Stößel Anne, Brox Regine, Purkayastha Nirupam, Hübner Harald, Hocke Carsten, Prante Olaf, Gmeiner Peter
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany.
Department of Nuclear Medicine, Ulmenweg 18, D-91054 Erlangen, Germany.
Bioorg Med Chem. 2017 Jul 1;25(13):3491-3499. doi: 10.1016/j.bmc.2017.04.036. Epub 2017 Apr 29.
Dopamine D receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D a highly promising biological target. The previously described dopamine D receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [F]2, a [F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.
多巴胺 D 受体介导的神经网络与多种神经精神疾病、药物成瘾及食物维持行为有关，这使得 D 成为一个极具前景的生物学靶点。先前描述的多巴胺 D 受体配体 FAUC 329（1）在帕金森病的 MPTP 小鼠模型中显示出对多巴胺耗竭的保护作用。我们使用放射性配体[F]2，它是先导化合物 1 的[F]氟乙氧基取代类似物，作为一种分子工具来可视化富含 D 的脑区，包括卡列哈岛。此外，据报道结构修饰导致嘧啶基哌嗪衍生物 3 和 9 显示出优于血清素能受体的亚型选择性和偏好性。对先导化合物 1 在非人灵长类动物中寻求可卡因行为的评估显示，可卡因自我给药行为和食物摄入量大幅减少。
