Gd-hydroxypyridinone (HOPO)-based high-relaxivity magnetic resonance imaging (MRI) contrast agents.
Gd-hydroxypyridinone (HOPO)-based high-relaxivity magnetic resonance imaging (MRI) contrast agents.
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DOI：
10.1021/ar800250h
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发表时间：
2009-07-21
影响因子：
18.3
通讯作者：
Raymond KN
中科院分区：
文献类型：
--
作者：
Datta A;Raymond KN
磁共振成像（MRI）在医学中是一种特别有效的工具，因为它具有高深度穿透性（1毫米到1米）以及分辨不同软组织的能力。MRI信号是由体内水分子质子的弛豫产生的。通过给予顺磁性试剂可以改善MRI图像，这些试剂会提高附近水质子的弛豫速率，从而增强MRI信号。由于其良好的电子特性，通常使用镧系阳离子Gd³⁺；然而，其高毒性使得在患者体内时需要强配位配体来使Gd³⁺完全结合。在这篇综述中，我们对基于Gd - 羟基吡啶酮（HOPO）的造影剂（CAs）进行配位化学概述，这些造影剂显示出改进的MRI对比度和高的热力学稳定性。
我们实验室开发的三齿双配位HOPO基配体是为了配合Gd³⁺的配位偏好而设计的，特别是其亲氧性。HOPO配体为Gd³⁺提供了一个六齿配位环境，其中所有供体原子都是氧。因为Gd³⁺倾向于八或九配位，这种设计为内界水分子提供了两到三个空位。这些水分子与本体溶液快速交换，因此影响本体水分子的弛豫速率。影响这些造影剂效率的参数已经过调整，以在提高对比度的同时仍保持Gd³⁺结合的高热力学稳定性。基于Gd - HOPO的造影剂优于目前市售的造影剂，因为其具有更多的内界水分子、通过缔合机制实现内界水分子的快速交换以及较长的电子弛豫时间。这些造影剂提供的对比度增强至少是基于多氨基羧酸盐配体的市售造影剂的两倍。
MRI技术的进步通过使潜在病理可视化，对临床诊断的改善做出了重大贡献。然而，在分子水平上理解疾病的机制需要提高成像灵敏度。最终目标是在生物学相关浓度（毫摩尔到纳摩尔）下直观地区分不同的疾病靶点或标志物，如酶、激素、蛋白质或小分子。尽管MRI技术可以提供这些生物标志物所调控的器官和组织的图像，但目前缺乏可视化组织内生物靶点所需的高灵敏度——要实现这一目标，需要比现有造影剂提高50倍的对比度增强。根据顺磁弛豫理论，通过减慢MRI造影剂的翻滚速率可以进一步提高对比度增强。理论上，对于具有最佳水交换速率的造影剂，这种增强会更大。基于Gd - HOPO的造影剂具有最佳的水交换速率，而市售造影剂具有较慢的非最佳水交换速率；因此，Gd - HOPO造影剂非常适合连接到大分子上，这将减慢翻滚速率并增加对比度。最近通过将Gd - HOPO造影剂与病毒衣壳共价连接对这一策略进行了测试，其对比度增强比市售造影剂高10倍。
Magnetic resonance imaging (MRI) is a particularly effective tool in medicine because of its high depth penetration (1 mm to 1 m) and ability to resolve different soft tissues. The MRI signal is generated by the relaxation of in vivo water molecule protons. MRI images can be improved by administering paramagnetic agents, which increase the relaxation rates of nearby water protons, thereby enhancing the MRI signal. The lanthanide cation Gd3+ is generally used because of its favorable electronic properties; high toxicity, however, necessitates strongly coordinating ligands to keep Gd3+ completely bound while in the patient. In this Account, we give a coordination chemistry overview of contrast agents (CAs) based on Gd-hydroxypyridinone (HOPO), which show improved MRI contrast and high thermodynamic stabilities. Tris-bidentate HOPO-based ligands developed in our laboratory were designed to complement the coordination preferences of Gd3+, especially its oxophilicity. The HOPO ligands provide a hexadentate coordination environment for Gd3+ in which all the donor atoms are oxygen. Because Gd3+ favors eight or nine coordination, this design provides two to three open sites for inner-sphere water molecules. These water molecules rapidly exchange with bulk solution, hence affecting the relaxation rates of bulk water molecules. The parameters affecting the efficiency of these contrast agents have been tuned to improve contrast while still maintaining a high thermodynamic stability for Gd3+ binding. The Gd-HOPO-based contrast agents surpass current commercially available agents because of a higher number of inner-sphere water molecules, rapid exchange of inner-sphere water molecules via an associative mechanism, and a long electronic relaxation time. The contrast enhancement provided by these agents is at least twice that of commercial contrast agents, which are based on polyaminocarboxylate ligands. Advances in MRI technology have made significant contributions to the improvement of clinical diagnostics by allowing visualization of underlying pathology. However, understanding the mechanism of a disease at the molecular level requires improved imaging sensitivity. The ultimate goal is to visually distinguish between different disease targets or markers—such as enzymes, hormones, proteins, or small molecules—at biologically relevant concentrations (millimolar to nanomolar). Although MRI techniques can provide images of the organs and tissues in which these biomarkers are regulated, the high sensitivity required to visualize the biological targets within the tissues is currently lacking—contrast enhancements of 50-fold beyond current agents are required to achieve this goal. According to the theory of paramagnetic relaxation, the contrast enhancement can be further improved by slowing the tumbling rate of the MRI agent. Theoretically, this enhancement would be greater for contrast agents with an optimal rate of water exchange. The Gd-HOPO-based contrast agents have optimal water-exchange rates, whereas the commercial agents have slower non-optimal water-exchange rates; thus, the Gd-HOPO agents are ideal for attachment to macromolecules, which will slow down the tumbling rate and increase contrast. This strategy has been recently tested with the Gd-HOPO agents via covalent attachment to virus capsids, affording contrast enhancements 10-fold beyond commercial agents.
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