S. Aime et al., GD(III) COMPLEXES AS CONTRAST AGENTS FOR MAGNETIC-RESONANCE-IMAGING -A PROTON RELAXATION ENHANCEMENT STUDY OF THE INTERACTION WITH HUMAN SERUM-ALBUMIN, JBIC. Journal of biological inorganic chemistry, 1(4), 1996, pp. 312-319
The non-covalent interaction between human serum albumin (HSA) and DOT
A-like Gd(III) complexes containing hydrophobic benzyloxymethyl (BOM)
substituents has been thoroughly investigated by measuring the solvent
proton relaxation rates of their aqueous solutions. The binding assoc
iation constants (K-A) to HSA are directly related to the number of hy
drophobic substituents present on the surface of the complexes. Furthe
rmore, an estimation of Delta H degrees and Delta S degrees has been o
btained by the temperature dependence of K-A. Assays performed with th
e competitor probes warfarin and ibuprofen established that the comple
xes interact with HSA through two nearly equivalent binding sites loca
ted in the subdomains IIA and IIIA of the protein. Strong relaxation e
nhancements, promoted by the formation of slowly tumbling paramagnetic
adducts, have been measured at 20 MHz for complexes containing two an
d three hydrophobic substituents. The macromolecular adduct with the l
atter species has a relaxivity of 53.2 +/- 0.7 mM(-1) s(-1), which rep
resents the highest value so far reported for a Gd(III) complex. The t
emperature dependence of the relaxivity for the paramagnetic adducts w
ith HSA indicates long exchange lifetimes for the water molecules dipo
larly interacting with the paramagnetic centre. This is likely to be r
elated to the formation, upon hydrophobic interaction of the complexes
with HSA, of a clathrate-like, second-coordination-sphere arrangement
of water molecules. Besides affecting the dissociative pathway of the
coordinated water molecule, this water arrangement may itself signifi
cantly contribute to enhancement of the bulk solvent relaxation rate.