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When are Two Waters Worse Than One? Doubling the Hydration Number of a Gd–DTPA Derivative Decreases Relaxivity
Author(s) -
Caravan Peter,
Amedio John C.,
Dunham Stephen U.,
Greenfield Matthew T.,
Cloutier Normand J.,
McDermid Sarah A.,
Spiller Marga,
Zech Stephan G.,
Looby Richard J.,
Raitsimring Arnold M.,
McMurry Thomas J.,
Lauffer Randall B.
Publication year - 2005
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200500338
Subject(s) - chemistry , ligand (biochemistry) , human serum albumin , molecule , metal , nuclear magnetic resonance spectroscopy , crystallography , proton , gadolinium , derivative (finance) , stereochemistry , receptor , organic chemistry , chromatography , biochemistry , physics , quantum mechanics , financial economics , economics
The synthesis of a novel ligand, based on N ‐methyl‐diethylenetriaminetetraacetate and containing a diphenylcyclohexyl serum albumin binding group ( L 1 ) is described and the coordination chemistry and biophysical properties of its Gd III complex Gd – L 1 are reported. The Gd III complex of the diethylenetriaminepentaacetate analogue of the ligand described here ( L 2 ) is the MRI contrast agent MS‐325. The effect of converting an acetate to a methyl group on metal–ligand stability, hydration number, water‐exchange rate, relaxivity, and binding to the protein human serum albumin (HSA) is explored. The complex Gd – L 1 has two coordinated water molecules in solution, that is, [Gd( L 1 )(H 2 O) 2 ] 2− as shown by D‐band proton ENDOR spectroscopy and implied by 1 H and 17 O NMR relaxation rate measurements. The GdH water distance of the coordinated waters was found to be identical to that found for Gd – L 2 , 3.08 Å. Loss of the acetate group destabilizes the Gd III complex by 1.7 log units (log K ML =20.34) relative to the complex with L 2 . The affinity of Gd – L 1 for HSA is essentially the same as that of Gd – L 2 . The water‐exchange rate of the two coordinated waters on Gd – L 1 ( k ex =4.4×10 5 s −1 ) is slowed by an order of magnitude relative to Gd – L 2 . As a result of this slow water‐exchange rate, the observed proton relaxivity of Gd – L 1 is much lower in a solution of HSA under physiological conditions ( ${r{{{\rm obs}\hfill \atop 1\hfill}}}$ =22.0 m M −1 s −1 for 0.1 m M Gd – L 1 in 0.67 m M HSA, HEPES buffer, pH 7.4, 35 °C at 20 MHz) than that of Gd – L 2 ( ${r{{{\rm obs}\hfill \atop 1\hfill}}}$ =41.5 m M −1 s −1 ) measured under the same conditions. Despite having two exchangeable water molecules, slow water exchange limits the potential efficacy of Gd – L 1 as an MRI contrast agent.