Abstract
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 (kex) 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 kex and a quenching of the CEST signal.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.
Highlights
The paramagnetic chemical exchange saturation transfer agents present an attractive alternative to gadolinium-based agents for molecular imaging applications
While a vast majority of studies of such complexes have focused on varying the functional groups on the amide side chains to alter the water molecule exchange rates, this study focused on how a change in pH alters the rate of exchange of protons between inner- and outer-sphere water molecules and how this impacts CEST sensitivity
It was shown that the pH dependence of CEST in these complexes is governed by the rate prototropic exchange between bulk solvent water protons and Eu3+-bound water protons
Summary
The paramagnetic chemical exchange saturation transfer (paraCEST) agents present an attractive alternative to gadolinium-based agents for molecular imaging applications. The CEST signal from the Eu3+-bound water molecule decreased in intensity between pH 8.5 and 4.5 while the proton exchange rates (kex) increased 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.
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