Seth-Olov Thorberg

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-HT1A-receptors in the rodent brain in vitro and in vivo. The aim of this positron emission tomography study was to determine 5-HT1A receptor occupancy in the cynomolgus monkey brain in vivo after IV injection of robalzotan. Two healthy monkeys were examined with Positron Emission Tomography (PET) and the radioligand [carbonyl-11C]WAY-100635, the first after IV administration of 2 μg/kg and 20 μg/kg, and the second after 10 μg/kg and 100 μg/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 μg/kg. The relationship between robalzotan drug concentration and 5-HT1A receptor occupancy could be described by a hyperbolic function, which can be 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.

PET-examination and metabolite evaluation in monkey of [11C]NAD-299, a radioligand for visualisation of the 5-HT1A receptor

NAD-299 is a selective 5-HT(1A) receptor antagonist that is currently developed as a putative antidepressant drug. [(11)C]NAD-299 was examined in the cynomolgus monkey brain with positron emission tomography (PET). After radioligand injection high accumulation of radioactivity was observed in the frontal and temporal cortex and the raphe nuclei, regions known to contain a high density of 5-HT(1A) receptors. Peak equilibrium appeared already at about 10 min after i.v. injection. Pre-treatment with a high dose of the antagonist WAY-100635 reduced the amount of radioactivity in the cortex and the raphe to the level of the cerebellum. A strong pre-treatment effect could also be achieved using pindolol, a partial agonist at the 5-HT(1A)-receptors. The appearance of labeled metabolites in monkey plasma was measured with HPLC. At 45 minutes after injection 49% (range 27-55%, n = 5) of radioactivity in monkey plasma represented unchanged radioligand. [(11)C]NAD-299 was metabolized to more polar labeled metabolites of which one has the same chromatographic mobility as the descyclobutyl analogue of NAD-299 (NAD-272). The results indicate that [(11)C]NAD-299 has potential as a PET radioligand for studies of 5-HT(1A) receptors in the primate brain.