title: Synthesis and Physicochemical Characterization of a New Gadolinium Chelate: The Liver-Specific Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA.
abstract: A convenient synthesis of disodium S-[4-(4-ethoxybenzyl)-3,6,9-tris[(carboxy-kappaO)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-soluble complex is presently undergoing phase III clinical trials as a liver-specific contrast agent for magnetic resonance imaging (MRI). The thermodynamic complex stability constant of 1 and the acid dissociation constants of the ligand have been determined as well as the stability constant of the calcium complex Ca-EOB-DTPA (2), which is used as an additive in the pharmaceutical formulation of the contrast agent. The solid-state structure of the ligand S-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid (H(5)EOB-DTPA), 3, has been elucidated in a single crystal X-ray diffraction study. Additionally, HPLC evidence is given that the enantiomerically pure ligand forms two diastereomeric gadolinium complexes in a 65:35 ratio. The kinetics of isomerization of the isolated diastereomers-as dependent on pH and temperature-has been investigated, and thus, the activation energy for the interconversion of these isomers has been estimated to be 75.3 kJ mol(-1). Finally, the structures of the two components of 1 are discussed in terms of four possible diastereomers.
authors.affiliation: Research Laboratories of Schering AG, D-13342 Berlin, Germany.
authors.forename: H.
authors.initials: H
authors.lastname: Schmitt-Willich
authors.forename: M.
authors.initials: M
authors.lastname: Brehm
authors.forename: Ch. L. J.
authors.initials: CL
authors.lastname: Ewers
authors.forename: G.
authors.initials: G
authors.lastname: Michl
authors.forename: A.
authors.initials: A
authors.lastname: Müller-Fahrnow
authors.forename: O.
authors.initials: O
authors.lastname: Petrov
authors.forename: J.
authors.initials: J
authors.lastname: Platzek
authors.forename: B.
authors.initials: B
authors.lastname: Radüchel
authors.forename: D.
authors.initials: D
authors.lastname: Sülzle