Two thulium-based ParaCEST responsive contrast agents, Tm-DOTAm-py and Tm-DOTAm-βAla-py, have been synthesized and evaluated for imaging copper and zinc. Unusual for responsive MRI contrast agents, both agents display a complete on/off response in the presence of transition metals. Both complexes function as paraCEST agents in the absence of copper and zinc, with the positively charged Tm-DOTAm-py being more sensitive than the neutrally charged Tm-DOTAm-βAla-py. In each case, the CEST signal arises from amide protons rather than from a water molecule coordinated to Tm³⁺ ions. Upon binding to Cu⁺, Cu²⁺, or Zn²⁺, the exchange rate of the amide protons increases substantially, resulting in a complete loss of the CEST signal. This efficient mode of action along with the lack of inner-sphere water molecules both in the presence and absence of transition metals was confirmed by 1/T₁ NMRD profiles, ¹⁷O NMR measurements, and molecular modelling simulations. Neither complex is selective for copper over zinc. Both form either a 1 : 1 TmL : Cu⁺ or a 2 : 1 TmL : Cu²⁺ and TmL : Zn²⁺ complexes with binding affinities comparable to that of other responsive MRI contrast agents and sensitivity comparable to that of other CEST contrast agents.

中文翻译：

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用于铜和锌的完整的开/关响应式ParaCEST MRI造影剂†

已经合成了两种基于Para的ParaCEST响应性造影剂Tm-DOTAm-py和Tm-DOTAm-βAla-py，并对其用于铜和锌的成像进行了评估。对于反应性MRI造影剂而言，这两种试剂不常见，在过渡金属存在的情况下，两种试剂均显示出完整的开/关响应。两种配合物在没有铜和锌的情况下均充当paraCEST试剂，带正电荷的Tm-DOTAm-py比带中性电荷的Tm-DOTAm-βAla-py更敏感。在每种情况下，CEST信号均来自酰胺质子，而不是来自与Tm ³⁺离子配位的水分子。与Cu ⁺，Cu ²⁺或Zn ^2+结合时，酰胺质子的交换速率大大增加，导致CEST信号完全消失。通过1 / T ₁ NMRD谱，¹⁷ O NMR测量和分子模拟模拟，证实了这种有效的作用方式以及在存在和不存在过渡金属的情况下都没有内层水分子。这两种络合物都没有铜比锌具有选择性。两者都形成1：1 TmL：Cu ⁺或2：1 TmL：Cu ²⁺和TmL：Zn ²⁺复合物，其结合亲和力可与其他反应性MRI造影剂相媲美，且敏感性可与其他CEST造影剂相媲美。 。