Hydroxypyridonate Gd Complexes: MRI Agents

描述(申请人提供)：磁共振成像(MRI)为诊断医学提供了戏剧性的新能力。磁共振成像能够获得高分辨率的三维图像来检测各种物理异常，而动态磁共振成像的最新进展是提供实时成像。现在超过30%的MRI扫描是使用顺磁造影剂获得的，这种造影剂增强了质子弛豫，从而提高了图像质量。目前使用最广泛的是Gd配合物，目前这些配合物都是基于多(氨基-羧酸盐)配体支架的。虽然有效，但这些试剂的弛豫值(3-5 mm-1s-1)只有理论上可能值的几个百分点，每次给药需要克量的Gd。将试剂附着到大分子上，通过降低旋转关联时间来增加弛豫度，但从Gd中心交换水的速度成为限制因素。该项目已经开发出(基于六齿羟基吡喃酸配体支架的)Gd络合物，由于水交换率至少比商业试剂高两个数量级，这种络合物是稳定的，并具有显著更高的弛豫度。在开发了这些试剂并展示了它们的稳定性和快速水交换速度之后，现在建议继续开发它们，以实现新类型的成像。目标是超过100 mm-1s-1的相对湿度。这将大大减少图像所需的Gd，更重要的是，可以使用MRI进行新类型的成像。目标包括开发具有3个(而不是目前的1个)配位水分子的稳定试剂，从而使弛豫度增加两倍；新设计的超分子Gd簇合物；对接到特定目标生物分子的试剂；以及与其MRI增强相关的这些络合物在水溶液中的热力学和动力学性质的全面表征。我们的目标是第二代核磁共振试剂，它利用的松弛系数比目前使用的临床药物高出两个数量级。

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.