Abstract
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.
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Acknowledgements
The members of the PET group at Karolinska Institutet and collaborators at AstraZeneca AB are gratefully acknowledged. The study was supported by a grant from AstraZeneca AB, Södertälje and the Human Frontier Science Program Organization (HFSPO). RG0235/1998-B.
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Farde, L., Andrée, B., Ginovart, N. et al. PET-Determination of Robalzotan (NAD-299) Induced 5-HT1A Receptor Occupancy in the Monkey Brain. Neuropsychopharmacol 22, 422–429 (2000). https://doi.org/10.1016/S0893-133X(99)00125-6
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DOI: https://doi.org/10.1016/S0893-133X(99)00125-6
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