Positron emission tomographic analysis of dose-dependent NAD-299 binding to 5-hydroxytryptamine-1A receptors in the human brain

• Published in: Psychopharmacologia Vol. 167; no. 1; pp. 37 - 45
• Main Authors: Andrée, Bengt, Hedman, Ann, Thorberg, Seth-Olav, Nilsson, Dag, Halldin, Christer, Farde, Lars
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.04.2003; Springer Nature B.V
• Subjects: Adult; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Benzopyrans - metabolism; Benzopyrans - pharmacology; Biological and medical sciences; Brain - diagnostic imaging; Brain - metabolism; Humans; Kinetics; Male; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Piperazines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyridines - pharmacology; Radioligand Assay; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT1; Serotonin Antagonists - pharmacology; Tomography, Emission-Computed; Human; Binding; Ligand binding; Agonist; Healthy subject; Robalzotan; Serotonin; Central nervous system; Oral administration; [carbonyl-11C]WAY-100635; Serotonin agonist; Dose activity relation; NAD-299; 5-HT1A Serotonine receptor; Activity concentration relation; Human brain; Antidepressant agent; Medical imagery; 5-HT1A-receptor antagonist; Pharmacokinetics; Positron emission tomography; Brain (vertebrata); Antidepressive drugs
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-002-1355-0

The serotonin 5-HT(1A) receptor has been ascribed a putative role in the pathophysiology and drug treatment of depression. NAD-299 (generic name robalzotan) is a new potential antidepressant with high affinity and selectivity for the 5-HT(1A) receptor. The aim of this positron emission tomography (PET) study was to examine the extent and time-course of 5-HT(1A) occupancy by NAD-299 in the human brain, in relation to plasma concentration after escalating single oral doses. Five healthy male subjects received one or more single oral doses of NAD-299 (0.5, 2.5 and 10 mg) in aqueous solution under fasting conditions. Total and unbound (after ultrafiltration) plasma concentrations of NAD-299 were determined by liquid chromatography-mass spectrometry (LC-MC), over a tentative dosage interval of 8 h. Regional 5-HT(1A) receptor occupancy in brain was calculated by the simplified reference tissue model using the radioligand [ carbonyl-(11)C]WAY-100635. After the 10 mg dose, occupancy was high in the raphe (62-85%) and neocortical regions (68-75%) at time for C(max), but had declined considerably (17-44%) at 7 h after dose intake. This study confirmed that the new selective 5-HT(1A) antagonist NAD-299 occupies 5-HT(1A) receptors in the living human brain in a dose-dependent manner following oral dosage. The curvilinear relationship between NAD-299 drug concentration and 5-HT(1A) receptor occupancy was established and can be used for dose selection in subsequent clinical patient studies.