Lanthanide complexes of DOTA-nitroxide conjugates for redox imaging: spectroelectrochemistry, CEST, relaxivity, and cytotoxicity.

The lanthanide(iii) complexes (Gd, Eu, Dy, and Yb) of DOTA tris(amide) and bis(amide) derivatives (L1 and L2) featuring one redox active TEMPO arm were prepared. Ligand L2 harbours an alkyne fragment for further functionalization. The X-ray crystal structure of ligand L2 in complexation with Na+ was solved. The complexes showed in their CV one oxidation wave (0.26-0. 34 V vs. Fc+/Fc) due to an oxoammonium/nitroxide redox couple and a broad reduction corresponding to the nitroxide/hydroxylamine system. The Eu complexes demonstrated the presence of one water molecule in their coordination sphere. The nitroxide complexes were characterized by EPR spectroscopy, showing the typical 3-line pattern in the high temperature regime, which is quenched upon the addition of ascorbate (reduction into hydroxylamine). In their nitroxide form, the complexes show essentially no CEST peak. Conversely, the reduced complexes demonstrate a 12% CEST peak at 51 ppm, corresponding to the metal bound water molecule. Fast exchange precluded the CEST activity for the amide protons. All the complexes proved to be essentially non-toxic for M21 cells at concentrations up to 50 µM.

EPR spectroscopy of MRI-related Gd(III) complexes: simultaneous analysis of multiple frequency and temperature spectra, including static and transient crystal field effects.

For the first time, a very general theoretical method is proposed to interpret the full electron paramagnetic resonance (EPR) spectra at multiple temperatures and frequencies in the important case of S-state metal ions complexed in liquid solution. This method is illustrated by a careful analysis of the measured spectra of two Gd3+ (S = 7/2) complexes. It is shown that the electronic relaxation mechanisms at the origin of the EPR line shape arise from the combined effects of the modulation of the static crystal field by the random Brownian rotation of the complex and of the transient zero-field splitting. A detailed study of the static crystal field mechanism shows that, contrarily to the usual global models involving only second-order terms, the fourth and sixth order terms can play a non-negligible role. The obtained parameters are well interpreted in the framework of the physics of the various underlying relaxation processes. A better understanding of these mechanisms is highly valuable since they partly control the efficiency of paramagnetic metal ions in contrast agents for medical magnetic resonance imaging (MRI).