Hydroxypyridonate Gd Complexes:MRI Agents

羟基吡啶酮酸钆复合物：MRI 试剂

• 批准号: 6865433
• 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/6865433
• 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(申请人提供)：在过去的二十年里，磁力 磁共振成像(MRT)使诊断医学发生了革命性的变化。核磁共振成像使 获取高分辨率的三维图像用于检测 各种物理异常和动态磁共振成像的最新进展 实时成像技术的发展前景。现在大约30%的核磁共振扫描是 使用顺磁造影剂获取的图像，增强了图像质量。 目前使用最广泛的是格拉络合物，这些络合物都是 基于一种聚氨基甲酸酯配体支架。“虽然很有效，但水 这些试剂的质子弛豫度只有理论上的百分之几。 有可能。试剂与大分子的连接，无论是合成的还是在 体内生物分子，可通过降低旋转率来增加松弛能力 关联时间，但水从Gd中心交换的速率 成为限制因素。我们有了一个新的Gd络合物家族 (基于六齿羟基吡啶配体支架)是稳定的和 比大多数聚氨基甲酸酯具有更高的松弛性能 由于复合体的水交换率高出约两个数量级。 本项目的主要目标是合成一系列新的Gd(III) 用于不同诊断需求的选择性结构磁共振造影剂 六齿配体支架的改性。解决方案属性， 包括稳定性，将被评估和基本物理化学 他们的松弛在合作研究中得到了探索。其他合作研究 将研究初步的生物分布和毒性筛选(使用细胞 化验)，将在小鼠或大鼠模型上进行进一步研究。我们的终极 目标是开发出精度更高的第二代磁共振造影剂 以及比目前可用的或理论上可能的基于 氨基羧酸配体。这些第二代试剂将由以下人员制造 引入一种新的Gd络合物单元，可以实现一到两个数量级的弛豫 比今天的常规规模更大。