TY - JOUR T1 - Occupancy of dopamine D<sub>2/3</sub> and serotonin 5-HT<sub>1A</sub> receptors by a novel D<sub>3</sub>/D<sub>2</sub> antipsychotic drug, RGH-188, in nonhuman primate brain: A PET study JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 242P LP - 242P VL - 48 IS - supplement 2 AU - N. Seneca AU - B. Gulyás AU - S. Finnema AU - I. Laszlovszky AU - B. Kiss AU - A. Horváth AU - G. Pásztor AU - M. Kapás AU - I. Gyertyán AU - S. Farkas AU - R. Innis AU - C. Halldin Y1 - 2007/05/01 UR - http://jnm.snmjournals.org/content/48/supplement_2/242P.3.abstract N2 - 1128 Objectives: Blockade of the dopamine D2 receptor is an essential mechanism of action of antipsychotic drugs. Positron emission tomography (PET) studies have demonstrated that the optimal therapeutic window of striatal D2 receptor occupancy is 65% to 80% and occupancy above 80% increases the likelihood of extrapyramidal symptoms. RGH-188 is a novel D3/D2 antagonist that binds with high affinity to D3 and D2 and moderate affinity to 5-HT1A receptors. The aim of present PET study was to determine D2/3 and 5-HT1A receptor occupancy in nonhuman primate brain following intravenous administration of RGH-188. Methods: We examined three monkeys using the following radioligands: [11C]MNPA (a selective D2/3 agonist), [11C]raclopride (an antagonist at D2/3 receptors), and [11C]WAY-100635 (selective antagonist for 5-HT1A receptors). RGH-188 was administered at doses of 1, 5, 30, and 300 µg/kg. During each experimental day, the first PET measurement was a baseline study, the second after a low dose of RGH-188, and third after administration of a high dose. We used an agonist and antagonist radiotracer to determine in vivo potency of RGH-188 and assess its intrinsic activity as an agonist vs. antagonist. Results: RGH-188 occupied D2/3 receptors in a dose dependent and saturable manner, with lowest dose occupying ~5% of receptors, and highest dose more than 90%. RGH-188 was equally potent to displace both [11C]raclopride and [11C]MNPA with an ED50 of ~5 µg/kg. 5-HT1A receptor occupancy was much lower compared to D2/3 occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei. Conclusions: RGH-188 binds to the D2/3 rather than the 5-HT1A receptors in nonhuman primate brain, and its equal potency to displace agonist and antagonist radiotracers, may suggest that RGH-188 is an antagonist. The occupancy values obtained from an i.v. dose of RGH-188 can guide the selection of doses for initial human studies. Research Support (if any): Gedeon Richter Ltd. ER -