title: Structural, kinetic, and thermodynamic characterization of the interconverting isomers of MS-325, a gadolinium(III)-based magnetic resonance angiography contrast agent.
abstract: The amphiphilic gadolinium complex MS-325 ((trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl] diethylenetriaminepentaacetato) (aquo)gadolinium(III)}) is a contrast agent for magnetic resonance angiography (MRA). MS-325 comprises a GdDTPA core with an appended phosphodiester moiety linked to a diphenylcyclohexyl group to facilitate noncovalent binding to serum albumin and extension of the plasma half-life in vivo. The chiral DTPA ligand (R) was derived from L-serine, and upon complexation with gadolinium, forms two interconvertible diastereomers, denoted herein as isomers A and B. X-ray crystallography of the tris(ethylenediamine)cobalt(III) salt derivative of isomer A revealed a structure in the polar acentric space group P32. The structure consisted of three independent molecules of the gadolinium complex in the asymmetric unit along with three Delta-[Co(en)3]3+ cations, and it represents an unusual example of spontaneous Pasteur resolution of the cobalt cation. The geometry of the coordination core was best described as a distorted trigonal prism, and the final R factor was 5.6%. The configuration of the chiral central nitrogen of the DTPA core was S. The Gd-water (2.47-2.48 A), the Gd-acetate oxygens (2.34-2.42 A), and the Gd-N bond distances (central N, 2.59-2.63 A; terminal N, 2.74-2.80 A) were similar to other reported GdDTPA structures. The structurally characterized single crystal was one of two interconvertable diastereomers (isomers A and B) that equilibrated to a ratio of 1.81 to 1 at pH 7.4 and were separable at elevated pH by ion-exchange chromatography. The rate of isomerization was highly pH dependent: k1 = (1.45 +/- 0.08) x 102[H+] + (4.16 +/- 0.30) x 105[H+]2; k-1 = (2.57 +/- 0.17) x 102[H+] + (7.54 +/- 0.60) x 105[H+]2.
authors.affiliation: EPIX Pharmaceuticals Inc, Cambridge, MA 02142, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Tyeklar
authors.forename: Stephen U
authors.initials: SU
authors.lastname: Dunham
authors.forename: Katarina
authors.initials: K
authors.lastname: Midelfort
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Scott
authors.forename: Hirano
authors.initials: H
authors.lastname: Sajiki
authors.forename: Karen
authors.initials: K
authors.lastname: Ong
authors.forename: Randall B
authors.initials: RB
authors.lastname: Lauffer
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McMurry
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003287:Contrast Media / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005682:Gadolinium / Q000737:chemistry* / Q000494:pharmacology; D019786:Gadolinium DTPA / Q000737:chemistry; D007700:Kinetics; D018810:Magnetic Resonance Angiography / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D004369:Pentetic Acid / Q000737:chemistry; D020033:Protein Isoforms; D012694:Serine / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; D020033:Protein Isoforms; D012694:Serine; D004369:Pentetic Acid; D005682:Gadolinium; D019786:Gadolinium DTPA; D009584:Nitrogen; C109932:gadofosveset trisodium