Department of Radiology, Case Center for Imaging Research, Division of Radiopharmaceutical Science, Case Western Reserve University, Cleveland, Ohio 44106, United States.
J Med Chem. 2012 Jan 12;55(1):94-105. doi: 10.1021/jm201010e. Epub 2011 Dec 16.
The vertebrate nervous system is characterized by myelination, a fundamental biological process that protects the axons and facilitates electric pulse transduction. Damage to myelin is considered a major effect of autoimmune diseases such as multiple sclerosis (MS). Currently, therapeutic interventions are focused on protecting myelin integrity and promoting myelin repair. These efforts need to be accompanied by an effective imaging tool that correlates the disease progression with the extent of myelination. To date, magnetic resonance imaging (MRI) is the primary imaging technique to detect brain lesions in MS. However, conventional MRI cannot differentiate demyelinated lesions from other inflammatory lesions and therefore cannot predict disease progression in MS. To address this problem, we have prepared a Gd-based contrast agent, termed MIC (myelin imaging compound), which binds to myelin with high specificity. In this work, we demonstrate that MIC exhibits a high kinetic stability toward transmetalation with promising relaxometric properties. MIC was used for in vivo imaging of myelination following intracerebroventricular infusion in the rat brain. MIC was found to distribute preferentially in highly myelinated regions and was able to detect regions of focally induced demyelination.
脊椎动物神经系统的特征是髓鞘化，这是一种保护轴突并促进电脉冲转导的基本生物学过程。髓鞘损伤被认为是多发性硬化症（MS）等自身免疫性疾病的主要影响因素。目前，治疗干预的重点是保护髓鞘完整性并促进髓鞘修复。这些努力需要伴随着一种有效的成像工具，将疾病进展与髓鞘化的程度相关联。迄今为止，磁共振成像（MRI）是检测 MS 脑损伤的主要成像技术。然而，常规 MRI 无法区分脱髓鞘病变与其他炎症病变，因此无法预测 MS 的疾病进展。为了解决这个问题，我们已经制备了一种基于 Gd 的造影剂，称为 MIC（髓鞘成像化合物），它与髓鞘具有高度特异性结合。在这项工作中，我们证明了 MIC 表现出对转金属化的高动力学稳定性和有前景的弛豫性能。MIC 用于在大鼠脑室内输注后对髓鞘化进行体内成像。发现 MIC 优先分布在高度髓鞘化的区域，并能够检测到局灶性诱导的脱髓鞘区域。
