Synthesis and physicochemical characterization of a new gadolinium chelate: The liver-specific magnetic resonance imaging contrast agent Gd-EOB-DTPA

A convenient synthesis of disodium S-[4-(4-ethoxybenzyl)-3,6,9-tris[(carbox y-kappa O)methyl]-3,6,9-triazaundecandioato)(5-)-kappa(3)N(3),N-6,N-9,kappa (2)O(1),O-11]gadolinate(2-) (Gd-EOB-DTPA), 1, is reported. This water-solub le complex is presently undergoing phase III clinical trials as a liver-spe cific contrast agent for magnetic resonance imaging (MRI). The thermodynami c complex stability constant of 1 and the acid dissociation constants of th e ligand have been determined as well as the stability constant of the calc ium complex Ca-EOB-DTPA (2), which is used as an additive in the pharmaceut ical formulation of the contrast agent. The solid-state structure of the li gand S-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecan edioic acid (H5EOB-DTPA), 3, has been elucidated in a single crystal X-ray diffraction study. Additionally, HPLC evidence is given that the enantiomer ically pure ligand forms two diastereomeric gadolinium complexes in a 65:35 ratio. The kinetics of isomerization of the isolated diastereomers-as depe ndent on pH and temperature-has been investigated, and thus, the activation energy for the interconversion of these isomers has been estimated to be 7 5.3 kJ mol(-1). Finally, the structures of the two components of 1 are disc ussed in terms of four possible diastereomers.