Hydroxypyridonate Gd Complexes:MRI Agents

描述（由申请人提供）：在过去的二十年里， 共振成像（MRT）已经彻底改变了诊断医学。MRI使 高分辨率，三维图像的采集在检测一个 各种各样的身体异常和动态MRJ的最新进展显示， 实时成像的前景。现在大约30%的核磁共振扫描 使用顺磁性造影剂采集，这提高了图像质量。 钆络合物是最广泛使用的，并且这些络合物目前都是 基于聚（氨基羧酸酯）配体支架。虽然有效， 这些试剂的质子弛豫率仅为理论上的百分之几 可能将药剂附着于合成的或非合成的大分子上， 体内生物分子，可以增加弛豫通过降低旋转 相关时间，但水交换率从钆中心，然后 成为限制因素。我们有一个新的钆络合物家族 （基于六齿羟基吡啶酮配体骨架），其是稳定的， 具有比大多数聚（氨基羧酸酯）高得多的弛豫率， 复合物由于水交换率约两个数量级高。 本项目的主要目标是合成一系列新颖的Gd（III） MRI造影剂通过选择性的结构， 六齿配体支架的修饰。溶液性质， 包括稳定性，将被评估和基本的物理化学， 在合作研究中探索了它们的放松性。其他合作研究 将研究初始生物分布和毒性筛选（使用细胞 测定），并将在小鼠或大鼠模型中进行进一步的研究。我们的最终 目标是开发具有更高准确性的第二代MRI造影剂 和特异性比目前可用的或理论上可能的基于 氨基羧酸配体上。这些第二代代理商将由 引入新的Gd配合物单元，使弛豫度达到一级或两级 比今天的常规更大的规模。

DESCRIPTION (provided by applicant): In the past two decades, magnetic resonance imaging (MRT) has revolutionized 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 MRJ show the prospect of real-time imaging. About 30 percent of MRI scans are now acquired using a paramagnetic contrast agent, which enhances the image quality. Gadolinium complexes are most widely used and these complexes currently are all based on a poly(aminoearboxylate) ligand scaffold . 'While effective, the water proton relaxivity of these agents are only a few percent of that theoretically possible. Attachment of the agent to macromolecules, either synthetic or in vivo biomolecules, can increase the relaxivity by lowering the rotational correlation time but the rate of water exchange from the gadolinium center then becomes the limiting factor. We have a new family of gadolinium complexes (based on a hexadentate hydroxypyridonate ligand scaffold) that are stable and have substantially higher relaxivity than most poly(amino-carboxylate) complexes due to a water exchange rate about two orders of magnitude higher. The main objective of this project is to synthesize a novel series of Gd(III) MRI contrast agents for different diagnostic needs through selective structural modifications of the hexadentate ligand scaffold. The solution properties, including stability, will be assessed and the fundamental physical chemistry of their relaxivity explored in collaborative studies. Other collaborative studies will investigate initial biodistribution and toxicity screening (with a cell assay) and further studies will be done in a mouse or rat model. Our ultimate goal is to develop second generation MRI contrast agents with greater accuracy and specificity than those currently available or theoretically possible based on amino carboxylate ligands. These second generation agents will be made by introducing a new Gd complex unit that enables relaxivity of one or two orders of magnitude greater than what is routine today.