Hepatobiliary MR contrast agents: 5‐substituted iron‐EHPG derivatives

Abstract

A series of iron(III) ethylenebis(2‐hydroxypheny1)glycine [Fe(EHPG)]‐ derivatives have been examined for their role as paramagnetic hepatobiliary contrast agents for magnetic resonance (MR) imaging. The 5‐substituted complexes, Fe(5‐Me‐EHPG)⁻, Fe(5‐Cl‐EHPG)⁻, and Fe(5‐Br‐EHPG)⁻, have been compared to the parent compound in rat bio‐distribution and MR imaging studies; correlative in vitro parameters for the complexes, including octanol‐buffer partition coefficients and albumin binding affinity, have also been obtained. The three new derivatives exhibited higher degrees of lipophilicity and albumin binding affinity and varying degrees of improvement in liver‐to‐blood and bile‐to‐liver concentration ratios measured at 30 min postinjection. The 5‐C1 complex had the best overall performance in terms of these tissue ratios as well as in terms of total biliary excretion. Sequential MR images of rats after administration of the complexes revealed subtle pharmacokinetic differences among the derivatives and, in general, correlated well with and complemented the biodistribution results. This study points to the sensitivity of hepatocellular uptake and excretion to simple chemical modifications and, moreover, demonstrates the importance of screening multiple derivatives to select optimal hepatobiliary MR imaging agents. © 1987 Academic press, Inc.