Impact of an Adenosine A 2A Receptor Agonist and Antagonist on Binding of the Dopamine D 2 Receptor Ligand [ 11 C]raclopride in the Rodent Striatum

• Published in: Molecular pharmaceutics Vol. 19; no. 8; pp. 2992 - 3001
• Main Authors: Prasad, Kavya, de Vries, Erik F J, Sijbesma, Jürgen W A, Garcia-Varela, Lara, Vazquez-Matias, Daniel A, Moraga-Amaro, Rodrigo, Willemsen, Antoon T M, Dierckx, Rudi A J O, van Waarde, Aren
• Format: Journal Article
• Language: English
• Published: United States 01-08-2022
• Subjects: Adenosine - metabolism; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Carbon Radioisotopes; Corpus Striatum - metabolism; Dopamine; Ligands; Male; Positron-Emission Tomography - methods; Raclopride; Rats; Rats, Wistar; Receptor, Adenosine A2A - metabolism; Receptors, Dopamine - metabolism; Rodentia - metabolism; D2 receptor; animal studies; A2A receptor; positron emission tomography; kinetic modeling
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.2c00450

Adenosine A
and dopamine D
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
receptor-mediated modulation of D
receptor binding in vivo using positron emission tomography (PET) with the D
antagonist tracer [
C]raclopride. Healthy male Wistar rats (
= 8) were scanned (60 min dynamic scan) with [
C]raclopride at baseline and 7 days later following an acute administration of the A
agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BP
) 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 [
C]raclopride BP
(
= 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
from the
/
ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [
C]raclopride scans after pretreatment with a vehicle (
= 5), a single dose of CGS21680 (1 mg/kg,
= 5), or a single dose of the A
antagonist KW6002 (1 mg/kg,
= 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group (
= 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal
/
ratio (
< 0.01), but
and
estimates may be less reliable. The BP
(DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 (
= 0.080) or 1.961 ± 0.11 (
= 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A
agonist CGS21680, but not the antagonist KW6002, may reduce the D
receptor availability in the striatum.