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: 7295700
• 负责人: Yanming Wang
• 金额: --
• 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/7295700
• 关键词: Address; Affinity; Binding; Biological Assay; Brain; Brain region; Contrast Media; Demyelinations; Detection; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Functional disorder; Goals; Image; Imaging Techniques; In Vitro; Inflammation; Intervention; Lead; Lesion; Localized; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Membrane; Molecular; Molecular Probes; Monitor; Mus; Myelin; Neuraxis; Neurodegenerative Disorders; Prevention; Property; Public Health; Research; Severities; Specificity; Staging; Symptoms; Testing; Tissue Stains; base; brain tissue; concept; efficacy evaluation; human subject; imaging probe; in vivo; insight; mouse model; nervous system disorder; novel therapeutics; repaired; small molecule

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特异性结合髓鞘膜的小分子探针。髓磷脂的异常和改变见于许多神经退行性疾病。因此，直接评估中枢神经系统体内髓磷脂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）通常用于高灵敏度的脑病变检测，但MRI不能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。对于髓磷脂的体内磁共振研究，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。髓磷脂成像探针的发展也将允许其他磁共振成像技术，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磷脂的变化。我们假设，小分子探针可以作为髓鞘显像剂，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。为了验证这一假设，我们已经确定了一种先导化合物，称为BMB，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该铅髓鞘显像剂，以实现以下具体目标：1)通过体外结合试验和组织染色进一步评估铅髓鞘结合化合物，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)在正常对照小鼠和小鼠脱髓鞘和再脱髓鞘模型中表征探针的体内MR特性。预计该项目的完成将证明分子探针可以用于髓磷脂的体内磁共振研究的概念，并为进一步开发和应用于人类受试者奠定基础。本研究对公众健康有以下影响：1)早期有效检测脱髓鞘，有助于明确诊断；2)脱髓鞘病变负担与症状严重程度的相关性，3)促进目前正在开发的脱髓鞘治疗的疗效评估。

项目成果

Myelin imaging compound (MIC) enhanced magnetic resonance imaging of myelination.

髓磷脂成像化合物 (MIC) 增强了髓鞘形成的磁共振成像。

• DOI: 10.1021/jm201010e
• 发表时间: 2012
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Frullano,Luca;Zhu,Junqing;Wang,Changning;Wu,Chunying;Miller,RobertH;Wang,Yanming
• 通讯作者: Wang,Yanming

Longitudinal near-infrared imaging of myelination.

• DOI: 10.1523/jneurosci.2698-10.2011
• 发表时间: 2011-02-16
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Wang C;Wu C;Popescu DC;Zhu J;Macklin WB;Miller RH;Wang Y
• 通讯作者: Wang Y

Design, synthesis, and evaluation of coumarin-based molecular probes for imaging of myelination.

• DOI: 10.1021/jm101489w
• 发表时间: 2011-04-14
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Wang C;Wu C;Zhu J;Miller RH;Wang Y
• 通讯作者: Wang Y