PREPARATION, PHYSICOCHEMICAL CHARACTERIZATION, AND RELAXOMETRY STUDIES OF VARIOUS GADOLINIUM(III)-DTPA-BIS(AMIDE) DERIVATIVES AS POTENTIAL MAGNETIC-RESONANCE CONTRAST AGENTS

Macroscopic protonation constants were measured for a series of DTPA m ono- and bis-amide ligands using potentiometric titrations. Proton NMR pH titrations yielded protonation populations of the various nitrogen and oxygen basic sites of the ligands for the different protonation s tages. Amide formation decreased the basicity of the backbone nitrogen s of the ligands and the thermodynamic stability of the corresponding Gd3+ chelates. Nuclear magnetic relaxation dispersion (NMRD) profiles and ESR linewidths were measured for the Gd3+ chelates, Some of these exhibited an elevated high field relaxivity relative to Gd(DTPA)(2-), in response to their high molecular weight. As opposed to Gd(DTPA)(2-) , at 5 degrees C the chemical exchange process of the single inner-sph ere water molecule of the bis-amide complexes becomes so slow that it governs the paramagnetic relaxation process, causing the observed NMRD profiles to be close to those expected for the outer-sphere contribut ion. The chelates containing long alkyl side chains, such as Gd(DTPA-H PA(2)), showed increased relaxivity values in the presence of human se rum albumin (HSA), indicative of noncovalent interaction with the prot ein, These chelates could be useful as nonionic hepatobiliary contrast agents.