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，帮助检测各种物理异常，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。虽然造影剂的使用已经成为常规，但临床上使用的造影剂在几个重要领域并不理想。目前的显像剂显示的弛豫度不到理论最大值的5%。这种低性能意味着进行全身核磁共振扫描时必须注射几克的Gd。这种低灵敏度也排除了靶向成像。考虑到最近的研究表明，肾源性系统性纤维化(NSF，或称NFD)是由于造影剂在Gd通过肾脏清除之前释放而引起的，因此使用大量的造影剂尤其成问题。改善性能，从而减少剂量，将显著提高患者的安全性。该项目开发了基于六齿羟基吡喃酸酯配体支架的Gd配合物，由于配位水分子(2-3)的数量更多，水交换率至少比商业试剂高两个数量级，这种支架是稳定的，具有显著更高的驰豫性能。在开发了这些试剂并展示了它们的热力学稳定性之后，我们打算继续开发它们，以实现新型的磁共振成像。释放度超过300 mm-1s-1是目标，通过开发同样高度稳定的大分子造影剂来实现。使用大分子共轭来提高弛豫度增加了对高对比剂动力学稳定性的需求。虽然大多数大分子的长时间肾脏清除时间允许在图像获取时间上有更大的灵活性，但即使在肾脏健康的患者中，Gd解离也会成为一个问题。因此，需要具有极高动力学稳定性的试剂。如果这些代理与当前代理相比也具有更高的性能，则获取映像所需的Gd将会少得多。这也将使新类型的MRI成像成为可能。因此，该项目的目标是提高造影剂的性能--既降低给药剂量，又实现靶点选择性成像--并开发具有极高运动稳定性的试剂，以确保患者的安全。 与公众健康相关：磁共振成像(MRI)为诊断医学提供了戏剧性的新能力，现在超过30%的MRI扫描是通过造影剂获得的，通常含有Gd，这可以提高图像质量。然而，由于目前药物的低性能，必须向患者体内注射克量的Gd，这最近导致了肾脏疾病患者的肾源性系统性纤维化。为了防止这种MRI造影剂的毒副作用，我们建议将MRI造影剂的性能提高到比现有造影剂高两个数量级，并最大限度地提高体内稳定性，以确保患者的安全。

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, aiding 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 . Although the use of contrast agents has become routine, agents in clinical use are sub optimal in several important areas. Current imaging agents show relaxivities of less than 5% of the theoretical maximum. This low performance means that grams of gadolinium must be administered for a full-body MRI scan. This low sensitivity also precludes targeted imaging. The large amounts of agent used are particularly problematic in light of the recent research suggesting that nephrogenic systemic fibrosis (NSF, alternately NFD) is caused by release of Gd from the contrast agent before it clears through the kidneys. Improving performance, and thereby reducing dosage, would significantly improve patient safety. This project has developed gadolinium complexes based on a hexadentate hydroxypyridonate ligand scaffold that are stable and have substantially higher relaxivity due to a higher number of coordinated water molecules (2-3) and a water exchange rate at least two orders of magnitude higher than commercial agents. Having developed the agents and demonstrated their thermodynamic stability, we intend to continue their development, to enable new kinds of MR imaging. Relaxivities of more than 300mM-1s-1 are the target, to be achieved through the development of macromolecular contrast agents that are also highly stable. The use of macromolecular conjugation to improve relaxivity increases the need for high contrast agent kinetic stability. While long renal clearance times of most macromolecules allows for greater flexibility in image acquisition time, Gd dissociation will become an issue even in patients with healthy kidneys. There is therefore a need for agents with extremely high kinetic stability. If these agents also have higher performance compared to current agents, much less Gd will be needed to obtain an image. This will also enable new types of imaging with MRI. Thus the goals of this project are to improve contrast agent performance--both to lower administered doses and to enable target-selective imaging-and to develop agents with extremely high kinetic stability, to ensure patient safety. PUBLIC HEALTH RELEVANCE: Magnetic resonance imaging (MRI) has provided dramatic new capabilities for diagnostic medicine, with over 30% of MRI scans now acquired using a contrast agent, usually containing gadolinium, which enhances image quality. However, due to the low performance of current agents, gram quantities of gadolinium have to be injected into a patient, which has recently led to Nephrogenic Systemic Fibrosis in patients with kidney disorders. In order to prevent this toxic side effect of MRI contrast agents, we propose to improve the performance of MRI contrast agents up to two orders of magnitude over current agents and maximize in vivo stability to ensure patient safety.