Macromolecular gadolinium complexes for use as contrast agents in medical magnetic resonance imaging

The eight coordinate Gd3+ complex of the tripodal ligand tris([3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]amine (TREN-Me-3,2-HOPO) is the parent of a family of compounds which coordinate two water molecules that rapidly exchange with bulk solvent water. These beneficial physical properties, together with the high stability of the complex, render it a promising candidate as a contrast agent for magnetic resonance imaging. However, the insufficient water solubility of this parent lanthanide complex challenged the study of high relaxivity macromolecular derivatives.; Mixed tripodal ligands incorporating both the 1-methyl-3-hydroxy-2-pyridinone (HOPO) and 2,3-dihydroxyterephthalamide (TAM) chelators are presented. The solution thermodynamic properties, including the stabilities of the Gd 3+ complexes and the selectivity of the ligands for Gd3+ over physiologically available metals, are described. The Gd3+ complex of a ligand of intermediate basicity comprising one TAM and two HOPO podands displays maximum stability. Its high selectivity further suggests its potentially low in vivo toxicity.; This heteropodal Gd-TREN-bisHOPO-TAM complex was subsequently functionalized with various water solubilizing substituents. The physical properties of these derivatives, including their stability, selectivity versus physiological anions and relaxivity, are presented. The charge of the complex significantly affects its stability, decreasing with negative charge. The hydrogen-bonding terminal group favors a nine (versus eight) coordinate ground state.; The synthesis of a water-soluble block dendrimer is described. The characterization of the macromolecule demonstrated its high purity and monodispersity. Relaxivity studies demonstrated that the dendrimer is, to the best of our knowledge, the first complex to display high relaxivity at medically relevant high magnetic fields.; A new class of macromolecular complexes, based on Fe3+-templated self-assembly of Gd3+ chelates, is illustrated. The ease of synthesis of the supramolecules together with their promising relaxivity behavior render them promising candidates as high relaxivity contrast agents.