Department of Molecular Biotechnology and Health Sciences, Molecular Imaging Centre, University of Torino, via Nizza 52, 10125, Torino, Italy.
Department of Sciences and Technological Innovation, University of Eastern Piedmont, viale T. Michel 11, 50121, Alessandria, Italy.
Chemistry. 2019 Mar 15;25(16):4184-4193. doi: 10.1002/chem.201806023. Epub 2019 Feb 20.
The new ligand HPDO3MA [(R,R,R,R)-10-(2-hydroxypropyl)-α,α',α''-trimethyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] was designed to combine and optimize the chemical properties of the macrocyclic ligands HPDO3A and DOTMA. The presence of the methyl groups on the acetic pendant arms of HPDO3A is expected to rigidify the structure of the ligand and favor an increase of the kinetic inertness of the Ln complexes. H NMR spectra of Eu(HPDO3MA) displayed the presence of two pairs of diastereoisomers: SAP (square antiprismatic) and TSAP (twisted square antiprismatic) isomers (56 and 44 %, respectively). In addition, H and O relaxometric NMR studies of Gd(HPDO3MA) showed approximately a 10 % increase in relaxivity and a faster water exchange rate with respect to Gd(HPDO3A). Moreover, a detailed chemical exchange saturation transfer (CEST) characterization of Yb(HPDO3MA) displayed a sensitivity about two times larger than that of Yb(HPDO3A) both in phantom and in cell labeling experiments. Finally, the kinetic inertness of Yb(HPDO3MA) was measured to be twice as high as that of Yb(HPDO3A), with a dissociation half-life at physiological pH of about 2500 years.
新型配体 HPDO3MA[(R,R,R,R)-10-(2-羟丙基)-α,α',α''-三甲基-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸]旨在结合和优化大环配体 HPDO3A 和 DOTMA 的化学性质。HPDO3A 乙酸侧臂上的甲基的存在预计将使配体的结构刚性化，并有利于增加 Ln 配合物的动力学惰性。Eu(HPDO3MA)的 H NMR 谱显示存在两对非对映异构体：SAP（正方形反棱柱体）和 TSAP（扭曲正方形反棱柱体）异构体（分别为 56%和 44%）。此外，Gd(HPDO3MA)的 H 和 O 弛豫 NMR 研究表明，相对于 Gd(HPDO3A)，弛豫率增加了约 10%，水交换速率更快。此外，Yb(HPDO3MA)的详细化学交换饱和转移（CEST）特性显示，在体模和细胞标记实验中，其灵敏度比 Yb(HPDO3A)大两倍。最后，测量了 Yb(HPDO3MA)的动力学惰性，其值是 Yb(HPDO3A)的两倍，在生理 pH 下的解离半衰期约为 2500 年。
