Development of Dopamine D1 Receptor Agonists for PET Imaging

描述（由申请人提供）：多巴胺D1受体（D1 R）在精神分裂症和帕金森病等神经精神疾病的病理生理学中起重要作用，是认知增强策略的重要靶点。目前可用的D1 R放射性配体[11 C] NNC 112和[11 C] SCH 23390是拮抗剂。我们的目标是利用已知的化学结构合成一种选择性的完全D1 R激动剂，对其进行修饰以引入用于放射性标记的侧基，从而合成D1 R-PET配体，并评估它们在啮齿动物和非人灵长类动物中作为D1 R成像剂的适用性。二氢西定和doxanthrine是有效的、高选择性的和完全有效的D1 R激动剂。此外，许多基于配体的计算建模方法，如药效团检测和在D1 R的结合位点的配体的相互作用，已被使用，并突出使用-苯基多巴胺药效团模板设计D1 R激动剂的有效性。在这方面，我们建议合成四个18F标记的PET配体在体内成像D1 R。将测定这些试剂的体外结合亲和力，并用于表征新化合物的效力和选择性。一个高纯度，高产量的放射性标记程序将开发使用18F-氟化物从回旋加速器和各自的前体。使用microPET扫描仪在大鼠中进行18F-D1 R-PET配体的动态PET研究。将在接受溶剂处理或用受体饱和剂量的SCH 23390预阻断的动物中计算放射性示踪剂的D1 R激动剂结合特征。将用在大鼠研究中证明足够潜力的18F-D1 R-PET配体进行非人灵长类动物PET研究。在这些临床前啮齿动物和灵长类动物PET研究中显示具有适当性质的配体将作为人类临床研究中示踪剂的未来检查候选物，并进一步支持通过R 01机制继续寻求项目。 多巴胺D1受体（D1 R）是中枢神经系统中最丰富的多巴胺受体。具体而言，D1 R与精神分裂症和帕金森病等多种神经精神疾病有关，并且是治疗和药物开发的目标。在这个项目中，我们建议开发D1 R激动剂PET配体，以允许在体内研究受体的功能状态。

DESCRIPTION (provided by applicant): The Dopamine D1 receptor (D1R) plays an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Parkinson's disease and is an important target for cognitive enhancement strategies. The currently available D1R radioligands, [11C]NNC112 and [11C]SCH23390, are antagonists. It is our goal to synthesize a selective, full D1R agonist utilizing known chemical structures, modifying them to introduce pendent groups for radiolabeling, resulting in the synthesis of D1R-PET-ligands, and to assess them in rodents and non-human primates for suitability as D1R imaging agents. Dihydrexidine and doxanthrine are potent, highly selective and fully efficacious D1R agonists. In addition, many ligand-based computational modeling approaches, such as pharmacophore detection and interaction of ligands at the binding sites of the D1R, have been used and highlight the effectiveness of designing D1R agonists using the -phenyldopamine pharmacophore template. In this regard, we propose to synthesize four 18F labeled PET ligands for imaging D1R in vivo. The in vitro binding affinities of these agents will be determined and used to characterize the potency and selectivity of the new compounds. A high purity, high yield radiolabeling procedure will be developed using 18F-fluoride from a cyclotron and respective precursors. Dynamic PET studies with the 18F- D1R-PET-ligands will be performed in rats using a microPET scanner. The D1R agonist binding characteristics of the radiotracers will be calculated in animals that are vehicle-treated or pre-blocked with receptor-saturating doses of SCH23390. Non-human primate PET studies will be carried out with the 18F- D1R-PET-ligands that demonstrate sufficient potential in the rat studies. Ligands that are shown to have appropriate properties in these preclinical rodent and primate PET studies will be candidates for future examination as tracers in human clinical studies, with further support to continue the project sought through the R01 mechanism. PUBLIC HEALTH RELEVANCE: The dopamine D1 receptor (D1R) is the most abundant dopamine receptor in the central nervous system. Specifically, the D1R has been implicated in a variety of neuropsychiatric disorders such as schizophrenia and Parkinson's disease, and is a target for therapeutics and drug development. In this project, we propose to develop D1R agonist PET ligands to allow in vivo investigation of the functional state of the receptor.