Hydroxypyridonate Gd Complexes: MRI Agents

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 能够获取高分辨率的三维图像，以检测各种 物理异常和动态核磁共振的最新进展提供了实时成像。超过30%的 核磁共振扫描现在是使用顺磁造影剂进行的，它增强了质子的弛豫 因此也就是图像质量。使用最广泛的是格拉络合物，目前这些络合物是 所有这些都是基于多(氨基羧酸盐)配体支架。虽然有效，但松弛系数值(3-5 mm“V1) 这些试剂只有理论上可能的百分之一，需要克量的Gd 行政管理。试剂与大分子的结合通过降低旋转率来增加弛豫度。 关联时间，但水的交换速率从Gd中心成为限制因素。 该项目已经开发了Gd配合物(基于六齿羟基吡喃酸配体 脚手架)是稳定的，并且由于水交换率至少为 比商业代理商高出几个数量级。已经开发了这些试剂并展示了他们的 稳定和快速的水交换，现在建议继续发展，以使新的 各种各样的影像。目标是超过100 mm~1s“1的相对论。这将需要更少的Gd 而且，更重要的是，它支持使用MRI进行新类型的成像。目标包括发展 稳定的试剂与3(与目前的1相反)配位水分子，从而使弛豫度增加三倍； 新设计的超分子Gd簇合物；与特定靶向生物分子对接的试剂；以及完整的 这些络合物在水溶液中的热力学和动力学性质的表征 都与他们的MRI增强有关。他们的目标是第二代利用松弛作用的核磁共振成像试剂 比目前使用的临床药物高出两个数量级。

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"V1) 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.