Hydroxypyridonate Gd Complexes: MRI Agents

磁共振成像（MRI）为诊断医学提供了引人注目的新功能。MRI 使得能够在检测各种各样的 身体异常，并且动态MRI的最新进展提供了实时成像。超过30%的 MRI扫描现在使用顺磁造影剂，这增强了质子弛豫 从而提高图像质量。钆络合物是最广泛使用的，并且这些络合物目前是 全部基于聚（氨基羧酸酯）配体支架。虽然有效，但是， 这些试剂仅为理论上可能的百分之几，每克需要Gd的量。 局试剂与大分子的连接通过降低旋转速度来增加弛豫率。 相关时间，但水从钆中心交换的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），其是稳定的，并且由于水交换速率至少为2 数量级高于商业代理商。在开发了代理人并证明了他们的 稳定和快速的水交换率，现在建议继续发展，使新的 各种成像。大于100mM-1s-1的弛豫率是目标。这将需要更少的Gd， 更重要的是，它使MRI成像成为可能。目标包括发展 具有3个（与当前的1个相反）配位水分子的稳定剂，从而使弛豫率增加三倍; 超分子Gd簇的新设计;与特定靶生物分子对接的试剂;以及完整的 表征这些络合物在水溶液中的那些热力学和动力学性质， 与他们的MRI增强有关。目标是第二代磁共振成像剂，利用弛豫 比目前使用的临床药物高两个数量级。

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.