Dopamine D2/D3 Receptor Agonists for PET Imaging

描述（由申请人提供）：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成像仅多巴胺D2/D3受体的ha状态使用氨基四联素和阿吗啡为基础的PET放射性示踪剂。这些研究证实了啮齿动物和猴子纹状体中的一些D2/D3受体存在于ha状态。成像和可靠地定量存在于ha状态的受体数量的能力有许多应用。这些包括：(a)研究精神分裂症、躁狂抑郁症和帕金森病等疾病状态的病因；(b)多巴胺释放的研究，因为多巴胺现在与仅（或主要）与ha状态结合的更敏感的PET放射性示踪剂竞争；(c)治疗药物的研究可能会改变人群的亲和力状态，从HA-到la -状态。我们的目标是这个应用程序是双重的：1。开发和评估适合纹状体和纹状体外受体ha状态成像的药物；和2。评估ha状态的放射性示踪剂，将能够区分D2和D3受体亚型。我们优化了5-羟胺四联蛋白成像多巴胺D2受体，从而开发了18F-5- OH-FPPAT作为一种合适的显像剂。我们建议优化放射性合成更活跃的S-18F-5-OH-FPPAT，并进行R-和s -异构体的体外和体内结合特性研究。将研究高亲和剂11C-PPHT对胃外ha状态的影响。R-和s -异构体都会被评估。将进行定量微pet研究，以测量纹状体和纹状体外区域安非他明诱导的多巴胺释放。为了将四联素导向D3受体，将研究FPPAT和PPHT的7-羟基类似物。具体来说，我们将合成18F-7- OH-FPPAT和11C-7-OH-PPHT的R-和s -异构体，它们可能有作为D3选择性剂的潜力。PPHT的氟-18类似物，18F-FPPHT（5-羟基和7-羟基）也将制备用于ha状态的胃外成像。将使用D3细胞系、脑匀浆、放射自显影研究、D2和D3受体敲除小鼠的微pet研究来对这些药物进行药理学表征。最后，PET研究将在使用这些药物的猴子身上进行，以证明ha状态结合和受体亚型选择性。

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.