Infoscience

Thesis

Novel chelators for MRI applications: stability and relaxation properties of their metal complexes

In the last two decades, Magnetic Resonance Imaging (MRI) has evolved into one of the most powerful techniques in diagnostic clinical medicine and biomedical research. MRI is primarily used to produce anatomical images, but may also give information on the physical-chemical state of tissues, flow diffusion and motion. The strong expansion of medical MRI has prompted the development of a new class of pharmacological products, called contrast agents, designed for administration to patients in order either to enhance the contrast between normal and diseased tissue or to indicate organ function or blood flow. Nowadays, around 30 % of all MRI investigations use a contrast medium, which number will certainly further increase with the development of new agents and applications. Since the first clinical application of MRI contrast agents in the eighties, many attempts have been made to ameliorate their efficiency. The aim of this work was to enlarge our knowledge on the physical chemistry of MRI related paramagnetic metal chelates in the perspective of contributing to the development of more efficient, more tissue specific and safer contrast agents. Thermodynamic stability and kinetic inertness of the metal complexes are crucial features for their safe biomedical application. We have carried out detailed kinetic studies on the dissociation of various Gd(III) chelates which have been recently proved to have optimal water exchange rate. The ligands involved both acyclic and macrocyclic molecules. In order to approach the biologically relevant conditions, we studied exchange reactions between these Gd(III) complexes and the endogenously most abundant Zn2+ ion. For the macrocyclic compounds, formation kinetic studies have also been performed for various lanthanides. Lanthanide and transition metal complexes of several novel chelators have been subject of thermodynamic stability studies, using pH-potentiometry, UV-Vis spectrophotometry or 1H NMR. Among the ligands, we find a series of linear, pyridine and phosphonate containing molecules, and diverse macrocyclic, dimeric structures. Their Gd(III) or Mn(II) complexes were characterized with regard to MRI contrast agent application. The rate and mechanism of the water exchange, as well as the rotational dynamics of the molecules have been assessed by variable temperature, variable pressure and multiple field 17O NMR and 1H NMRD measurements. On the Gd(III) complexes of xylene-cored DO3A dimers, we have identified an unexpected aggregation phenomenon. With one of the pyridine and phosphonate containing complexes, we have demonstrated that water exchange rates as high as that on the aqua ion are possible to achieve.

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