Hydroxypyridonate Gd Complexes: MRI Agents

描述（由申请人提供）：磁共振成像（MRI）为诊断医学提供了引人注目的新功能。MRI能够采集高分辨率的三维图像，帮助检测各种各样的身体异常，并且动态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获得的，这增强了质子弛豫，从而提高了图像质量。钆配合物是最广泛使用的，并且这些配合物目前都是基于聚（氨基-羧酸酯）配体支架。尽管造影剂的使用已成为常规，但临床使用的造影剂在几个重要领域中是次优的。目前的成像剂显示出小于理论最大值的5%的弛豫率。这种低性能意味着全身MRI扫描必须使用克钆。这种低灵敏度也排除了靶向成像。鉴于最近的研究表明，肾源性系统性纤维化（NSF，或者NFD）是由造影剂在通过肾脏清除之前释放Gd引起的，因此使用大量造影剂特别成问题。提高性能，从而减少剂量，将显着提高患者的安全性。 该项目已经开发了基于六齿羟基吡啶酮配体支架的钆络合物，其是稳定的，并且由于更高数量的配位水分子（2-3）和比商业试剂高至少两个数量级的水交换率而具有显著更高的弛豫率。在开发了这些试剂并证明了它们的热力学稳定性之后，我们打算继续开发它们，以实现新的MR成像。弛豫率超过300 mM-1 s-1是目标，通过开发也高度稳定的大分子造影剂来实现。使用大分子缀合来改善弛豫性增加了对高造影剂动力学稳定性的需要。虽然大多数大分子的长肾脏清除时间允许图像采集时间的更大灵活性，但即使在具有健康肾脏的患者中，Gd解离也将成为一个问题。因此，需要具有极高动力学稳定性的试剂。如果这些试剂与当前试剂相比也具有更高的性能，则将需要更少的Gd来获得图像。这也将使新类型的成像与MRI。因此，该项目的目标是提高造影剂的性能-既降低给药剂量，又使靶选择性成像成为可能-并开发具有极高动力学稳定性的造影剂，以确保患者安全。 公共卫生相关性：磁共振成像（MRI）为诊断医学提供了引人注目的新功能，现在超过30%的MRI扫描使用造影剂获得，通常含有钆，这提高了图像质量。然而，由于目前试剂的低性能，必须将克量的钆注射到患者中，这最近导致患有肾脏疾病的患者中的肾源性系统性纤维化。为了防止MRI造影剂的这种毒副作用，我们建议将MRI造影剂的性能提高到比当前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.