• Radiopharmaceuticals
• Receptor, Serotonin, 5-HT1A (metabolism)
• Serotonin 5-HT1 Receptor Antagonists
• Serotonin Antagonists (administration & dosage, adverse effects, metabolism, pharmacokinetics)
• Time Factors