The Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, USA.
Inorg Chem. 2013 Apr 1;52(7):4084-96. doi: 10.1021/ic400227k. Epub 2013 Mar 21.
Gadolinium chelates with octadentate ligands are widely used as contrast agents for magnetic resonance imaging (MRI), with macrocyclic ligands based on DO3A being preferred for the high kinetic inertness of their Gd chelates. A major challenge in the design of new bifunctional MRI probes is the need to control the rotational motion of the chelate, which greatly affects its relaxivity. In this work we explored facile alkylation of a secondary amine in macrocyclic DO3A-like ligands to create a short, achiral linkage to limit the undesired internal motion of chelates within larger molecular constructs. The acetate moiety on the trans nitrogen was also replaced with either a bidentate (ethoxyacetate, L1 or methyl picolinate, L2) or bulky monodentate (methyl phosphonate, L3) donor arm to give octa- or heptadentate ligands, respectively. The resultant Gd(III) complexes were all monohydrated (q = 1) and exhibited water residency times that spanned 2 orders of magnitude (τM = 2190 ± 170, 3500 ± 90, and 12.7 ± 3.8 ns at 37 °C for GdL1, GdL2, and GdL3, respectively). Alkylation of the secondary amine with a noncoordinating biphenyl moiety resulted in coordinatively saturated q = 0 complexes of octadentate ligands L1 and L2. Relaxivities were limited by slow water exchange and/or lack of water coligand. All complexes showed decreased inertness compared to [Gd(DO3A)] despite higher ligand denticity, and inertness was further decreased upon N-alkylation. These results demonstrate that high kinetic inertness and in vivo safety of Gd chelates with macrocyclic ligands should not be generalized.
钆螯合物与八齿配体广泛用于磁共振成像(MRI)的造影剂,基于 DO3A 的大环配体因其 Gd 螯合物的高动力学惰性而受到青睐。在新型双功能 MRI 探针的设计中,一个主要挑战是需要控制螯合物的旋转运动,这会极大地影响其弛豫率。在这项工作中,我们探索了在大环 DO3A 样配体中的仲胺进行简便的烷基化,以创建短的、手性的连接基,从而限制螯合物在较大分子结构内的不期望的内旋转运动。反式氮上的乙酸酯部分也被双齿(乙氧基乙酸酯,L1 或甲基吡啶酸酯,L2)或大位阻单齿(甲基膦酸酯,L3)供体取代,分别得到八齿或七齿配体。所得的 Gd(III) 配合物均为一水化物(q = 1),表现出跨越两个数量级的水停留时间(在 37 °C 下,GdL1、GdL2 和 GdL3 的 τM 值分别为 2190 ± 170、3500 ± 90 和 12.7 ± 3.8 ns)。仲胺与非配位联苯部分的烷基化导致八齿配体 L1 和 L2 的配位饱和 q = 0 配合物。弛豫率受到缓慢的水交换和/或缺乏水配位体的限制。与大环配体的 [Gd(DO3A)] 相比,所有配合物的惰性都较低,尽管配体的齿密度较高,但 N-烷基化后惰性进一步降低。这些结果表明,大环配体的 Gd 螯合物的高动力学惰性和体内安全性不应被一概而论。