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 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 r(2ex) 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 r(1) remained unchanged. A fit of the CEST data (Eu3+ complexes) to Bloch theory and the T-2ex 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 Ln(3+)-bound water protons even though their pK(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.