Molecular Probes for In Vivo MR Studies of Myelin

描述（由申请人提供）：拟议的研究旨在开发易于进入大脑并特异性结合髓鞘膜的小分子探针。与髓鞘相关的异常和变化见于许多神经退行性疾病。因此，在中枢神经系统中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。尽管磁共振成像（MRI）通常用于以高灵敏度检测脑病变，但MRI不直接监测髓鞘含量。它不能区分由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。我们建议开发适用于磁共振成像研究髓鞘的分子探针。髓鞘成像探针的发展也将允许其他MR成像技术，如扩散张量成像（DTI）和磁共振波谱（MRS），以更好地研究大脑中髓鞘的变化。我们假设，小分子探针可以开发为髓鞘成像剂，选择性地积累在有髓鞘的大脑区域与合适的体外和体内MR研究的属性。为了验证这一假设，我们已经确定了一种称为BMB的先导化合物，它很容易进入大脑并选择性地与髓鞘结合。我们计划进一步评估这种领先的髓鞘成像剂，以解决以下具体目标：1）通过体外结合测定和组织染色进一步评估领先的髓鞘结合化合物，以定量确定结合亲和力和特异性; 2）表征BMB与分离的脑髓鞘组分结合并在脑组织切片中孵育后的体外MR特性; 3）在正常对照小鼠和脱髓鞘和髓鞘再生的小鼠模型中表征探针的体内MR特性。预计该项目的完成将证明可以开发用于髓磷脂体内MR研究的分子探针的概念，并作为进一步开发和应用于人类受试者的基础。这项研究对公共卫生有以下影响：1）在早期阶段有效检测脱髓鞘，以帮助明确诊断; 2）脱髓鞘病变负荷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。

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.