Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Symeres B.V., Kadijk 3, 9747 AT Groningen, The Netherlands.
Mol Pharm. 2022 Jul 4;19(7):2287-2298. doi: 10.1021/acs.molpharmaceut.2c00121. Epub 2022 Jun 22.
: 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/D agonist/H 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). : Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D/D receptor ligand [C]raclopride or the histamine H receptor ligand [C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [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 [C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution () as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. : Dopamine D 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 values of [C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. : Target engagement of AG-0029 as an agonist at dopamine D/D receptors and an antagonist at histamine H receptors could be demonstrated in the rat brain with [C]raclopride and [C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D/D and moderate (submicromolar) affinity to H receptors.
帕金森病（PD）是一种神经退行性疾病，其特征是运动功能障碍和多种非运动症状。多巴胺能和组胺能系统之间的功能关系表明，像 AG-0029（D/D 激动剂/H 拮抗剂）这样的双重作用药物可以改善 PD 的运动和认知症状。本研究旨在使用正电子发射断层扫描（PET）证明 AG-0029 与其在哺乳动物大脑中的预期靶点的相互作用。
健康雄性 Wistar 大鼠在接受静脉内单次急性剂量的 AG-0029 前后，使用小动物 PET 相机扫描多巴胺 D/D 受体配体 [C]raclopride 或组胺 H 受体配体 [C]GSK-189254。使用小脑作为参比组织的简化参考组织模型 2（SRTM2）分析动态 [C]raclopride PET 数据（持续 60 分钟），并以不可置换结合潜力作为结果参数。使用 Logan 图形分析（以分布容积 () 作为结果参数）分析具有动脉血取样的动态 [C]GSK-189254 扫描（持续 60 分钟）的数据。使用 Lassen 图估计受体占有率。
纹状体中的多巴胺 D 受体占有率分别为给予 0.1 和 1 mg/kg AG-0029 后的 22.6 ± 18.0%和 84.0 ± 3.5%（平均值 ± 标准差）。在大鼠用 1 或 10 mg/kg AG-0029 预处理后，[C]GSK-189254 的几个脑区的 值显著降低。AG-0029 的 H 受体占有率分别为 11.9 ± 8.5%和 40.3 ± 11.3%，用于 1 和 10 mg/kg 的 AG-0029 剂量。
使用 [C]raclopride 和 [C]GSK-189254 PET，分别可以证明 AG-0029 作为多巴胺 D/D 受体激动剂和组胺 H 受体拮抗剂在大鼠大脑中的靶标结合。测量的占有率值反映了先前报道的 AG-0029 对 D/D 的高（亚纳摩尔）亲和力和对 H 受体的中等（亚微摩尔）亲和力。
