Agents de contraste pour l'IRM - théorie et synthèse
P. Delangle, P. H. Fries, C. Gateau, D. Imbert, M. Mazzanti

The synthesis of biocompatible complexes of paramagnetic gadolinium Gd3+ ions, used as contrast enhancers in 40 % of magnetic resonance imaging (MRI) examinations, has accompanied the rapid growth of this non-invasive diagnosis tool. Images are maps of the spatial variation in the organism of the relaxation rates of the hydrogen proton spins on the water molecules. The intermolecular dynamics of the water molecules with respect to the complexes governs the relaxation rate enhancement, i.e., contrast enhancement in the tissues where these complexes spread out. In RICC team, Gd3+-based contrast agents are prepared by coupling coordination chemistry with theory to get a proper description of the dynamics of water molecules in terms of molecular properties tailor-made by the chemist to attain the highest contrast efficiency.


The relaxation rate enhancement of the observed proton spins in a given region of the organism is due to their fluctuating magnetic dipolar interactions with the surrounding complexed Gd3+ ions. The contrast enhancement is proportional to the spectral density of these interactions calculated at the imager frequency. The fluctuations of the dipolar interaction have two origins. First, they stem from the relative random spatial motion of the Gd3+ ions with respect to the hydrogen protons caused by the translational and rotational Brownian dynamics of the water molecules and complexes, and by the exchange kinetics of the water molecules that coordinate Gd3+ or form H-bonds with its ligand. Second, they result from the quantum relaxation dynamics of the Gd3+ electronic spin induced by the magnetic field of the imager and the fluctuating electric field of the ligand. The complexity of these mechanisms explains the continuing efforts to obtain a reliable description of the contrast enhancement.


Some time ago, through careful analysis of EPR spectra, we had evidenced the importance of the "static" ZFS Hamiltonian that accounts for the time-average of the ligand field in a molecular frame rigidly bound to the complex. This property was the starting point of important simplifications and renewed theoretical interpretations. We showed that the ZFS Hamiltonian dramatically quenches the contrast efficiency at vanishing field, but has negligible effect at the present standard imaging fields of 1.5 T and above. Thus, the contrast efficiency, named relaxivity, depends only on the water/complex spatial motion and the chemist should be hardly concerned by electronic spin relaxation when designing new ligands. We developed rigorous theoretical tools to interpret the contrast efficiency of the complexes with our new families of synthesized ligands.



Gd3+ ligands derived from natural molecules, like cyclodextrins or peptides, are prepared to benefit from the hydrophilicity of these scaffolds, giving rise to a large second-sphere (2S) contribution to the relaxation rate due to H-bonded water molecules. Thus, the Gd3+ complex with a cyclodecapeptide, bearing four carboxyl groups oriented on the same face of the scaffold to bind the cation, shows a very high relaxivity. Rigorous theoretical tools were used to decipher the different relaxivity mechanisms. We showed that the relaxation rate enhancements are 30% higher than the expected values for this complex with two inner-sphere water molecules and a medium-range rotational correlation time tR » 400 ps. Cyclic peptides are thus promising ligands of Gd3+ as they combine optimal tR and important 2S hydration leading to particularly large relaxivity at high imaging fields.


Polydentate ligands with different geometries are designed to produce Gd3+ complexes with unusually high relaxivity and good stability in biological media. Among the most interesting results is the development of a picolinate based tris-aqua Gd3+ complex which is very soluble in water, reasonably stable (pGd = 12.3), and has a high relaxivity r1 at high field, still better in physiological conditions (in serum, r1=17.3 s-1 mM-1 is larger than the value 4 s-1 mM-1 of commercial contrast agents). Moreover, with an appropriate ligand design, we combined the magnetic properties of the Gd3+ complexes with the photophysical properties of the analogous complexes of luminescent UV-Vis and Near-IR lanthanide Ln3+ emitters to propose bimodal imaging probes. Notably, the inclusion of two picolinate groups in tripodal frameworks affords new ligands leading to Ln3+ complexes with both optimized relaxivity in the case of Gd3+ and high luminescence quantum yield (45%) in the case of terbium Tb3+.


Selected publication(s) C. S. Bonnet et al., J. Am. Chem. Soc. 130 (2008) 10401; C. S. Bonnet et al., Chem. Eur. J. 15 (2009) 7083; A. Nonat et al., Chem. Eur. J. 12 (2006) 7133. A. Nonat et al., Chem. Eur. J. 13 (2007) 8489


Maj : 20/08/2012 (551)


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