Hugues Jaccard
The two last decades have witnessed the appearance and the successful development of magnetic resonance imaging (MRI) contrast agents (CAs). Though MRI, which has become an essential medical diagnostic tool, can be performed without contrast agents, its rather low sensitivity implies long and tedious examination times. This time can be considerably reduced by the use of CAs. Paramagnetic ion complexes, and particularly gadolinium (III) complexes, can thus significantly accelerate the longitudinal relaxation rate 1/T1 of the water proton, one of the most common parameters measured in MRI experiments. The relaxivity, the property describing the paramagnetic relaxation enhancement, or PRE, is mainly affected by four parameters : the number of water molecules in the inner coordination sphere of the complex, the proton exchange rate in this inner sphere, the rotational correlation times, related to the size of the molecule, and the electron spin relaxation rates. This work deals with the development of four new types of compounds designed as potential MRI T1 contrast agents. The four compounds have different properties and were therefore developed to observe different effect on the relaxivity. High-field CAs, medium-field CA aggregates, linear polymeric and nanoparticular CAs, and targeted CAs are the four different specificities studied in this work. The first compound, presented in Chapter II, is the tricephalous complex {Mes[Gd(DO3A)(H2O)2]}. This mid-size molecule was designed as a potential high-field CA. The standard complexation method does not lead to the complete complexation, most probably due to an intramolecular folding of the compound. The complexation is therefore performed in two steps : a complete pre-complexation with magnesium (II) followed by a transmetallation to replace Mg2+ by Gd3+ in the three complexation sites. This newly developed complexation method can be really useful to achieve complete complexation of mid-size molecules, where complexation shared by two neighboring chelating units can occur. Chapter III deals with another mid-size trimeric complex, the {Ph4[Gd(DTTA)(H2O)2]-3}. The central core of this compound, composed of four phenyl rings, was designed to favor aggregation. The relaxivities of the big entities formed is expected to increase significantly in the medium resonance frequency range, i.e. between 10 and 200 MHz. The dynamic aggregation is observed by the concentration dependence of the relaxivity. The parameters obtained by fitting the experimental data allow the estimation of the number of molecule in the entities, ranging from the monomer in diluted solution to a few units for more concentrated solutions. Chapter IV presents Gd3+ chelate complexes conjugated to the linear polysaccharide chitosan. The coupling reaction, performed directly with the Gd3+ complex, is achieved through the condensation of a carboxylate uncomplexing arm on the chelating unit with the free amine of the chitosan. The ratio of modified chitosan units in the compound {Chi[Gd(DTTA-N'but)(H2O)2]-} is determined by ICP-MS and elemental analysis. Porous hydrogels nanoparticles, or nanogels, are subsequently formed from the modified linear chitosan by the ionic gelation method. As the material becomes bigger and more rigid, the relaxivities of the formed nanogels were expected to become higher than that of the linear chain. This does unfortunately not occur, most probably because of a partial complexation of the anion triphosphate, used for the formation of the particles, or by limited water diffusion inside the nanogels. The final chapter of results, Chapter V, presents a family of four compounds designed as target CAs for a specific kind of malignant tumor, such as prostate, breast or some lung cancer cells, which overexpress bombesin receptors. The four studied compounds are therefore composed by the peptide bombesin conjugated to a Gd3+ chelate complexe. In order to optimize the peptide-receptor interaction, two bombesin analogues, the Lys3-bombesin and the Ahx-bombesin(4-14), are used for the synthesis of the monovalent and the divalent peptide conjugates. The relaxometric properties of the four compounds are measured and compared.
EPFL2011
