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.

Classification and basic properties of contrast agents for magnetic resonance imaging

“…4) (62), is completely eliminated from the body, with 50% hepatobiliary and 50% renal excretion. After entering the intracellular space of the hepatocyte, it is sequestered in the bile.…”

Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents

“…To assess the pharmacokinetic parameters of GBCAs, Omniscan, Magnevist, MultiHance and Gadovist were [8], b [9], c [9,10], d [2], e [11], f [12], g [13], h calculated from [14], i calculated from [15], j calculated from [16,17], k calculated from [18], l calculated from [19] injected once at a dose of 2.5 mmol/kg b.w. into the tail vein, and blood samples were taken from the cannulated carotid vein at various time-points p.i.…”

The presence of halide salts influences the non‐covalent interaction of MRI contrast agents and human serum albumin

“…On the contrary, in protein-containing solutions (4% HSA, 1 mM Gd-complex), the relaxation rate drops markedly from about $14 s À1 in the absence of salt to $9 s À1 when [NaCl] ¼ 150 mM and $8 s À1 when [NaCl] ¼ 600 mM. The principal role of the Cl À anion was demonstrated by the use of other electrolytes, NH 4 Cl, KCl, KF, KBr and KI. The observed decreases of the relaxation rates were indeed similar for all electrolytes containing chloride anion, independent of the nature of the cation.…”