Hydroxypyridonate Gd Complexes:MRI Agents

羟基吡啶酮酸钆复合物：MRI 试剂

• 批准号: 6622801
• 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/6622801
• 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）：在过去的二十年里，磁性 共振成像 (MRT) 彻底改变了诊断医学。 MRI 使 在检测中获取高分辨率三维图像 各种各样的身体异常和动态 MRJ 的最新进展显示 实时成像的前景。现在大约 30% 的 MRI 扫描 使用顺磁造影剂获取，从而提高图像质量。 钆配合物应用最广泛，目前这些配合物都是 基于聚（氨基羧酸盐）配体支架。 “虽然有效，但水 这些试剂的质子弛豫率仅为理论值的百分之几 可能的。将试剂附着到合成或合成的大分子上 体内生物分子，可以通过降低旋转来增加弛豫度 相关时间，但来自钆中心的水交换率 成为限制因素。我们有一个新的钆络合物家族 （基于六齿羟基吡啶酮酸配体支架），稳定且 比大多数聚（氨基羧酸酯）具有更高的弛豫率 由于水交换率高出约两个数量级，因此复合物。 该项目的主要目标是合成一系列新颖的 Gd(III) MRI造影剂通过选择性结构满足不同的诊断需求 六齿配体支架的修饰。溶液性质， 包括稳定性，将被评估和基本物理化学 他们在合作研究中探索了他们的放松。其他合作研究 将研究初始生物分布和毒性筛选（使用细胞 测定），并将在小鼠或大鼠模型中进行进一步的研究。我们的终极 目标是开发更准确的第二代 MRI 造影剂 和特异性高于目前可用的或理论上可能的基础 在氨基羧酸配体上。这些第二代药剂将由 引入新的 Gd 复合单元，可实现一阶或二阶弛豫 其规模比今天的常规情况还要大。