Molecular Probes for In Vivo MR Studies of Myelin

用于髓磷脂体内 MR 研究的分子探针

• 批准号: 7146860
• 负责人: Yanming Wang
• 金额: $ 17.38万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-26 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146860
• 关键词: brain; molecular probes; myelin; myelinopathy

DESCRIPTION (provided by applicant): The proposed research is directed at developing small-molecule probes that readily enter the brain and specifically bind to myelin membranes. Abnormality and changes associated with myelin are seen in many neurodegenerative disorders. Thus, direct assessment of the myelin content in vivo in the central nervous system has been an important goal in protection and repair of axonal damage. Although magnetic resonance imaging (MRI) is conventionally used for detection of brain lesions with high sensitivity, MRI does not directly monitor myelin content. It does not differentiate between lesions caused by demyelination and inflammation. For in vivo MR studies on myelin, molecular probes are required as contrast agents that are specific for myelin membranes. We propose to develop molecular probes suitable for magnetic resonance imaging studies of myelin. Development of myelin-imaging probes would also allow other MR imaging techniques such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) to better studies myelin changes in the brain. We hypothesize that small-molecule probes can be developed as myelin-imaging agents that selectively accumulate in the myelinated brain regions with suitable in vitro and in vivo properties for MR studies. To test this hypothesis, we have identified a lead compound, termed BMB, which readily enters the brain and selectively binds to myelin. We plan to further evaluate this lead myelin-imaging agent to address the following specific aims: 1) Further evaluate the lead myelin-binding compound through in vitro binding assays and tissue staining to quantitatively determine the binding affinity and specificity; 2) Characterize the in vitro MR properties of BMB following binding to isolated brain myelin fractions and incubation in brain tissue sections; 3) Characterize the in vivo MR properties of the probes in normal control mice and mouse models of demyelination and remyelination. It is anticipated that completion of the project will prove the concept that molecular probes can be developed for in vivo MR studies of myelin, and serve as a basis for further development and application in human subjects. This research has following impacts on public health: 1) effective detection of demyelination at early stages to aid in definitive diagnosis; 2) correlation of the demyelinated lesion burden with the severity of symptoms, and 3) facilitation of efficacy evaluation of remyelination therapies currently under development.

描述（由申请人提供）：拟议的研究旨在开发易于进入大脑并与髓磷脂膜特异性结合的小分子探针。在许多神经退行性疾病中都可以看到与髓磷脂相关的异常和变化。因此，直接评估中枢神经系统体内髓磷脂含量一直是保护和修复轴突损伤的重要目标。虽然磁共振成像（MRI）通常用于检测脑部病变的灵敏度很高，但 MRI 并不直接监测髓磷脂含量。它不能区分脱髓鞘和炎症引起的病变。对于髓磷脂的体内 MR 研究，需要分子探针作为髓磷脂膜特异性的造影剂。我们建议开发适合髓磷脂磁共振成像研究的分子探针。髓磷脂成像探针的开发还将使其他磁共振成像技术（例如扩散张量成像（DTI）和磁共振波谱（MRS））能够更好地研究大脑中髓磷脂的变化。我们假设小分子探针可以开发为髓磷脂成像剂，选择性地积聚在有髓鞘的大脑区域，具有适合 MR 研究的体外和体内特性。为了检验这一假设，我们鉴定了一种称为 BMB 的先导化合物，它很容易进入大脑并选择性地与髓磷脂结合。我们计划进一步评估这种先导髓磷脂显像剂，以实现以下具体目标：1）通过体外结合测定和组织染色进一步评估先导髓磷脂结合化合物，以定量确定结合亲和力和特异性； 2) 表征 BMB 与分离的脑髓磷脂组分结合并在脑组织切片中孵育后的体外 MR 特性； 3) 表征探针在正常对照小鼠和脱髓鞘和髓鞘再生小鼠模型中的体内 MR 特性。预计该项目的完成将证明分子探针可用于髓鞘质体内磁共振研究的概念，并为人类受试者的进一步开发和应用奠定基础。这项研究对公众健康有以下影响：1）在早期有效检测脱髓鞘，以帮助明确诊断； 2) 脱髓鞘病变负担与症状严重程度的相关性，以及 3) 促进目前正在开发的髓鞘再生疗法的疗效评估。