New strategies for highly efficient medical MRI contrast agents : Gd(III) poly(amino carboxylates) with fast water exchange and Gd(III) trapped in carbon cages

During the last two decades, magnetic resonance imaging (MRI) has evolved into one of the most powerful techniques in medical diagnosis. Among the various medical diagnostic modalities, such as X-ray or ultra-sound imaging, MRI is the technique of choice especially because of its non-invasive character, the absence of ionizing radiations and its high spatial resolution. The principle of an MRI examination relies on the relaxation of water protons in the human body placed in a magnetic field after radiofrequency excitations. MRI is sensitive to the nature of the soft tissues, to the proton density and to the relaxation rate of protons to produce a contrast. The development of MRI is closely related to the successful use of paramagnetic contrast agents, essentially gadolinium(III) complexes. Unlike contrast agents used in other clinical imaging techniques, the MRI contrast agents are not themselves imaged but rather enhance the nuclear relaxation rate of water protons in their vicinity. The use of MRI contrast agents induces not only a better image contrast and a better delineating of diseased tissues but also a shortening of the examination time. Since the discovery of GdIII chelates as MRI contrast agents, a lot of effort has been made to increase their relaxivity, i.e. the gauge of efficiency of the contrast agent. In the work presented in this thesis, two groups of paramagnetic compounds have been studied: GdIII poly(amino carboxylates) and GdIII trapped in carbon cage compounds. For traditional monohydrated GdIII poly(amino carboxylate) complexes, the Solomon- Bloembergen-Morgan equations predict maximum proton relaxivities of 100 mM-1 s-1, instead of 4-5 mM-1 s-1 for commercial agents, when the three most important influencing factors, the rotation, the electron spin relaxation and the water exchange rate are simultaneously optimized. On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated GdIII poly(amino carboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA5- ligand by replacing one ethylene bridge of the amine backbone by a propylene one (EPTPA5--based ligand), leading to a water exchange rate two orders of magnitude higher than that for the commercial [Gd(DTPA)(H2O)]2-. The replacement of two ethylene bridges (DPTPA5-) results in the elimination of the water molecule from the inner sphere. Although the thermodynamic stability of [Gd(EPTPA-bz-NO2)(H2O)]2- is reduced to a slight extent in comparison to [Gd(DTPA)(H2O)]2-, it is stable enough to be used in medical diagnosis. The next step to obtain high relaxivity contrast agents is the covalent coupling of GdIII EPTPA complexes to three generations (5, 7 and 9) of PAMAM dendrimers to ensure fast water exchange rate and slow rotation. These macromolecular GdIII complexes allow high relaxivities with maximum values at magnetic fields presently used