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

描述（由申请人提供）：拟定的研究旨在开发易于进入大脑并通过直接结合髓鞘膜选择性定位于白色物质的放射性药物。 中枢神经系统中与髓鞘膜相关的异常和变化在多发性硬化和其他相关神经退行性疾病的发病机制中起关键作用。 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，并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，我们计划开发髓鞘成像剂，特别适用于临床成像方式，如正电子发射断层扫描（PET）。 我们假设可以开发小分子PET探针，其将自由进入大脑，直接和选择性地结合到髓鞘膜上。 为了验证这一假设，我们筛选出了一些具有良好结合活性的先导化合物，并进行了以下几方面的研究：1）合理设计合成了一系列髓鞘显像剂，并对它们的结合活性进行了体外定量评价，以进行构效关系研究; 2）用发射正电子的11 C或18F放射性标记选择的试剂，并评估脱髓鞘动物模型中的体内结合性质，以确定脑进入、清除和脑中特异性保留的速率; 3）通过在非人灵长类动物中的PET研究评估所选髓鞘成像剂的药代动力学特征和代谢，以用于在人类受试者中的潜在应用。 预计该项目的完成将导致开发适用于人类受试者的成像标记物。 公共卫生相关性：该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相关性; 3）有助于MS和相关疾病的早期和准确诊断和亚型分型。

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.