PET STUDIES OF CATECHOL-OMICRON-METHYLTRANSFERASE

描述：（改编自研究者摘要）本提案 涉及放射性标记的儿茶酚-O-甲基转移酶的发展 （COMT）抑制剂用于正电子发射断层扫描（PET）研究 体内酶系统。 COMT可调节 中枢和外周神经系统中的神经递质， 一个重要的分子靶点，在药物的发展，以治疗 帕金森病（PD），因为其代谢的左旋多巴限制药物 生物利用度 COMT分布在整个身体和大脑中， 其活性的异常可能与神经学， 精神和心血管疾病。 它也在乳房中升高 在癌组织中，它在雌激素代谢中起作用。 有 关于COMT区域分布或变化的信息有限 在疾病中的活性。 布鲁克海文PET集团拥有 最近开发了F-18标记的Ro 41 -0960的合成路线， 和选择性COMT抑制剂。 最初的PET研究表明， 能够标记器官如肾、肝和肾中的COMT位点， 心 本提案的目标是进一步描述F-18-Ro 41 -0960的特性， 一种体内外周COMT的示踪剂;合成并表征C-11- 标记的Ro 40 -7592，一种临床上用于治疗PD的COMT抑制剂;以及 用PET检查COMT抑制的药效学。 提出 研究包括测量基线COMT分布和 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，该假设将通过互补的离体测试， 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COMT的功能图，从而提供了一个科学工具 用于生命系统中COMT的研究，沿着 应用于药物开发和肿瘤学。

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.