Hydroxypyridonate Gd Complexes: MRI Agents

羟基吡啶酮酸钆复合物：MRI 试剂

• 批准号: 7021488
• 负责人: KENNETH N RAYMOND
• 金额: $ 26.11万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021488
• 关键词: bioimaging /biomedical imaging; chemical kinetics; chemical property; chemical synthesis; contrast media; electron spin resonance spectroscopy; gadolinium; image enhancement; intermolecular interaction; magnetic resonance imaging; metal complex; nuclear magnetic resonance spectroscopy; physical chemical interaction; physical property; thermodynamics

DESCRIPTION (provided by applicant): Magnetic resonance imaging (MRI) has provided dramatic new capabilities for 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 MRI are providing real-time imaging. Over 30% of MRI scans are now acquired using a paramagnetic contrast agent, which enhances the proton relaxation and hence image quality. Gadolinium complexes are most widely used, and these complexes currently are all based on a poly(amino-carboxylate) ligand scaffold . While effective, the relaxivity values (3 - 5mM-1s-1) of these agents are only a few percent of that theoretically possible, requiring gram amounts of Gd per administration. Attachment of the agent to macromolecules increases the relaxivity by lowering the rotational correlation time, but the rate of water exchange from the gadolinium center then becomes the limiting factor. This project has developed gadolinium complexes (based on a hexadentate hydroxypyridonate ligand scaffold) that are stable and have substantially higher relaxivity due to a water exchange rate at least two orders of magnitude higher than commercial agents. Having developed the agents and demonstrated their stability and fast rates of water exchange, it is now proposed to continue their development for enabling new kinds of imaging. Relaxivities of more than 100mM-1s-1 are the target. This would require much less Gd for images and, more significantly, enable new types of imaging with MRI. Aims include the development of stable agents with 3 (as opposed to the current 1) coordinated water molecules, thus tripling the relaxivity; novel designs of supramolecular Gd clusters; agents that dock to specific targeted biomolecules; and full characterization of those thermodynamic and kinetic properties of these complexes in aqueous solution that are related to their MRI enhancement. The goal is a second generation of MRI agents that utilize relaxivities of up to two orders of magnitude greater than the clinical agents in use today.

描述（由申请人提供）：磁共振成像（MRI）为诊断医学提供了引人注目的新功能。 MRI 能够在检测各种身体异常时采集高分辨率的三维图像，动态 MRI 的最新进展正在提供实时成像。现在超过 30% 的 MRI 扫描是使用顺磁造影剂进行的，该造影剂增强了质子弛豫，从而提高了图像质量。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）配体支架。虽然有效，但这些药物的弛豫值 (3 - 5mM-1s-1) 仅是理论上可能值的百分之几，每次给药需要克量的 Gd。试剂与大分子的附着通过降低旋转相关时间来增加弛豫率，但来自钆中心的水交换速率则成为限制因素。该项目开发了钆配合物（基于六齿羟基吡啶酮配体支架），该配合物稳定且由于水交换率比商业试剂高至少两个数量级而具有更高的弛豫率。在开发出这些试剂并证明其稳定性和快速水交换率之后，现在建议继续开发它们以实现新型成像。目标是弛豫率超过 100mM-1s-1。这将需要更少的 Gd 来获取图像，更重要的是，可以使用 MRI 进行新型成像。目标包括开发具有 3 个（而不是目前的 1 个）配位水分子的稳定剂，从而使弛豫率增加两倍；超分子 Gd 簇的新颖设计；与特定目标生物分子对接的试剂；以及这些复合物在水溶液中与其 MRI 增强相关的热力学和动力学特性的全面表征。我们的目标是开发第二代 MRI 试剂，其弛豫率比当今使用的临床试剂高出两个数量级。