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