@article {Seneca242P, author = {N. Seneca and B. Guly{\'a}s and S. Finnema and I. Laszlovszky and B. Kiss and A. Horv{\'a}th and G. P{\'a}sztor and M. Kap{\'a}s and I. Gyerty{\'a}n and S. Farkas and R. Innis and C. Halldin}, title = {Occupancy of dopamine D2/3 and serotonin 5-HT1A receptors by a novel D3/D2 antipsychotic drug, RGH-188, in nonhuman primate brain: A PET study}, volume = {48}, number = {supplement 2}, pages = {242P--242P}, year = {2007}, publisher = {Society of Nuclear Medicine}, abstract = {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 {\textmu}g/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 {\textmu}g/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.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/48/supplement_2/242P.3}, eprint = {https://jnm.snmjournals.org/content}, journal = {Journal of Nuclear Medicine} }