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

The CEST and T1/T2 relaxation properties of a series of Eu3+ and Dy3+ DOTA‐tetraamide complexes with four appended primary amine groups are measured as a function of pH. The CEST signals in the Eu3+ complexes show a strong CEST signal after the pH was reduced from 8 to 5. The opposite trend was observed for the Dy3+ complexes where the r2ex of bulk water protons increased dramatically from ca. 1.5 mm−1 s−1 to 13 mm−1 s−1 between pH 5 and 9 while r1 remained unchanged. A fit of the CEST data (Eu3+ complexes) to Bloch theory and the T2ex data (Dy3+ 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 Ln3+‐bound water protons even though their pKa’s are much higher than the observed CEST or T2ex effects. This demonstrated the utility of using appended acidic/basic groups to catalyze prototropic exchange for imaging tissue pH by MRI. CEST bon: The NMR properties of lanthanide ion complexes formed with DOTA‐tetraamide ligands with four pendant primary amine groups were examined by relaxometry and chemical exchange saturation transfer (CEST). The CEST signal of the EuIII complexes increased dramatically at low pH while the r2 relaxivity of the DyIII complexes increased dramatically at higher pH values.