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Introduction : Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D 2 /D 3 agonist/H 3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods : Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D 2 /D 3 receptor ligand [ 11 C]raclopride or the histamine H 3 receptor ligand [ 11 C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [ 11 C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [ 11 C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution ( V T : Dopamine D Results : Dopamine D 2/3 receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the V T values of [ 11 : Target engagement of AG-0029 as an agonist at dopamine D 3 /D Conclusions : Target engagement of AG-0029 as an agonist at dopamine D 2 /D 3 receptors and an antagonist at histamine H 3 C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D 11 /D 11 C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D 2 /D 3 and moderate (submicromolar) affinity to H 3 receptors.

[ 18 F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood-brain barrier with positron emission tomography. This study evaluates [ 18 F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant K 1 increased by 40.7% and the volume of distribution ( V T ) by 30.4% after P-gp inhibition, while the efflux constant k 2 did not change significantly. Similar changes were found for all evaluated scan durations. K 1 did not depend on scan duration (10 min- K 1 = 0.2191 vs 91 min- K 1 = 0.2258), while V T and k 2 did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using K 1 obtained with 1-TCM. For the 91-min scan, V T and K 1 can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function.