Department of Inorganic Chemistry, Faculty of Science, Universita Karlova (Charles University), Hlavova 2030, 128 43 Prague 2, Czech Republic.
Inorg Chem. 2010 Apr 5;49(7):3224-38. doi: 10.1021/ic9020756.
Given its five unpaired d-electrons, long electronic relaxation time, and fast water exchange, Mn(2+) is a potential candidate for contrast agent application in medical magnetic resonance imaging. Nevertheless, the design of chelators that ensure stable Mn(2+) complexation and optimal relaxation properties remains a coordination chemistry challenge. Here, we report the synthesis of two pyridine-containing ligands L1 and L2, with 15-membered triaza-dioxa-crown and pentaaza-crown ether macrocycles, respectively, and the characterization of their Mn(2+) complexes. Protonation constants of the ligands and stability constants of various metal complexes were determined by potentiometry. The presence of the pyridine in the macrocyclic ring induces rigidity of the complexes which results in a greater thermodynamic stability with respect to the nonpyridine analogues. Solid-state structures of MnL1 and MnL2 confirmed seven-coordination of Mn(2+) with Cl(-) and H(2)O in axial positions. The dissociation kinetics of MnL2 in the presence of Zn(2+) were followed by relaxometric measurements. They proved the prime importance of the proton-assisted dissociation while the zinc(II)-assisted pathway is not important at physiological pH. For MnL1, the dissociation was too fast to be studied by conventional relaxivity measurements under pH 6. A combined (17)O NMR and (1)H NMRD study on MnL1 and MnL2 yielded the parameters that govern the relaxivity of these complexes. The water exchange rate for MnL1, k(ex)(298) = 0.38 x 10(7) s(-1), is the lowest value ever reported for a Mn(2+) complex, while a considerably higher value was obtained for MnL2 (k(ex)(298) = 6.9 x 10(7) s(-1)). Anion binding was studied by relaxometric titrations. They revealed weak interactions between MnL2 and phosphate or citrate, leading to the formation of monohydrated species. Overall, the incorporation of a pyridine into a polyaza macrocycle scaffold has several beneficial effects on the Mn(2+) chelates with respect to potential MRI contrast agent applications: (i) The thermodynamic and the kinetic stability of the complexes is increased. (ii) The rigidified ligand backbone results in higher coordination numbers of the metal ion, allowing for two inner-sphere water molecules in aqueous solution.
鉴于其五个不成对的 d 电子、长电子弛豫时间和快速水交换，Mn(2+) 是医学磁共振成像中潜在的对比剂应用候选物。然而，设计确保稳定的 Mn(2+) 络合和最佳弛豫性能的配体仍然是配位化学的挑战。在这里，我们报告了两种含有吡啶的配体 L1 和 L2 的合成，它们分别具有 15 元三氮杂二氧杂-冠和五氮杂-冠醚大环，以及它们的 Mn(2+) 配合物的表征。通过电位法测定了配体的质子化常数和各种金属配合物的稳定常数。大环中环上吡啶的存在诱导了配合物的刚性，从而相对于非吡啶类似物具有更大的热力学稳定性。MnL1 和 MnL2 的固态结构证实了 Mn(2+) 的七配位，带有 Cl(-) 和 H2O 在轴向位置。通过弛豫测量跟踪 MnL2 存在 Zn(2+) 时的解离动力学。它们证明了质子辅助解离的首要重要性，而生理 pH 下锌(II)辅助途径并不重要。对于 MnL1，由于解离速度太快，无法在 pH 6 下通过常规弛豫率测量进行研究。对 MnL1 和 MnL2 的（17）O NMR 和（1）H NMRD 联合研究得出了控制这些配合物弛豫率的参数。MnL1 的水交换速率，k(ex)(298) = 0.38 x 10(7) s(-1)，是迄今为止报道的 Mn(2+) 配合物中最低的值，而 MnL2 的值则高得多（k(ex)(298) = 6.9 x 10(7) s(-1)）。通过弛豫滴定研究了阴离子结合。它们表明 MnL2 与磷酸盐或柠檬酸盐之间存在弱相互作用，导致形成一水合物种。总的来说，将吡啶引入多氮大环骨架对 Mn(2+) 配合物具有以下几个有利于潜在 MRI 对比剂应用的优点：（i） 增加了配合物的热力学和动力学稳定性。（ii）刚性配体骨架导致金属离子的配位数增加，允许在水溶液中有两个内球水分子。
