In Vivo Characterization and Quantification of Myelin in the Central Nervous Syst

中枢神经系统髓磷脂的体内表征和定量

• 批准号: 7581860
• 负责人: Yanming Wang
• 金额: $ 34.34万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7581860
• 关键词: Address; Animal Model; Binding; Biodistribution; Biological Assay; Brain; Brain region; Carbon; Characteristics; Clinical; Clinical Research; Demyelinations; Development; Diagnosis; Disease; Disease Progression; Drug Kinetics; Early Diagnosis; Event; Exhibits; Fluorine; Functional disorder; Future; Goals; Human; Image; Image Analysis; In Vitro; Lead; Localized; Measures; Membrane; Metabolism; Methods; Modality; Modeling; Molecular Probes; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Neuraxis; Neurodegenerative Disorders; Outcome; Papio; Parents; Pathogenesis; Play; Positron; Positron-Emission Tomography; Prevention; Property; Public Health; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Range; Rate; Research; Research Project Grants; Role; Screening procedure; Series; Structure; Structure-Activity Relationship; Surrogate Markers; Techniques; Testing; Therapeutic Intervention; Tissue Model; Tissue Stains; analog; base; design; dysmyelination; efficacy evaluation; human subject; in vivo; insight; lipophilicity; myelination; nervous system disorder; neuropathology; nonhuman primate; novel; novel therapeutics; radioligand; radiotracer; repaired; small molecule; tool; uptake; white matter

DESCRIPTION (provided by applicant): The proposed research is aimed at developing radiopharmaceuticals that readily enter the brain and selectively localize in the white matter via direct binding to myelin membranes. Abnormality and changes associated with myelin membranes in the central nervous system play a key role in the pathogenesis of multiple sclerosis and other related neurodegenerative disorders. Thus, direct assessment of myelin content in vivo has been an important goal in protection and repair of axonal damage. However, the lack of molecular probes has limited the progress of myelin imaging and hindered efficacy evaluation of novel myelin repair therapies currently under development. To meet this need, we plan to develop myelin-imaging agents uniquely suited for use in clinical imaging modalities such as positron emission tomography (PET). We hypothesize that small-molecule PET probes can be developed, which will freely enter the brain, directly and selectively bind to myelin membranes. To test this hypothesis, we have identified some lead compounds with promising binding properties for in vivo studies, which allows us to address the following specific aims: 1) Rationally design and synthesize a selected series of myelin-imaging agents and quantitatively evaluate their binding properties in vitro for structure-activity relationship studies; 2) Radiolabel selected agents with positron-emitting 11C or 18F and assess the in vivo binding properties in animal models of demyelination to determine the rates of brain entry, clearance, and specific retention in the brain; 3) Evaluate the pharmacokinetic profiles and metabolism of selected myelin-imaging agents through PET studies in non-human primates for potential application in human subjects. It is anticipated that completion of the project will lead to the development of imaging markers that are suitable for application in human subjects. PUBLIC HEALTH RELEVANCE: This research project has following important impacts on public health: 1) facilitation of efficacy evaluation of therapies currently under development that are aimed at prevention of axonal damage and myelin repair; 2) direct correlation of myelin changes with clinical outcomes; 3) aid in early and accurate diagnosis and subtyping of MS and related diseases.

描述(申请人提供)：拟议的研究旨在开发易于进入大脑并通过直接与髓鞘膜结合而选择性地定位在白质中的放射性药物。中枢神经系统髓鞘膜的异常和改变在多发性硬化症和其他相关神经退行性疾病的发病机制中起着关键作用。因此，直接评估体内髓鞘含量已成为轴突损伤保护和修复的重要目标。然而，分子探针的缺乏限制了髓鞘成像的进展，阻碍了目前正在开发的新型髓鞘修复疗法的疗效评估。为了满足这一需求，我们计划开发专门适用于正电子发射断层扫描(PET)等临床成像方式的髓鞘显像剂。我们假设可以开发出小分子的PET探针，它可以自由地进入大脑，直接和选择性地结合到髓鞘膜上。为了验证这一假说，我们已经确定了一些具有良好结合性能的先导化合物，用于体内实验，从而使我们能够达到以下具体目标：1)合理设计和合成一系列精选的髓鞘显像剂，并在体外定量评估其结合性能，以便进行构效关系研究；2)选择具有正电子发射11C或18F的显像剂并在动物脱髓鞘模型中评估其体内结合特性，以确定脑进入、清除和特异性脑内滞留的速率；3)通过PET研究，评估选定的髓鞘显像剂在非人灵长类动物体内的药代动力学和代谢规律，以便潜在应用于人体受试者。预计该项目的完成将导致适合于人类受试者应用的成像标记的开发。公共卫生相关性：这项研究项目对公共卫生有以下重要影响：1)促进目前正在开发的旨在预防轴突损伤和髓鞘修复的疗法的疗效评估；2)髓鞘变化与临床结果的直接关联；3)有助于MS和相关疾病的早期准确诊断和分型。