Protein binding contrast agents for potential use in MRI

Heptadentate ligands form lanthanide (III) complexes, which allow an increased hydration state about the metal centre, resulting in an improvement in the relaxivity of the contrast agents administered. A series of analogues based upon the compound (2) was pursued, incorporating aromatic functionalised groups, consequently increasing the hydrophobicity of the complexes. The aryl moiety significantly enhances the binding to human serum albumin (HSA), consequently improving the observed relaxivity. Relaxivity enhancements were seen for each of the carboxylate complexes in the presence of increasing serum protein concentrations. (DIAGRAM-Chemical structure of the ligand aD03A) (2)The phosphonate analogue of the aD03A ligand (2) was identified as a target and synthesised as a key ligand whose lanthanide (III) complex possesses a higher peripheral negative charge, repelling the attraction towards anions, potentially maintaining higher relaxivity values in serum solutions. A trifluoromethanesulphonamide moiety was introduced into the aD03A moiety that exhibited a high binding affinity to human serum albumin resulting in high values for the observed relaxivity. The solution structures of the diastereoisomers for the model albumin binding complex (S)-[Eu-(EOB)-(DTPA)](^2-) were analysed by (^1)Ή NMR, CD and CPL spectroscopy. The major species observed were found to possess similar (^1)Ή NMR paramagnetic shifts and emission spectra, consistent with a 9-coordinate structure involving one bound water molecule.