Hydroxypyridonate Gd Complexes: MRI Agents

描述（由申请人提供）：磁共振成像（MRI）为诊断医学提供了戏剧性的新能力。MRI能够获得高分辨率的三维图像，用于检测各种各样的身体异常，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，这可以增强质子弛豫，从而提高图像质量。钆配合物是应用最广泛的配合物，目前这些配合物都是基于聚氨基羧酸酯配体支架。虽然有效，但这些药物的弛豫值（3 - 5mM-1s-1）仅为理论可能值的百分之几，每次给药需要克数的Gd。药剂与大分子的附着通过降低旋转相关时间增加了弛豫度，但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（基于六齿羟基配体支架），由于水交换速率至少比商业试剂高两个数量级，因此稳定且具有更高的弛豫度。在开发了这些试剂并证明了它们的稳定性和快速的水交换速率之后，现在建议继续开发它们以实现新型成像。目标松弛度大于100mM-1s-1。这将大大减少图像所需的Gd，更重要的是，可以使用MRI进行新型成像。目标包括开发具有3个（而不是目前的1个）协调水分子的稳定剂，从而使弛豫度增加三倍；超分子Gd簇的新设计；与特定的靶向生物分子对接的制剂；并全面表征了这些配合物在水溶液中的热力学和动力学性质，这些性质与它们的MRI增强有关。目标是开发第二代MRI试剂，使其弛豫度比目前使用的临床试剂高两个数量级。

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.