title: Toward optimized high-relaxivity MRI agents: thermodynamic selectivity of hydroxypyridonate/catecholate ligands.
abstract: The thermodynamic selectivity for Gd(3+) relative to Ca(2+), Zn(2+), and Fe(3+) of two ligands of potential interest as magnetic resonance imaging (MRI) contrast agents has been determined by NMR spectroscopy and potentiometric and spectrophotometric titration. The two hexadentate ligands TREN-6-Me-3,2-HOPO (H(3)L2) and TREN-bisHOPO-TAM-EA (H(4)L3) incorporate 2,3-dihydroxypyridonate and 2,3-dihydroxyterephthalamide moieties. They were chosen to span a range of basicity while maintaining a structural motif similar to that of the parent ligand, TREN-1-Me-3,2-HOPO (H(3)L1), in order to investigate the effect of the ligand basicity on its selectivity. The 1:1 stability constants (beta(110)) at 25 degrees C and 0.1 M KCl are as follows. L2: Gd(3+), 20.3; Ca(2+), 7.4; Zn(2+), 11.9; Fe(3+), 27.9. L3: Gd(3+), 24.3; Ca(2+), 5.2; Zn(2+), 14.6; Fe(3+), 35.1. At physiological pH, the selectivity of the ligand for Gd(3+) over Ca(2+) increases with the basicity of the ligand and decreases for Gd(3+) over Fe(3+). These trends are consistent with the relative acidities of the various metal ions;- more basic ligands favor harder metals with a higher charge-to-radius ratio. The stabilities of the Zn(2+) complexes do not correlate with basicity and are thought to be more influenced by geometric factors. The selectivities of these ligands are superior to those of the octadentate poly(aminocarboxylate) ligands that are currently used as MRI contrast agents in diagnostic medicine.
authors.affiliation: Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.
authors.forename: Valérie C
authors.initials: VC
authors.lastname: Pierre
authors.forename: Marco
authors.initials: M
authors.lastname: Melchior
authors.forename: Dan M J
authors.initials: DM
authors.lastname: Doble
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Raymond
mesh_terms: D002118:Calcium / Q000737:chemistry; D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry; D005290:Ferric Compounds / Q000138:chemical synthesis / Q000737:chemistry; D005682:Gadolinium / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry; D013816:Thermodynamics; D015032:Zinc / Q000737:chemistry
chemical_list: D003287:Contrast Media; D005290:Ferric Compounds; D008024:Ligands; D009942:Organometallic Compounds; D011728:Pyridones; D005682:Gadolinium; D015032:Zinc; D002118:Calcium