Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30001, 9713 GZ Groningen, The Netherlands.
Mol Pharm. 2022 Aug 1;19(8):2992-3001. doi: 10.1021/acs.molpharmaceut.2c00450. Epub 2022 Jul 18.
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.
腺苷 A 和多巴胺 D 受体在基底神经节形成异源四聚体结构，参与调节运动活动和神经精神功能。本研究使用正电子发射断层扫描 (PET) 技术，通过 D 拮抗剂示踪剂 [C]raclopride，研究了 A 受体对体内 D 受体结合的调节作用。健康雄性 Wistar 大鼠（n = 8）在基线时进行 [C]raclopride 扫描（60 分钟动态扫描），7 天后，急性给予 A 激动剂 CGS21680（1mg/kg），使用 MicroPET Focus-220 相机进行扫描。使用简化参考组织模型（SRTM）计算不可置换结合潜力（BP）值，以小脑为参考组织。SRTM 分析显示，与基线相比，CGS21680 给药后纹状体 [C]raclopride BP（n = 0.102）无明显变化。由于 CGS21680 强烈影响血液动力学，我们还使用动脉血取样和代谢校正的血浆输入函数，使用可逆双组织室模型（2TCM），从 / 比和纹状体/小脑体积分布比（DVR）获得 BP 在另一组动物中。这些大鼠在预处理后进行动态 [C]raclopride 扫描，预处理药物为载体（n = 5）、单次剂量 CGS21680（1mg/kg，n = 5）或 A 拮抗剂 KW6002（1mg/kg，n = 5）。与载体处理组相比，CGS21680 处理组的血浆中母体分数明显升高（p < 0.0001）。GCS21680 给药显著降低纹状体 / 比（p < 0.01），但 和 估计可能不太可靠。BP（DVR-1）从载体处理组的 1.963 ± 0.27 降至 CGS21680 或 KW6002 给药后的 1.53 ± 0.55（p = 0.080）或 1.961 ± 0.11（p = 0.993）。我们的研究表明，A 激动剂 CGS21680，而不是拮抗剂 KW6002，可能会降低纹状体中 D 受体的可用性。
