Structural, Kinetic, and Thermodynamic Characterization of the Interconverting Isomers of MS-325, a Gadolinium(III)-Based Magnetic Resonance Angiography Contrast Agent

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 Δ-[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 Å), the Gd−acetate
oxygens (2.34−2.42 Å), and the Gd−N bond distances (central N, 2.59−2.63 Å; terminal N, 2.74−2.80 Å) 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) × 102[H+] + (4.16 ± 0.30) × 105[H+]2; k-1 = (2.57 ± 0.17) × 102[H+] + (7.54 ± 0.60) × 105[H+]2.