Syntheses and relaxation properties of mixed gadolinium hydroxypyridinonate MRI contrast agents
Syntheses and relaxation properties of mixed gadolinium hydroxypyridinonate MRI contrast agents
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DOI：
10.1021/ic000563b
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发表时间：
2000-12-11
影响因子：
4.6
通讯作者：
Aime, S
中科院分区：
文献类型：
--
作者：
Cohen, SM;Xu, JD;Aime, S
三脚架形配体三[（3 - 羟基 - 1 - 甲基 - 2 - 氧代 - 1,2 - 二脱氢吡啶 - 4 - 甲酰胺基）乙基]胺（TREN - Me - 3,2 - HOPO）形成一种稳定的Gd³⁺配合物，它是一种很有前景的磁共振成像（MRI）造影剂候选物。然而，其低水溶性阻碍了详细的磁特性研究和实际应用。本文介绍了一系列基于TREN - Me - 3,2 - HOPO平台的新型混合配体体系。这些新配体具有两个羟基吡啶酮（HOPO）螯合剂和一个其他螯合剂，后者易于官能化。所描述的配体使用水杨酰胺、2 - 羟基间苯二甲酰胺、2,3 - 二羟基对苯二甲酰胺和双（乙酸盐）作为可衍生的螯合剂。介绍了这些新体系的溶液热力学和弛豫性能。四种配合物中的三种（基于水杨酰胺、2 - 羟基间苯二甲酰胺和2,3 - 二羟基对苯二甲酰胺的配体）具有足够的体内应用热力学稳定性。在20 MHz、25°C和pH 8.5条件下，三种相应的Gd³⁺配合物的弛豫率在7.2至8.8 mM⁻¹ s⁻¹之间，明显高于临床使用的多氨基羧酸盐配合物的值（3.5 - 4.8 mM⁻¹ s⁻¹）。这些配合物的高弛豫率与其更快的水交换速率（<100 ns）、更高的分子量（>700）以及相对于多氨基羧酸盐配合物更多的内球配位水分子数（q = 2）相符。提出了一种水交换快速进行的机制，涉及基于HOPO的配体的镧系配合物的8 - 和9 - 配位几何结构之间的低能垒。该途径得到了La[TREN - Me - 3,2 - HOPO]的晶体结构（三斜晶系P$\overline{1}$：Z = 4，a = 15.6963(2) Å，b = 16.9978(1) Å，c = 17.1578(2) Å，α = 61.981(1)°，β = 75.680(1)°，γ = 71.600(1)°）的支持，该结构在不对称单元中显示出8 - 和9 - 配位的金属中心，表明这些结构在能量上非常接近。这些性质使杂足配体Gd³⁺配合物成为大分子造影剂应用的有前景的候选物，特别是在较高磁场强度下。
The tripodal ligand tris[(3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]amine (TREN-Me-3,2-HOPO) forms a stable Gd3+ complex that is a promising candidate gs a magnetic resonance imaging (MRT) contrast agent. However, its low water solubility prevents detailed magnetic characterization and practical applicability. Presented here are a series of novel mixed ligand systems that are based on the TREN-Me-3,2-HOPO platform. These new ligands possess two hydroxypyridinone (HOPO) chelators and one other chelator, the latter of which can be easily functionalized. The ligands described use salicylamide, 2-hydroxyisophthalamide, 2,3-dihydroxyterephthalamide, and bis(acetate) as the derivatizable chelators. The solution thermodynamics and relaxivity properties of these new systems are presented. Three of the four complexes (salicylamide-, 2-hydroxyisophthalamide-, and 2,3-dihydroxyterephthalamide-based ligands) possess sufficient thermodynamic stability for in vivo applications. The relaxivities of the three corresponding Gd3+ complexes range from 7.2 to 8.8 mM(-1) s(-1) at 20 MHz, 25 degreesC, and pH 8.5, significantly higher than the values for the clinically employed polyaminocarboxylate complexes (3.5-4.8 mM(-1) s(-1)). The high relaxivities of these complexes are consistent with their faster rates of water exchange (< 100 ns), higher molecular weights (> 700), and greater numbers of inner-sphere coordinated water molecules (q = 2) relative to those of polyaminocarboxylate complexes. A mechanism for the rapid rates of water exchange is proposed involving a low energy barrier between the 8- and 9-coordinate geometries for lanthanide complexes of HOPO-based ligands. The pathway is supported by the crystal structure of La[TREN-Me-3,2-HOPO] (triclinic P (1) over bar: Z = 4, a 15.6963(2) Angstrom, b = 16.9978(1) Angstrom, c 17.1578(2) Angstrom, alpha alpha = 61.981(1)degrees, beta = 75.680(1)degrees, gamma = 71.600(1)degrees), which shows both 8- and 9-coordinate metal centers in the asymmetric unit, demonstrating that these structures are very close in energy. These properties make heteropodate Gd3+ complexes promising candidates for use in macromolecular contrast media, particularly at higher magnetic field strengths.