title: When are two waters worse than one? Doubling the hydration number of a Gd-DTPA derivative decreases relaxivity.
abstract: The synthesis of a novel ligand, based on N-methyl-diethylenetriaminetetraacetate and containing a diphenylcyclohexyl serum albumin binding group (L1) is described and the coordination chemistry and biophysical properties of its Gd(III) complex Gd-L1 are reported. The Gd(III) complex of the diethylenetriaminepentaacetate analogue of the ligand described here (L2) 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-L1 has two coordinated water molecules in solution, that is, [Gd(L1)(H2O)2]2- as shown by D-band proton ENDOR spectroscopy and implied by 1H and 17O NMR relaxation rate measurements. The Gd-H(water) distance of the coordinated waters was found to be identical to that found for Gd-L2, 3.08 A. 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 L2. The affinity of Gd-L1 for HSA is essentially the same as that of Gd-L2. The water-exchange rate of the two coordinated waters on Gd-L1 (k(ex) = 4.4x10(5) s(-1)) is slowed by an order of magnitude relative to Gd-L2. As a result of this slow water-exchange rate, the observed proton relaxivity of Gd-L1 is much lower in a solution of HSA under physiological conditions (r1(obs) = 22.0 mM(-1) s(-1) for 0.1 mM Gd-L1 in 0.67 mM HSA, HEPES buffer, pH 7.4, 35 degrees C at 20 MHz) than that of Gd-L2 (r1(obs) = 41.5 mM(-1) s(-1)) measured under the same conditions. Despite having two exchangeable water molecules, slow water exchange limits the potential efficacy of Gd-L1 as an MRI contrast agent.
authors.affiliation: EPIX Pharmaceuticals, Inc., 67 Rogers Street, Cambridge, MA 02142-1118, USA. pcaravan@epixpharma.com
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
authors.forename: John C
authors.initials: JC
authors.lastname: Amedio
authors.forename: Stephen U
authors.initials: SU
authors.lastname: Dunham
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Greenfield
authors.forename: Normand J
authors.initials: NJ
authors.lastname: Cloutier
authors.forename: Sarah A
authors.initials: SA
authors.lastname: McDermid
authors.forename: Marga
authors.initials: M
authors.lastname: Spiller
authors.forename: Stephan G
authors.initials: SG
authors.lastname: Zech
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Looby
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Raitsimring
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McMurry
authors.forename: Randall B
authors.initials: RB
authors.lastname: Lauffer
mesh_terms: D003287:Contrast Media; D019786:Gadolinium DTPA / Q000737:chemistry*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D014462:Ultrafiltration; D014867:Water / Q000737:chemistry*
chemical_list: D003287:Contrast Media; D014867:Water; D019786:Gadolinium DTPA