Next generation, high relaxivity gadolinium MR1 agents
Next generation, high relaxivity gadolinium MR1 agents
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DOI：
10.1021/bc049817y
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发表时间：
2005-01-01
影响因子：
4.7
通讯作者：
Pierre, VC
中科院分区：
文献类型：
--
作者：
Raymond, KN;Pierre, VC
磁共振成像（MRI）已发展成为诊断临床医学和生物医学研究中最强大的技术之一，可以获取体内水分布的高分辨率三维图像（1）。医用MRI的强劲发展促进了一类新型药理产品的开发，称为造影剂。这些试剂催化缩短附近水分子的弛豫时间，从而增强与背景组织的对比度。1999年，大约30%的MRI扫描使用造影剂，其中大部分基于钆络合物（1）。到目前为止，这一数字可能已增加到40%至50%之间。这种实用性促进了对改进的Gd基造影剂的研究，最近发表了几篇综述（1-15）。Gd（III）具有高顺磁性，具有七个未配对电子和长的电子弛豫时间，使其成为弛豫剂的优秀候选者。然而，[Gd（H2O）8] 3+的非常高的体内毒性要求在将其施用于患者之前通过强有机螯合剂络合该金属。目前的MRI试剂需要注射克量的Gd，以便在所得图像中获得满意的对比度。由于合理的图像增强需要如此大的剂量，目前的造影剂被限制在靶向部位，在这些部位，它们可以预期以高浓度积累，例如在血流中。理想情况下，第二代造影剂将是位点特异性的;需要更高的弛豫率来解释伴随组织特异性增加的浓度降低。造影剂的图像增强能力与顺磁性离子对相邻水分子的弛豫成正比;也就是说，与弛豫率增加成正比，无论是纵向（1/T1）还是横向（1/T2）。这种效应包括内层（来自直接与Gd配位的水分子）和外层贡献（来自附近的氢键沃茨）。后者通常相对较小，通常被忽视。对于Gd（III）络合物，内层弛豫率主要来自偶极贡献（由于电子场的随机波动引起的通过空间的相互作用），并且可以被描述为
Magnetic resonance imaging (MRI) has evolved into one of the most powerful techniques in diagnostic clinical medicine and biomedical research by enabling the acquisition of high resolution, three-dimensional images of the distribution of water in vivo (1). The strong expansion of medical MRI has prompted the development of a new class of pharmacological products, called contrast agents. These agents catalytically shorten the relaxation time of nearby water molecules, thereby enhancing the contrast with background tissues. In 1999, approximately 30% of all MRI scans used a contrast agent, most of which were based on gadolinium complexes (1). By now, this number has probably increased to between 40 and 50%. This utility has prompted research on improved Gd-based contrast agents, about which several reviews have recently been published (1-15). Gd (III) is highly paramagnetic with seven unpaired electrons and a long electronic relaxation time, making it an excellent candidate as a relaxation agent. However, the very high in vivo toxicity of [Gd (H2O) 8] 3+ requires that the metal be complexed by strong organic chelators before it is administered to patients. Current MRI agents require injection of gram quantities of Gd in order to obtain satisfactory contrast in the resulting image. With such large doses required for reasonable image enhancement, current contrast agents are limited to targeting sites where they can be expected to accumulate in high concentrations, such as in the blood stream. Ideally, second generation agents will be site-specific; much higher relaxivities will be required to account for the decrease in concentration that accompanies increased tissue specificity.The image-enhancing capability of a contrast agent is directly proportional to its relaxation of neighboring water molecules by the paramagnetic ion; that is, to the relaxation rate increase, either longitudinal (1/T1) or transverse (1/T2). This effect includes both inner-sphere (from water molecules directly coordinated to the Gd) and outer-sphere contributions (from nearby, H-bonded waters). The latter are usually relatively small and are usually neglected. For Gd (III) complexes, the innersphere relaxivity primarily results from a dipolar contribution (through-space interactions due to the random fluctuations of the electronic field) and can be described