Centre de Biophysique Moléculaire, Centre National pour la Recherche Scientifique (CNRS), rue Charles, Sadron, 45071 Orléans, France.
Inorg Chem. 2011 Oct 17;50(20):10371-8. doi: 10.1021/ic201445e. Epub 2011 Sep 9.
Gallium complexes are gaining increasing importance in biomedical imaging thanks to the practical advantages of the (68)Ga isotope in Positron Emission Tomography (PET) applications. (68)Ga has a short half-time (t(1/2) = 68 min); thus the (68)Ga complexes have to be prepared in a limited time frame. The acceleration of the formation reaction of gallium complexes with macrocyclic ligands for application in PET imaging represents a significant coordination chemistry challenge. Here we report a detailed kinetic study of the formation reaction of the highly stable Ga(NOTA) from the weak citrate complex (H(3)NOTA = 1,4,7-triazacyclononane-1,4,7- triacetic acid). The transmetalation has been studied using (71)Ga NMR over a large pH range (pH = 2.01-6.00). The formation of Ga(NOTA) is a two-step process. First, a monoprotonated intermediate containing coordinated citrate, GaHNOTA(citrate), forms in a rapid equilibrium step. The rate-determining step of the reaction is the deprotonation and slow rearrangement of the intermediate accompanied by the citrate release. The observed reaction rate shows an unusual pH dependency with a minimum at pH 5.17. In contrast to the typical formation reactions of poly(amino carboxylate) complexes, the Ga(NOTA) formation from the weak citrate complex becomes considerably faster with increasing proton concentration below pH 5.17. We explain this unexpected tendency by the role of protons in the decomposition of the GaHNOTA(citrate) intermediate which proceeds via the protonation of the coordinated citrate ion and its subsequent decoordination to yield the final product Ga(NOTA). The stability constant of this intermediate, log K(GaHNOTA(citrate)*) = 15.6, is remarkably high compared to the corresponding values reported for the formation of macrocyclic lanthanide(III)-poly(amino carboxylates). These kinetic data do not only give mechanistic insight into the formation reaction of Ga(NOTA), but might also contribute to establish optimal experimental conditions for the rapid preparation of Ga(NOTA)-based radiopharmaceuticals for PET applications.
镓配合物由于在正电子发射断层扫描（PET）应用中（68）Ga 同位素的实际优势，在生物医学成像中变得越来越重要。（68）Ga 的半衰期很短（t(1/2) = 68 分钟）；因此，（68）Ga 配合物必须在有限的时间内制备。加速镓配合物与大环配体的形成反应，用于 PET 成像，代表了一个重要的配位化学挑战。在这里，我们报告了对从弱柠檬酸配合物（H(3)NOTA = 1,4,7-三氮杂环壬烷-1,4,7-三乙酸）形成高稳定 Ga(NOTA)的形成反应的详细动力学研究。在较大的 pH 范围内（pH = 2.01-6.00），使用（71）Ga NMR 研究了转金属反应。Ga(NOTA)的形成是一个两步过程。首先，在快速平衡步骤中形成含有配位柠檬酸的单质子化中间体 GaHNOTA(citrate)*。反应的速率决定步骤是中间体的去质子化和缓慢重排，并伴随着柠檬酸的释放。观察到的反应速率表现出不寻常的 pH 依赖性，在 pH 5.17 处有最小值。与典型的多（氨基羧酸盐）配合物的形成反应相反，随着 pH 值低于 5.17，从弱柠檬酸配合物形成 Ga(NOTA)的反应速度大大加快。我们通过 GaHNOTA(citrate)中间体分解中质子的作用来解释这种出乎意料的趋势，该中间体通过配位柠檬酸离子的质子化及其随后的去配位来进行，从而生成最终产物 Ga(NOTA)。这个中间体的稳定常数，log K(GaHNOTA(citrate)) = 15.6，与形成大环镧系元素（III）-多（氨基羧酸盐）的相应值相比非常高。这些动力学数据不仅为 Ga(NOTA)的形成反应提供了机制上的见解，而且可能有助于建立用于 PET 应用的基于 Ga(NOTA)的放射性药物快速制备的最佳实验条件。
