Development of Dopamine D1 Receptor Agonists for PET Imaging

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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.