Dopamine D2/D3 Receptor Agonists for PET Imaging
用于 PET 成像的多巴胺 D2/D3 受体激动剂
基本信息
- 批准号:7617602
- 负责人:
- 金额:$ 34.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-06 至 2011-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAgonistAmphetaminesApomorphineAutopsyBindingBiodistributionBrainBrain regionCell LineCorpus striatum structureCyclic AMPDevelopmentDiseaseDopamineDopamine D2 ReceptorDopamine ReceptorDue ProcessEtiologyFluorineFunctional disorderG-Protein-Coupled ReceptorsGoalsGuanine NucleotidesGuanylyl ImidodiphosphateHumanHydroxyl RadicalImageImageryIn VitroIsomerismKineticsKnockout MiceLeadLifeMacaca mulattaManicMeasuresMediatingMental disordersMethodsMicrodialysisMonkeysMusNeurologicNucleotidesParkinson DiseasePharmaceutical PreparationsPopulationPositioning AttributePositronProcessPropertyRadiolabeledRattusReceptor GeneReportingResearchResearch PersonnelResolutionRodentSchizophreniaSiteSkeletonSpiperoneStructureSubstance abuse problemTechniquesThalamic structureThe SunTherapeutic StudiesTraceranalogbasedepressiondesigndopamine D3 receptorin vivointerestnonhuman primateprogramsradioligandradiotracerreceptorreceptor bindingresearch studytetralinuptake
项目摘要
DESCRIPTION (provided by applicant): Antagonists used for positron emission tomographic (PET) studies of dopamine D2/D3 receptors do not distinguish between the high-affinity (HA) and low-affinity (LA) states of the receptors. We and others have now accomplished imaging only the HA-state of dopamine D2/D3 receptors using aminotetralin-based and apomorphine-based PET radiotracers. These studies confirm that some of the D2/D3 receptors in the striatum of the living rodent and monkey are present in the HA-state. The ability to image and reliably quantitate the amount of receptors present in the HA-state has a number of applications. These include: (a), the study of etiology of disease states such as schizophrenia, manic depression and Parkinson's disease; (b). study of dopamine release since dopamine now competes with a more sensitive PET radiotracer that is bound only (or predominantly) to the HA-state; (c). study of therapeutic drugs that may shift population of affinity states, from HA- to LA-state. Our goal is this application is two-fold: 1. Develop and evaluate agents that are suitable for HA-state imaging of striatal and extrastriatal receptors; and 2. Evaluate HA-state radiotracers that will be able to discriminate between D2 and D3 receptor subtypes. We have optimized 5- hydroxyaminotetralins for imaging dopamine D2 receptors which has resulted in the development of 18F-5- OH-FPPAT as a suitable imaging agent. We propose to optimize radiosynthesis of the more active isomer S-18F-5-OH-FPPAT and carry out in vitro and in vivo binding properties of both R- and S-isomers. The high- affinity agent 11C-PPHT will be studied for extrastriatal HA-states. Both, R- and S-isomers will be evaluated. Quantitative microPET studies to measure amphetamine-induced dopamine release in striatal and extrastriatal regions will be carried out. In order to direct the tetralins to the D3 receptor, the 7-hydroxy analogs of FPPAT and PPHT will be investigated. Specifically we will synthesize R- and S-isomers of 18F-7- OH-FPPAT and 11C-7-OH-PPHT that may have potential as D3 selective agents. Fluorine-18 analog of PPHT, 18F-FPPHT (both 5- and 7-hydroxy) will also be prepared for extrastriatal imaging of HA-states. Pharmacological characterization of these agents using D3 cell lines, brain homogenates, autoradiographic studies, D2 and D3 receptor knock-out mice microPET studies will be carried out. Finally PET studies will be carried out in monkeys with these agents to demonstrate HA-state binding and receptor subtype selectivity.
描述(由申请方提供):用于多巴胺D2/D3受体正电子发射断层扫描(PET)研究的拮抗剂不能区分受体的高亲和力(HA)和低亲和力(LA)状态。我们和其他人现在已经完成了成像只有HA状态的多巴胺D2/D3受体使用氨基四氢萘和阿朴吗啡为基础的PET放射性示踪剂。这些研究证实,活体啮齿动物和猴子纹状体中的一些D2/D3受体以HA状态存在。对HA状态下存在的受体的量进行成像和可靠定量的能力具有许多应用。其中包括:(a)精神分裂症、躁狂抑郁症和帕金森病等疾病的病因学研究;(B)。多巴胺释放的研究,因为多巴胺现在与仅(或主要)结合至HA状态的更灵敏的PET放射性示踪剂竞争;(c).研究治疗药物,可能会改变人口的亲和状态,从HA-到LA-状态。我们的目标是这个应用程序是双重的:1.开发和评估适用于纹状体和纹状体外受体HA状态成像的试剂;和2.评估HA状态放射性示踪剂,能够区分D2和D3受体亚型。我们已经优化了5-羟基氨基四氢萘用于多巴胺D2受体成像,这导致了18 F-5- OH-FPPAT作为合适的成像剂的发展。我们建议优化活性更高的异构体S-18 F-5-OH-FPPAT的放射合成,并进行R-和S-异构体的体外和体内结合特性。将针对纹状体外HA状态研究高亲和力试剂11 C-PPHT。将评价R-和S-异构体。将进行定量microPET研究,以测量纹状体和纹状体外区域中安非他明诱导的多巴胺释放。为了将四氢萘导向D3受体,将研究FPPAT和PPHT的7-羟基类似物。具体而言,我们将合成可能具有作为D3选择剂的潜力的18 F-7- OH-FPPAT和11 C-7-OH-PPHT的R-和S-异构体。还将制备PPHT的氟-18类似物18F-FPPHT(5-和7-羟基)用于HA状态的纹状体外成像。将使用D3细胞系、脑匀浆、放射自显影研究、D2和D3受体敲除小鼠microPET研究对这些药物进行药理学表征。最后,将在猴中使用这些药物进行PET研究,以证明HA状态结合和受体亚型选择性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jogeshwar Mukherjee其他文献
Jogeshwar Mukherjee的其他文献
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