Department of Chemistry, University at Buffalo, The State University of New York Amherst, New York 14260, United States.
Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhoria Street, 35516 Mansoura, Egypt.
Inorg Chem. 2023 Oct 9;62(40):16513-16522. doi: 10.1021/acs.inorgchem.3c02344. Epub 2023 Sep 25.
Fe(III) complexes containing a triamine framework and phenolate or hydroxypyridine donors are characterized and studied as MRI probes. In contrast to most Fe(III) MRI probes of linear chelates reported to date, the ligands reported here are pentadentate to give six-coordinate complexes with a coordination site for inner-sphere water. The crystal structure of the complex containing unsubstituted phenolate donors, Fe(L1)Cl, shows a six-coordinate iron center and contains a chloride ligand that is displaced in water. Two additional derivatives are sufficiently water-soluble for study as MRI probes, including a complex with a hydroxypyridine group, Fe(L2), and a hydroxybenzoic acid group, Fe(L3). The pH potentiometric titrations give protonation constants of 7.2 and 7.5 for Fe(L2) and Fe(L3), respectively, which are assigned to deprotonation of the bound water. Changes in the electronic absorbance spectra of the complexes as a function of pH are consistent with the deprotonation of phenol pendants at acidic pH values. However, the inner-sphere water ligand of Fe(L2) and Fe(L3) does not exchange rapidly on the NMR timescale at pH 6.0 or 7.4, as shown by variable-temperature O NMR spectroscopy. The pH-dependent proton relaxivity profiles show a maximum in relaxivity at a near-neutral pH, suggesting that exchange of the protons of the bound water is an important contribution. Competitive binding studies with ethylenediaminetetraacetic acid (EDTA) show effective stability constants for Fe(L2) and Fe(L3) at pH 7.4 with log values of 21.1 and 20.5, respectively. These two complexes are kinetically inert in carbonate phosphate buffer at 37 °C for several hours but transfer iron to transferrin. Fe(L2) and Fe(L3) show enhanced contrast in -weighted imaging analyses in BALB/c mice. These studies show that Fe(L2) clears through mixed renal and hepatobiliary routes, while Fe(L3) has a similar pharmacokinetic clearance profile to a macrocyclic Gd(III) contrast agent.
含三胺骨架和酚或羟吡啶供体的 Fe(III) 配合物被表征并作为 MRI 探针进行研究。与迄今为止报道的大多数线性螯合 Fe(III) MRI 探针相比，这里报道的配体是五齿配体，可形成具有内球水分子配位位的六配位配合物。含有未取代酚供体的配合物 Fe(L1)Cl 的晶体结构显示出六配位的铁中心，并含有在水中被取代的氯配体。另外两个衍生物足够水溶性，可作为 MRI 探针进行研究，包括一个含有羟吡啶基团的配合物 Fe(L2)和一个含有羟基苯甲酸基团的配合物 Fe(L3)。pH 电位滴定给出 Fe(L2)和 Fe(L3)的质子化常数分别为 7.2 和 7.5，这归因于结合水的去质子化。配合物电子吸收光谱随 pH 的变化与酸性 pH 值下酚侧链的去质子化一致。然而，如变温 O NMR 光谱所示，在 pH 6.0 或 7.4 时，Fe(L2)和 Fe(L3)的内球水分子配体在 NMR 时间尺度上不会快速交换。pH 依赖性质子弛豫率谱在近中性 pH 下显示出弛豫率的最大值，表明结合水的质子交换是一个重要贡献。与乙二胺四乙酸 (EDTA) 的竞争结合研究表明，在 pH 7.4 时，Fe(L2)和 Fe(L3)的有效稳定常数分别为 log 值 21.1 和 20.5。这两个配合物在 37°C 的碳酸磷酸盐缓冲液中在数小时内是动力学惰性的，但将铁转移到转铁蛋白。Fe(L2)和 Fe(L3)在 BALB/c 小鼠的 T1 加权成像分析中显示出增强的对比度。这些研究表明，Fe(L2)通过混合的肾和肝胆途径清除，而 Fe(L3)具有与大环 Gd(III) 造影剂相似的药代动力学清除特征。
