[18F]FPEB Studies of the mGluR5 Receptor and Methamphetamine Abuse

描述(申请人提供)：mGluR5受体是一种I型代谢性谷氨酸受体，与许多大脑疾病密切相关，包括精神刺激性药物滥用、脆性X综合征、亨廷顿病、抑郁症和焦虑障碍，以及在帕金森病的运动障碍中发挥重要作用。尽管mGluR5在这些疾病中很重要，但由于缺乏适当的成像方法，关于mGluR5功能的人类数据一直很少。最近发现了mGluR5受体的新的PET放射配基；动物和初步的人类研究表明，[18F]FPEB是最有希望的。在[18F]FPEB可以用于临床研究之前，需要进行[18F]FPEB的人体辐射剂量学研究，验证区域mGluR5水平的量化方法，以及这些估计的测试-再测试可靠性。这项应用的R21阶段将提供设计未来临床研究所需的这些数据，mGluR5受体的PET研究。该应用的R33阶段将研究mGluR5受体在甲基苯丙胺(冰毒)滥用中的作用。虽然冰毒的形成与其显著而迅速地提高细胞外多巴胺水平有关，但动物研究表明，反复给予精神刺激剂会导致腹侧纹状体mGluR5受体水平增加和mGluR5介导的神经传递的高紧张性水平，这似乎是维持冰毒成瘾的关键因素。选择性mGluR5拮抗剂逆转动物体内增强的紧张性mGluR5信号和冰毒的成瘾效应。其他研究表明，抑郁症患者额叶皮质mGluR5受体水平下降，额叶皮质mGluR5神经传递介导了包括执行功能在内的认知功能，这些功能在冰毒滥用者中受到损害。吸毒者的抑郁症状和执行功能受损是药物复发的重要危险因素。本应用程序R33阶段的目标是使用PET[18F]FPEB研究来测量冰毒滥用者的区域性mGluR5水平，并将区域性mGluR5受体水平与冰毒滥用者改变的奖励行为、认知障碍、精神症状和终生冰毒使用相关。这项拟议的研究将是首次研究mGluR5受体在人类滥用冰毒中的作用，并将显著增强我们对mGluR5受体在人类滥用冰毒中所起作用的了解。 公共卫生相关性：虽然mGluR5受体与许多重要脑部疾病的病理生理学有关，直到最近发现了放射性配基，如[18F]FPEB，但还没有放射性配基用于研究mGluR5在人类中的功能。该应用程序的R21阶段将执行临床研究执行之前所需的人体PET[18F]FPEB研究，使用[18F]FPEB对mGluR5进行的人体研究，辐射剂量测定，定量建模，以及重复性和可靠性测试。这项应用的R33阶段将研究甲基苯丙胺滥用者的局部大脑mGluR5水平，以及它们与甲基苯丙胺滥用者的奖励行为、认知功能和精神症状的损害以及甲基苯丙胺终身使用的关系。

DESCRIPTION (provided by applicant): The mGluR5 receptor is a Type I metabotropic glutamatergic receptor which is critically involved in a number of brain disorders including psychostimulant drug abuse, the Fragile X syndrome, Huntington's disease, depression, and anxiety disorders as well as playing an important role in motor dyskinesias in Parkinsons disease. Despite its importance in these disorders there has been a paucity of data in humans regarding mGluR5 function due to a lack of appropriate imaging methods. Recently new PET radioligands for the mGluR5 receptors have been discovered; animal and initial human studies suggest that [18F]FPEB is the most promising. Before [18F]FPEB can be used in clinical research, studies in humans of radiation dosimetry of [18F]FPEB , validation of methods of quantitation of regional mGluR5 levels, and the test-retest reliability of these estimates need to be performed. The R21 phase of this application will provide these data which are needed for design of future clinical research PET studies of the mGluR5 receptor. The R33 phase of this application will examine the role of the mGluR5 receptor in methamphetamine (METH) abuse. While the development of METH addiction has been related to its ability to markedly and rapidly elevate extracellular dopamine levels, animal studies indicate that repeated psychostimulant administration produces increased mGluR5 receptor levels and a high tonic level of mGluR5 mediated neurotransmission in the ventral striatum which appears to be a critical factor in the maintenance of METH addiction. Selective mGluR5 antagonists reverse both the increased tonic mGluR5 signaling and the addictive effects of METH in animals. Other studies indicate that decreased frontal cortical mGluR5 receptor levels are seen in depression and that frontal cortical mGluR5 neurotransmission mediates cognitive functions including executive function which are impaired in METH abusers. Depressive symptoms and impaired executive function in METH abusers are significant risk factors for drug relapse. The goals of the R33 phase of this application are to measure regional mGluR5 levels in METH abusers using PET [18F]FPEB studies, and to correlate regional mGluR5 receptor levels with the altered reward behaviors, cognitive impairments, psychiatric symptoms seen in METH abusers and with lifetime METH use. The proposed studies will be the first studies the of mGluR5 receptor in METH abuse in humans, and will significantly enhance our knowledge of the role of the mGluR5 receptor in humans abusing METH. PUBLIC HEALTH RELEVANCE: While the mGluR5 receptor has been implicated in the pathophysiology of a number of important brain disorders until the recent discovery of radioligands such as [18F]FPEB there have been no radioligands for studying mGluR5 function in humans. The R21 phase of this application will perform human PET [18F]FPEB studies which are needed prior to performance of clinical research human studies of the mGluR5 using [18F]FPEB, radiation dosimetry, quantitative modeling, and test-retest reproducibility and reliability. The R33 phase of this application will study regional brain mGluR5 levels in methamphetamine abusers, and their relationships to the impairments in reward behaviors, cognitive function, and psychiatric symptoms seen in methamphetamine abusers as well as to lifetime methamphetamine use.