Mechanistic studies of a calcium-dependent MRI contrast agent
Mechanistic studies of a calcium-dependent MRI contrast agent
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DOI：
10.1021/ic0200390
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发表时间：
2002-07-29
影响因子：
4.6
通讯作者：
Meade, TJ
中科院分区：
文献类型：
--
作者：
Li, WH;Parigi, G;Meade, TJ
细胞内钙离子在信号转导中起着重要的作用，我们正在开发新的磁共振成像技术来研究其在活体动物中的调节。我们已经报道了一种MR1造影剂(DOPTA-Gd)，其中络合物的弛豫度由二价离子钙的存在或不存在来控制。通过结构上调节水对Gd3+离子的内部访问，我们观察到在添加了钙离子而不是其他二价离子的情况下，T发生了显著的可逆变化。获得了该配合物的发光寿命和NMRD测量结果，发现有几个参数对DOPTA-Gd的依赖于钙离子的弛豫度变化有贡献。提高Ca~(2+)浓度后，球内水分子数增加一倍以上。这一发现有力地支持了钙离子结合时DOPTA-Gd的构象变化。松弛测量证实了这些结果，并提供了一个迹象，即在没有钙离子的情况下，第二球形水分子可能是顺磁松弛增强的原因。在钙离子与DOPTA-Gd结合后，分子发生了实质性的构象变化，打开了四氮杂环十二烷大环的亲水面。这一变化极大地增加了螯合Gd3+离子对本体溶剂的可及性。这类钙激活的磁共振造影剂的设计主要是基于这样的假设，即配位的内球水分子的数量将是观察到的弛豫度测量的主导因素。这一结果已经得到证实；然而，仔细的机制研究表明，这一过程中还涉及其他因素。
Intracellular Ca2+ plays an important role in signal transduction, and we are developing new MRI techniques to study its regulation in living animals. We have reported on an MR1 contrast agent (DOPTA-Gd) where the relaxivity of the complex is controlled by the presence or absence of the divalent ion Ca2+. By structurally modulating innersphere access of water to a chelated Gd3+ ion, we observe a substantial and reversible change in T, upon the addition of Ca2+ and not other divalent ions. Luminescence lifetime and NMRD measurements of the complex have been acquired, and several parameters contribute to the Ca2+ dependent relaxivity change of DOPTA-Gd. The number of inner-sphere water molecules is more than doubled after the Ca2+ concentration is increased. This finding strongly supports the proposed conformational change of DOPTA-Gd when Ca2+ is bound. Relaxometric measurements confirm these results and provide an indication that second-sphere water molecules are probably responsible for paramagnetic relaxation enhancement in the absence of Ca2+. After Ca2+ is bound to DOPTA-Gd, the molecule undergoes a substantial conformational change that opens up the hydrophilic face of the tetraazacyclododecane macrocycle. This change dramatically increases the accessibility of chelated Gd3+ ion to bulk solvent. The design of this class of calcium-activated MR contrast agent was based primarily on the assumption that the number of coordinated inner-sphere water molecules would be the dominating factor in observed relaxivity measurements. This result has been confirmed; however, careful mechanistic studies reveal that additional factors are involved in this process.