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Adenosine A 2A and dopamine D 2 receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A 2A receptor-mediated modulation of D 2 receptor binding in vivo using positron emission tomography (PET) with the D 2 antagonist tracer [ 11 C]raclopride. Healthy male Wistar rats ( n = 8) were scanned (60 min dynamic scan) with [ 11 C]raclopride at baseline and 7 days later following an acute administration of the A 2A agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BP ND ) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [ 11 C]raclopride BP ND ( p = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BP ND from the k 3 / k 4 ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [ 11 C]raclopride scans after pretreatment with a vehicle ( n = 5), a single dose of CGS21680 (1 mg/kg, n = 5), or a single dose of the A 2A antagonist KW6002 (1 mg/kg, n = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group ( p = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal k 3 / k 4 ratio ( p < 0.01), but k 3 and k 4 estimates may be less reliable. The BP ND (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 ( p = 0.080) or 1.961 ± 0.11 ( p = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A 2A agonist CGS21680, but not the antagonist KW6002, may reduce the D 2 receptor availability in the striatum.

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 receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions : Target engagement of AG-0029 as an agonist at dopamine D 2 /D 3 receptors and an antagonist at histamine H 3 receptors could be demonstrated in the rat brain with [ 11 C]raclopride and [ 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.