title: The effect of ligand scaffold size on the stability of tripodal hydroxypyridonate gadolinium complexes.
abstract: The variation of the size of the capping scaffold which connects the hydroxypyridonate (HOPO) binding units in a series of tripodal chelators for gadolinium (Gd) complexes has been investigated. A new analogue of TREN-1-Me-3,2-HOPO (1) (TREN = tri(ethylamine)amine) was synthesized: TREN-Gly-1-Me-3,2-HOPO (2) features a glycine spacer between the TREN cap and HOPO binding unit. TRPN-1-Me-3,2-HOPO (3) has a propylene-bridged cap, as compared to the ethylene bridges within the TREN cap of the parent complex. Thermodynamic equilibrium constants for the acid-base properties of 2 and the Gd(3+) complexation strength of 2 and 3 were measured and are compared with that of the parent ligand. The most basic ligand is 2 while 3 is the most acidic. Both 2 and 3 form Gd(3+) complexes of similar stability (pGd = 16.7 and 15.6, respectively) and are less stable than the parent complex Gd-1 (pGd = 19.2). Two of the three complexes are more stable than the bis(methylamide)diethylenetriamine pentaacetate complex Gd(DTPA-BMA) (pGd = 15.7) while the other is of comparable stability. Enlargement of the ligand scaffold decreases the stability of the Gd(3+) complexes and indicates that the TREN scaffold is superior to the TRPN and TREN-Gly scaffolds. The proton relaxivity of Gd-2 is 6.6 mM(-)(1) s(-)(1) (20 MHz, 25 degrees C, pH 7.3), somewhat lower than the parent Gd-1 but higher than that of the MRI contrast agents in clinical practice. The pH-independent relaxivity of Gd-2 is uncharacteristic of this family of complexes and is discussed.
authors.affiliation: Department of Chemistry, University of California, Berkeley, California 94720, USA.
authors.forename: Brendon
authors.initials: B
authors.lastname: O'Sullivan
authors.forename: Dan M J
authors.initials: DM
authors.lastname: Doble
authors.forename: Marlon K
authors.initials: MK
authors.lastname: Thompson
authors.forename: Carsten
authors.initials: C
authors.lastname: Siering
authors.forename: Jide
authors.initials: J
authors.lastname: Xu
authors.forename: Mauro
authors.initials: M
authors.lastname: Botta
authors.forename: Silvio
authors.initials: S
authors.lastname: Aime
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Raymond
mesh_terms: D003287:Contrast Media; D005682:Gadolinium / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D011728:Pyridones / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D003287:Contrast Media; D008024:Ligands; D009942:Organometallic Compounds; D011728:Pyridones; D005682:Gadolinium