Development of Dopamine D1 Receptor Agonists for PET Imaging

描述（由申请人提供）：多巴胺D1受体（Dopamine D1 receptor, D1R）在精神分裂症、帕金森病等神经精神疾病的病理生理中起重要作用，是认知增强策略的重要靶点。目前可用的D1R放射性配体[11C]NNC112和[11C]SCH23390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、完整的D1R激动剂，修改它们以引入用于放射性标记的附属基团，从而合成D1R- pet配体，并在啮齿动物和非人灵长类动物中评估它们作为D1R显像剂的适用性。二氢西啶和强蒽醌是强效、高选择性和完全有效的D1R激动剂。此外，许多基于配体的计算建模方法，如药效团检测和配体在D1R结合位点的相互作用，已经被使用，并强调了使用-苯基多巴胺药效团模板设计D1R激动剂的有效性。因此，我们建议合成四种18F标记的PET配体用于D1R的体内成像。这些试剂的体外结合亲和力将被确定并用于表征新化合物的效力和选择性。将利用来自回旋加速器和各自前体的18f -氟化物开发一种高纯度、高产量的放射性标记程序。18F- d1r -PET配体的动态PET研究将在使用微型PET扫描仪的大鼠中进行。放射性示踪剂的D1R激动剂结合特性将在用载体处理或受体饱和剂量SCH23390预先阻断的动物中计算。非人灵长类动物PET研究将使用在大鼠研究中显示出足够潜力的18F- d1r -PET配体进行。在这些临床前啮齿动物和灵长类动物PET研究中显示出适当性质的配体将成为未来人类临床研究中作为示踪剂的候选体，并进一步支持通过R01机制继续寻求的项目。

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.