title: 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.affiliation: Wyeth Research, Early Development and Clinical Pharmacology, Collegeville, Pennsylvania, USA. rajes@wyeth.com
authors.forename: S
authors.initials: S
authors.lastname: Raje
authors.forename: A A
authors.initials: AA
authors.lastname: Patat
authors.forename: V
authors.initials: V
authors.lastname: Parks
authors.forename: L
authors.initials: L
authors.lastname: Schechter
authors.forename: A
authors.initials: A
authors.lastname: Plotka
authors.forename: J
authors.initials: J
authors.lastname: Paul
authors.forename: B
authors.initials: B
authors.lastname: Langstrom
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003198:Computer Simulation; D004146:Dioxanes / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011725:Pyridines; D019275:Radiopharmaceuticals; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D002250:Carbon Radioisotopes; D004146:Dioxanes; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C500836:lecozotan; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide