Protonation of carboxyl groups in EuDOTA-tetraamide complexes results in catalytic prototropic exchange and quenching of the CEST signal

The CEST properties of EuDOTA-tetraamide complexes bearing pendant carboxylate and carboxyl ethyl esters were measured as a function of pH. The CEST signal from the Eu³⁺-bound water molecule decreased in intensity between pH 8.5 and 4.5 while the proton exchange rates (<i>k</i>_ex) increased over this same pH range. In comparison, the CEST signal in the corresponding carboxyl ester derivatives was nearly constant. Both observations are consistent with stepwise protonation of the four carboxylic acid groups over this same pH range. This indicates that negative charges on the carboxyl groups above pH 6 facilitate the formation of a strong hydrogen-bonding network in the coordination second sphere above the single Eu³⁺-bound water molecule, thereby decreasing prototropic exchange of protons on the bound water molecule with bulk water protons. The percentage of square antiprismatic versus twisted square antiprism coordination isomers also decreased as the appended carboxylic acid groups were positioned further away from the amide. The net effect of lowering the pH was an overall increase in <i>k</i>_ex and a quenching of the CEST signal

Enantiomeric Recognition of d- and l‑Lactate by CEST with the Aid of a Paramagnetic Shift Reagent

A previous report demonstrated that EuDO3A could be used as an NMR shift reagent for imaging extracellular lactate produced by cancer cells using CEST imaging. In this work, a series of heptadentate macrocyclic YbDO3A-trisamide complexes with δ-chiral carbons in the three pendant side-arms were examined as shift reagents for lactate detection. High resolution ¹H NMR spectra and DFT calculations provided evidence for the formation of stereoselective lactate·YbDO3A-trisamide complexes each with a different CEST signature. This stereoselectivity allowed discrimination of d- versus l-lactate by both high-resolution NMR and CEST. This work demonstrates that lanthanide-based paramagnetic shift reagents can be designed to detect important metabolites by CEST MRI selectively