Fluorine-18 Labeled Functional Dopamine Receptor Imaging Agents

 描述(申请人提供)：由于缺乏选择性显像剂，功能性(G蛋白偶联，处于高亲和力状态)多巴胺受体的成像受到限制。在加州大学欧文分校(UCI)，我们有几个主要的项目，可以从成像功能性多巴胺受体中获益。这些措施包括：(A)。对药物成瘾的研究，因为腹侧纹状体的D3受体与药物成瘾密切相关；研究多巴胺的释放，因为多巴胺在功能部位与更灵敏的PET放射性示踪剂竞争；对精神分裂症、躁郁症和帕金森氏症等与多巴胺能系统有强烈牵连的疾病状态的病因学的研究；及(D)研究可能选择性影响功能性受体的治疗药物。我们成功地研制了一种选择性氟-18显像剂，18F-5-OH-FPPAT和18F-7-OH-FHXPAT，用于功能性多巴胺D2和D3受体的成像。在动物PET研究中，18F-5-OH-FPPAT和18F-7-OH-FHXPAT在背侧和腹侧纹状体有选择性结合，在小脑有有限的结合。18F-5-OH-FHXPAT和18F-7-OH-FHXPAT的脑区特异性结合和扫描时间短，提示它们有可能作为人体功能受体的PET显像剂。因此，我们在NIH应用程序中的目标是为18F-5-OH-FPPAT和18F-7-OH-FHXPAT建立自动化放射合成化学、制造和控制程序。随后将进行正电子发射计算机断层扫描研究，以建立体内定量方法，用于药物滥用(甲基苯丙胺、可卡因、酒精和尼古丁)的慢性影响。将用18F-5-OH-FPPAT和18F-7-OH-FHXPAT对死后的人脑组织进行放射自显影研究，以评价其诊断价值。因此，这项申请的总体拟议研究将支持对涉及多巴胺受体功能异常的几种大脑疾病的研究。

 DESCRIPTION (provided by applicant): Imaging of functional (G-protein coupled, in high-affinity state) dopamine receptors has been limited due to a lack of selective imaging agents. At University of California-Irvine (UCI), we have several major programs that would gain from imaging functional dopamine receptors. These include: (a). study of addiction to substance abuse drugs since D3 receptors in the ventral striatum are strongly implicated; (b). study of dopamine release since dopamine competes with a more sensitive PET radiotracer at functional sites; (c). the study of etiology of disease states such as schizophrenia, manic depression and Parkinson's disease where the dopaminergic system is strongly implicated; and (d). study of therapeutic drugs that may selectively affect functional receptors. We have successfully developed a selective fluorine-18 agents, 18F-5-OH-FPPAT and 18F-7-OH-FHXPAT for imaging functional dopamine D2 and D3 receptor. In animal PET studies selective binding of 18F-5-OH-FPPAT and 18F-7-OH-FHXPAT was in the dorsal and ventral striatum with limited binding in the cerebellum. The specific brain region binding and short scan time suggest that 18F-5-OH-FPPAT and 18F- 7-OH-FHXPAT may have good potential as a PET imaging agent for functional receptors in humans. Therefore, our goal in this NIH application is to establish automated radiosynthesis chemistry, manufacturing and control procedures for 18F-5-OH-FPPAT and 18F-7-OH-FHXPAT. This will be followed by PET studies to establish in vivo quantitation methods which will be applied to chronic effects of substance abuse drugs (methamphetamine, cocaine, alcohol and nicotine). Autoradiographic studies on postmortem human brain tissue will be carried out with 18F-5-OH-FPPAT and 18F-7-OH-FHXPAT to evaluate diagnostic use. The overall proposed research in this application will thus support investigations in several brain disorders involving anomalies in the function of dopamine receptors.