Lanthanide‐Based T2ex and CEST Complexes Provide Insights into the Design of pH Sensitive MRI Agents

The CEST and T 1 / T 2 relaxation properties of a series of Eu 3+ and Dy 3+ DOTA‐tetraamide complexes with four appended primary amine groups are measured as a function of pH. The CEST signals in the Eu 3+ complexes show a strong CEST signal after the pH was reduced from 8 to 5. The opposite trend was observed for the Dy 3+ complexes where the r 2ex of bulk water protons increased dramatically from ca. 1.5 m m −1 s −1 to 13 m m −1 s −1 between pH 5 and 9 while r 1 remained unchanged. A fit of the CEST data (Eu 3+ complexes) to Bloch theory and the T 2ex data (Dy 3+ complexes) to Swift–Connick theory provided the proton‐exchange rates as a function of pH. These data showed that the four amine groups contribute significantly to proton‐catalyzed exchange of the Ln 3+ ‐bound water protons even though their p K a ’s are much higher than the observed CEST or T 2ex effects. This demonstrated the utility of using appended acidic/basic groups to catalyze prototropic exchange for imaging tissue pH by MRI.