title: Brain uptake and distribution of the dopamine D3 /D2 receptor partial agonist [11 C]cariprazine: an in vivo positron emission tomography study in nonhuman primates.
abstract: Cariprazine is a dopamine D(3)/D(2) receptor partial agonist antipsychotic candidate, which binds with high affinity to dopamine D(3) and D(2) receptors (with ∼10-fold higher in vitro affinity to D(3) vs. D(2) receptors) and with moderate affinity to 5-HT(1A) receptors. The main objective of the present molecular imaging investigation was to evaluate the uptake and reversible binding of 11-C labeled cariprazine in the nonhuman primate brain, in relation to the known distributions of dopamine D(2) and D(3) receptors. We examined the brains of two cynomolgus monkeys at baseline condition as well as during a pharmacological blocking condition, using unlabeled cariprazine or raclopride as blockers before injection of [(11) C]cariprazine. Of the total injected radioactivity, ∼7% entered the brain and ∼3-4% remained in the brain after 90 min, indicating good blood brain barrier penetration and slow washout. It was possible to block cariprazine binding with unlabeled cariprazine and raclopride indicating that [(11) C]cariprazine binds to dopamine D(3)/D(2) receptors. Nondisplaceable binding potential (BPND) measurements, using a simplified reference tissue model and cerebellum as the reference region, yielded values of ∼1.5 and 0.3 in the striatum and thalamus, respectively. Striatum BPND values were reduced by 80 and 85% following pretreatment with 0.1 mg/kg IV injection of unlabeled cariprazine and 1 mg/kg IV injection of unlabeled raclopride, respectively. The data confirm that cariprazine, a novel antipsychotic drug candidate, enters the nonhuman primate brain readily and binds to dopamine D(3)/D(2) receptors. Furthermore, in PET imaging [(11) C]cariprazine can effectively visualize dopamine D(3)/D(2) receptors in the nonhuman primate brain.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centrum for Psychiatry Research, S-171 76, Stockholm, Sweden. miklos.toth@ki.se
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.forename: Carsten
authors.initials: C
authors.lastname: Steiger
authors.forename: István
authors.initials: I
authors.lastname: Laszlovszky
authors.forename: Attila
authors.initials: A
authors.lastname: Horváth
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.forename: Nika
authors.initials: N
authors.lastname: Adham
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001923:Brain Chemistry; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D018491:Dopamine Agonists / Q000493:pharmacokinetics*; D005260:Female; D008252:Macaca fascicularis; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000032:analysis*; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000032:analysis*; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D010879:Piperazines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C533287:cariprazine