Hydroxypyridonate Gd Complexes:MRI Agents

羟基吡啶酮酸钆复合物：MRI 试剂

• 批准号: 6456410
• 负责人: KENNETH N RAYMOND
• 金额: $ 22.18万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6456410
• 关键词: chemical stability; chemical structure function; chemical synthesis; contrast media; cytotoxicity; gadolinium; image enhancement; laboratory mouse; magnetic resonance imaging; physical property; pyridine

DESCRIPTION (provided by applicant): In the past two decades, magnetic resonance imaging (MRT) has revolutionized diagnostic medicine. MRI enables the acquisition of high resolution, three-dimensional images in the detection of a wide variety of physical abnormalities and recent advances in dynamic MRJ show the prospect of real-time imaging. About 30 percent of MRI scans are now acquired using a paramagnetic contrast agent, which enhances the image quality. Gadolinium complexes are most widely used and these complexes currently are all based on a poly(aminoearboxylate) ligand scaffold . 'While effective, the water proton relaxivity of these agents are only a few percent of that theoretically possible. Attachment of the agent to macromolecules, either synthetic or in vivo biomolecules, can increase the relaxivity by lowering the rotational correlation time but the rate of water exchange from the gadolinium center then becomes the limiting factor. We have a new family of gadolinium complexes (based on a hexadentate hydroxypyridonate ligand scaffold) that are stable and have substantially higher relaxivity than most poly(amino-carboxylate) complexes due to a water exchange rate about two orders of magnitude higher. The main objective of this project is to synthesize a novel series of Gd(III) MRI contrast agents for different diagnostic needs through selective structural modifications of the hexadentate ligand scaffold. The solution properties, including stability, will be assessed and the fundamental physical chemistry of their relaxivity explored in collaborative studies. Other collaborative studies will investigate initial biodistribution and toxicity screening (with a cell assay) and further studies will be done in a mouse or rat model. Our ultimate goal is to develop second generation MRI contrast agents with greater accuracy and specificity than those currently available or theoretically possible based on amino carboxylate ligands. These second generation agents will be made by introducing a new Gd complex unit that enables relaxivity of one or two orders of magnitude greater than what is routine today.

描述（由申请人提供）：在过去的二十年中，磁性 共振成像（MRT）彻底改变了诊断医学。 MRI启用 在检测中获取高分辨率的三维图像 多种身体异常和动态MRJ显示的最新进展 实时成像的前景。现在约有30％的MRI扫描 使用顺磁对比剂获得，从而增强了图像质量。 Gadolinium综合体是最广泛使用的，这些复合物当前都是 基于聚（氨基羧酸盐）配体支架。 '虽然有效，但水 这些药物的质子松弛性仅占理论​​上的百分之几的 可能的。代理附着于合成或中的大分子 体内生物分子可以通过降低旋转来提高松弛度 相关时间，但从gadolinium中心的水交换速率 成为限制因素。我们有一个新的Gadolinium综合体系列 （基于六氢羟基甲酸配体支架）是稳定的 比大多数聚（氨基羧酸盐）具有更高的放松性 由于水汇率高约两个数量级，因此复合物。 该项目的主要目的是合成一系列新型GD（III） 通过选择性结构为不同诊断需求的MRI对比剂 六源配体支架的修饰。解决方案属性， 包括稳定性，将评估，并将 他们的放松性在协作研究中探讨了。其他协作研究 将研究初始生物分布和毒性筛查（使用细胞 测定）和进一步的研究将在小鼠或大鼠模型中进行。我们的最终 目标是以更高的精度开发第二代MRI对比剂 比当前可用或理论上可能的特异性 在氨基羧酸盐配体上。这些第二代特工将由 引入一个新的GD复合单元，可以放松一个或两个订单 比今天的常规大小要大。