General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, 7000 Mons, Belgium.
University of Bordeaux, CNRS, Bordeaux INP, ENSCBP, Laboratory of Organic Polymer Chemistry (LCPO), 33607 Pessac, France.
Inorg Chem. 2021 Mar 15;60(6):3604-3619. doi: 10.1021/acs.inorgchem.0c03120. Epub 2021 Feb 24.
Magnetic resonance imaging (MRI) has a leading place in medicine as an imaging tool of high resolution for anatomical studies and diagnosis of diseases, in particular for soft tissues that cannot be accessible by other modalities. Many research works are thus focused on improving the images obtained with MRI. This technique has indeed poor sensitivity, which can be compensated by using a contrast agent (CA). Today, the clinically approved CAs on market are solely based on gadolinium complexes that may induce nephrogenic systemic fibrosis for patients with kidney failure, whereas more recent studies on healthy rats also showed Gd retention in the brain. Consequently, researchers try to elaborate other types of safer MRI CAs like manganese-based complexes. In this context, the synthesis of Mn complexes of four 12-membered pyridine-containing macrocyclic ligands based on the pyclen core was accomplished and described herein. Then, the properties of these Mn(II) complexes were studied by two relaxometric methods, O NMR spectroscopy and H NMR dispersion profiles. The time of residence (τ) and the number of water molecules () present in the inner sphere of coordination were determined by these two experiments. The efficacy of the pyclen-based Mn(II) complexes as MRI CAs was evaluated by proton relaxometry at a magnetic field intensity of 1.41 T near those of most medical MRI scanners (1.5 T). Both the O NMR and the nuclear magnetic relaxation dispersion profiles indicated that the four hexadentate ligands prepared herein left one vacant coordination site to accommodate one water molecule, rapidly exchanging, in around 6 ns. Furthermore, it has been shown that the presence of an additional amide bond formed when the paramagnetic complex is conjugated to a molecule of interest does not alter the inner sphere of coordination of Mn, which remains monohydrated. These complexes exhibit relaxivities, large enough to be used as clinical MRI CAs (1.7-3.4 mM·s, at 1.41 T and 37 °C).
磁共振成像（MRI）作为一种高分辨率的解剖学研究和疾病诊断成像工具，在医学中占有领先地位，特别是对于其他方式无法检测到的软组织。因此，许多研究工作都集中在提高 MRI 获得的图像质量上。然而，该技术的灵敏度较差，可以通过使用造影剂（CA）来补偿。目前，市场上临床批准的 CA 仅基于钆复合物，对于肾衰竭患者可能会引起肾源性系统性纤维化，而最近对健康大鼠的研究也显示出 Gd 在大脑中的蓄积。因此，研究人员试图开发其他类型的更安全的 MRI CA，如基于锰的复合物。在这种情况下，完成并描述了基于 pyclen 核的四个包含 12 个成员吡啶的大环配体的 Mn 配合物的合成。然后，通过两种弛豫测量方法，即 O NMR 光谱和 H NMR 弥散谱来研究这些 Mn(II)配合物的性质。通过这两个实验确定了内配位球中存在的停留时间（τ）和水分子的数量（）。通过质子弛豫率评价了基于 pyclen 的 Mn(II)配合物作为 MRI CA 的功效，在 1.41 T 的磁场强度下进行了评价，该磁场强度接近大多数医学 MRI 扫描仪（1.5 T）的磁场强度。O NMR 和核磁共振弛豫弥散谱都表明，本文制备的四个六齿配体中有一个空配位位，可容纳一个水分子，在约 6 ns 内快速交换。此外，已经表明，当顺磁配合物与感兴趣的分子缀合时形成的额外酰胺键不会改变 Mn 的内配位球，其仍然是单水合的。这些配合物具有足够大的弛豫率，可以用作临床 MRI CA（1.7-3.4 mM·s，在 1.41 T 和 37°C 下）。
