PET-determination of robalzotan (NAD-299) induced 5-HT1A receptor occupancy in the monkey brain

The serotonin 5-hydroxytryptamine-1a (5-HT1A) receptor subtype is of central interest in research, particularly in the area of pathophysiology and pharmacological treatment of psychiatric disorders. Robalzotan (generic name for NAD-299) is a new putative drug that binds with high selectivity and affinity to 5-HT3A-receptors in the rodent brain in vitro and in vivo. The aim of this positron emission tomography study was to determine 5-HT3A receptor occupancy in the cynomolgus monkey brain in vivo after IV injection of robalzotan. Two healthy monkeys were examine with Positron Emission Tomography (PET) and the radioligand [carbonyl-C-11]WAY-100635, the first after IV administration of 2 mu g/kg and 20 mu g/kg, and the second after 10 mu g/kg and 100 mu g/kg IV. 5-HT1A receptor occupancy was calculated using an equilibrium-ratio analysis. Robalzotan occupied 5-HT1A receptors in a dose-dependent and saturable manner. The highest 5-HT1A receptor occupancy (70-80%) was attained after 100 mu g/kg. The relationship between robalzotan drug concentration and 5-HT1A receptor occupancy could be described by a hyperbolic function, which can used to guide the selection of appropriate doses for the initial studies in man. The study further corroborates that quantitative neuroimaging of receptor binding has potentials for the evaluation and dose finding of new CNS drugs. (C) 2000 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.