A MULTINUCLEAR MR STUDY OF GD-EOB-DTPA - COMPREHENSIVE PRECLINICAL CHARACTERIZATION OF AN ORGAN-SPECIFIC MRI CONTRAST AGENT

The characterization of the hepatobiliary contrast agent Gd-EOB-DTPA ( gadolinium 3, 6, 9-triaza-3, 6, boxymethyl)-4-(4-ethoxybenzyl)-undecan dicarboxylic acid) in various media (water solution, protein containin g solution, phosphorylated metabolites solution, and excised and perfu sed liver) was performed using different NMR approaches: water H-1 nuc lear magnetic relaxation dispersion profiles, H-2 NMR longitudinal and transverse relaxation rates of labeled complex, water O-17 transverse relaxation rates and chemical shifts, P-31 relaxation rates and peak area of phosphorylated metabolites, The higher proton relaxivity of Gd -EOB-DTPA in water compared with Gd-DTPA is related to a shorter dista nce (r) between the water proton and the gadolinium ion and to a [ange r rotational correlation time (tau(R)) of the hydrated complex, Althou gh the thermodynamic stability of Gd-EOB-DTPA is identical to the one of Gd-DTPA, its kinetic stability in solutions containing phosphorylat ed metabolites (ATP, phosphocreatine, and inorganic phosphate) as meas ured by P-31 relaxation rates analysis is higher than for the parent c ompound. Gd-EOB-DTPA binds noncovalently to serum proteins, Its intera ction with human serum albumin is characterized by a dissociation cons tant of 1-4.1 mM as calculated from proton and deuterium relaxation ra tes and equilibrium dialysis, This noncovalent interaction involves th e subdomain IIA of human serum albumin. P-31 spectroscopy of the excis ed and perfused rat livers was used to monitor the uptake of Gd-EOB-DT PA by the hepatocytes where it enhances the nuclear relaxation of the intracellular metabolites without impairing the adenosine triphosphate metabolism of the cells.