The aim of this work was to design new pH‐sensitive paramagnetic chemical exchange saturation transfer (paraCEST) agents with a more acidic pH readout window with respect to the Yb complex of the 10‐(2‐hydroxypropyl)‐1,4,7,10‐ tetraazacyclododecane‐1,4,7‐triacetic acid (HPDO3A). In particular, three HPDO3A derivatives have been synthesized by substituting the methyl group on the 2‐hydroxypropyl arm with the electron withdrawing substituents –CF₃, –CH₂NH₂ and –CH₂OH. The Yb complexes have been characterized in terms of i) number and relative abundance of isomers present and, ii) pH sensitivity range in CEST applications. The influence of the introduced substituents on the –OH proton acidity and k_ex has been investigated and the new agents have been compared with the parent Yb‐HPDO3A. All complexes showed an increased acidity and an enhanced exchange rate of the –OH proton. As a consequence, the pH‐CEST sensitivity has been shifted to more acidic values. Eventually, the –CH₂OH bearing derivative has been tested to assess the intra‐endosomal pH which is too acidic to be determined with Yb‐HPDO3A.

中文翻译：

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pH响应性Yb-HPDO3A衍生物作为ParaCEST剂中质子交换率的调节

这项工作的目的是设计新的pH敏感的顺磁性化学交换饱和转移（paraCEST）试剂，该试剂相对于10-（2-羟丙基）-1,4,7的Yb络合物具有更酸性的pH读数窗口。 10-四氮杂环十二烷-1,4,7-三乙酸（HPDO3A）。特别是，通过用吸电子取代基–CF ₃，–CH ₂ NH ₂和–CH ₂ OH取代2-羟丙基臂上的甲基，合成了三种HPDO3A衍生物。Yb配合物的特征是：i）存在的异构体的数量和相对丰度，以及ii）CEST应用中的pH敏感性范围。引入的取代基对-OH质子酸度和k _ex的影响已进行了研究，并将新试剂与母体Yb-HPDO3A进行了比较。所有复合物都显示出增加的酸性和–OH质子的交换速率。结果，pH-CEST灵敏度已转变为更酸性的值。最终，已对带有–CH ₂ OH的衍生物进行了测试，以评估太酸性以至于无法用Yb-HPDO3A测定的内膜内pH。