PET STUDIES OF CATECHOL-OMICRON-METHYLTRANSFERASE

描述：(改编自调查人员摘要)本提案 涉及放射性标记的儿茶酚-O-甲基转移酶的发展 用于正电子发射断层扫描(PET)研究的(COMT)抑制剂 体内的酶系统。COMT规定的是 中枢和周围神经系统中的神经递质，以及 治疗药物开发中的一个重要分子靶点 帕金森病(PD)自代谢L-多巴限药以来的研究 生物利用度。COMT分布于全身和大脑，而且 它的活动异常可能与神经学， 精神疾病和心血管疾病。它在乳房中也会升高。 在雌激素代谢中起作用的癌症组织。有一种 关于COMT或变化的区域分布的信息有限 在疾病中发生的活动。布鲁克海文宠物集团已经 最近开发了一条合成路线，合成F-18标记的Ro41-0960，一种有效的 和选择性COMT抑制剂。初步的PET研究证明了它的 能够标记器官中的COMT位点，如肾脏、肝脏和 心。 该提案的目标是进一步将F-18-Ro41-0960描述为 活体外周COMT示踪剂C-11-的合成与表征 标记为Ro40-7592的COMT抑制剂，临床用于治疗帕金森病； 用正电子发射计算机断层扫描检测COMT抑制作用的药效学。建议 研究包括基线COMT分布的测量和 放射性示踪剂对COMT变化的敏感性评估 活动。假设标记的COMT抑制剂将映射COMT 在体内，这一假说将通过补充的体外实验进行验证 放射性示踪剂摄取与COMT相关的方法 啮齿动物的活动。拟议的研究将提供第一个 灵长类动物COMT的功能图谱，从而提供了一个科学工具 用于研究生命系统中的COMT及其潜力 在药物开发和肿瘤学方面的应用。

DESCRIPTION: (Adapted from investigator's abstract) This proposal involves the development of radiolabeled catechol-O-methyltransferase (COMT) inhibitors for positron emission tomography (PET) studies of the enzyme system in vivo. COMT regulates the concentration of neurotransmitters in the central and peripheral nervous systems and is an important molecular target in the development of drugs to treat Parkinson's disease (PD) since its metabolism of L-DOPA limits drug bioavailability. COMT is distributed throughout the body and brain, and abnormalities in its activity may be associated with neurological, psychiatric and cardiovascular disorders. It is also elevated in breast cancer tissue where it plays a role in estrogen metabolism. There is limited information on the regional distribution of COMT or of changes in its activity occurring in diseases. The Brookhaven PET Group has recently developed a synthetic route to F-18-labeled Ro41-0960, a potent and selective COMT inhibitor. Initial PET studies demonstrated its ability to label the COMT sites in organs such as kidney, liver and heart. The goals of this proposal are to further characterize F-18-Ro41-0960 as a tracer for peripheral COMT in vivo; synthesize and characterize C-11- labeled Ro40-7592, a COMT inhibitor used clinically to treat PD; and to examine the pharmacodynamics of COMT inhibition wih PET. Proposed studies include the measurement of baseline COMT distribution and the assessment of the sensitivity of the radiotracers to changes in COMT activity. The hypothesis is that labeled COMT inhibitors will map COMT in vivo, and the hypothesis will be tested by a complementary ex vivo approach in which radiotracer uptake will be correlated with COMT activities in rodents. The proposed studies will provide the first functional maps of COMT in the primate, thus affording a scientific tool for the investigation of COMT in living systems along with potential applications to drug development and oncology.