Fluorine-18 Labeled Functional Dopamine Receptor Imaging Agents

氟 18 标记的功能性多巴胺受体显像剂

基本信息

批准号：
8974173
负责人：
Jogeshwar Mukherjee
金额：
$ 23.18万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8974173
关键词：
Affect Affinity Aggressive behavior Agonist Alcoholism Alcohols Animals Antibodies Autopsy Basal Ganglia Binding Brain Brain Diseases Brain region California Central Nervous System Diseases Cerebellum Chemistry Chronic Cocaine Coupled Dementia Development Diagnosis Diagnostic Disease Dopamine Dopamine Receptor Dorsal Early Diagnosis Etiology Evaluation Female Fluorine Functional Imaging Funding GTP-Binding Proteins Goals Half-Life Human Hypertension Investigation Investigational New Drug Application Label Lead Manic Mental Depression Methamphetamine Methods Modeling Movement Disorders Mus Nicotine Organ PET/CT scan Parkinson Disease Pharmaceutical Preparations Physiological Physiology Positron-Emission Tomography Principal Investigator Procedures Radiolabeled Radiometry Rattus Relative (related person)Reporting Research Reserpine Rodent Model Role Scanning Schizophrenia Site Sleep Disorders Slice Specificity Substance abuse problem Substantia nigra structure System Testing Therapeutic Therapeutic Studies Time Toxic effect United States National Institutes of Health Universities Validation Ventral Striatum Work addiction brain tissue desmethoxyfallypride dosimetry drug of abuse human subject imaging agent imaging probe improved in vivo male novel programs public health relevance radiotracer receptor whole body imaging

项目摘要

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.

描述（适用提供）：由于缺乏选择性成像剂，功能性（G蛋白耦合，高亲和力状态）的成像受到限制。在加利福尼亚大学 - IRVINE大学（UCI）中，我们有几个主要计划，可以从成像功能性多巴胺受体中获得。这些包括：（a）。由于腹侧纹状体中的D3受体对滥用药物的成瘾研究很大。（b）。多巴胺释放的研究由于多巴胺在功能部位与更敏感的PET放射性示踪剂竞争。（c）。疾病状态的病因研究，例如精神分裂症，躁狂抑郁症和帕金森氏病，其中多巴胺能体系是强烈涉及的；（d）。研究可能选择性影响功能受体的热药。我们成功地开发了一种选择性氟-18剂，18f-5-OH-fPPAT和18F-7-OH-FHXPAT，用于成像功能性多巴胺D2和D3受体。在动物宠物研究中，选择性结合18F-5-OH-FPPAT和18F-7-OH-FHXPAT在小脑的背侧和腹侧纹状体中有限结合。特定的大脑区域结合和短扫描时间表明，18F-5-OH-FPPAT和18F-7-OH-FHXPAT可能是人类功能接收器的PET成像剂的潜力。因此，我们在NIH应用中的目标是建立18F-5-OH-FPPAT和18F-7-OH-FHXPAT的自动放射合成化学，制造和控制程序。随后将进行宠物研究，以建立体内定量方法，该方法将应用于药物滥用药物（甲基苯丙胺，可卡因，酒精和尼古丁）的慢性作用。关于死后人脑组织的放射自显影研究将使用18F-5-OH-FPPAT和18F-7-OH-FHXPAT进行，以评估诊断使用。因此，该应用程序的总体拟议研究将支持多巴胺受体功能中涉及异常的几种脑疾病的研究。