Physicochemical Characterization of MS-325, a New Gadolinium Complex, by Multinuclear Relaxometry

The physicochemical characterization of MS-325 [trisodium {4-(R)-[(4,4-diphenylcyclohexyl)phosphanooxymethyl]-3,6,9-triaza-3,6,9-tris(methoxycarbonyl)undecanedioato}gadolinium(III)], a new derivative of Gd-DTPA {Magnevist®: dimeglumin [{3,6,9-triaza3,6,9-tris(methoxycarbonyl)undecanedioato}gadolinium(III)], presented as a potentially useful angiographic contrast agent, was carried out in various media. Water solution, protein-containing solution, phosphorylated metabolites solution, and Zn2+-containing solution were investigated using different NMR techniques such as water 1H nuclear magnetic relaxation rates, water 17O transverse relaxation rates, and 31P longitudinal relaxation rates of phosphorylated metabolites. The proton relaxivity of MS-325 in water was found to be higher than that of the parent compound Gd-DTPA; this can be attributed to the longer rotational correlation time (τR) of the hydrated complex, and possibly to an apparently shorter mean distance (r) between the protons of the coordinated water molecule and the gadolinium ion. The kinetic and thermodynamic stability of MS-325 in solutions containing phosphorylated metabolites (ATP, phosphocreatine and inorganic phosphate) were measured by 31P relaxation rate analysis and found to be higher than for Gd-DTPA. Similarly, the Zn2+ transmetallation process studied by proton relaxometry is slower than for the same reference compound. Finally, an analysis of the noncovalent binding of MS-325 to serum proteins by proton relaxometry showed that MS-325 interacts with human serum albumin (HSA) and that the association constant of this interaction is equal to 6100 ± 2130 M−1. A peak relaxivity of approx. 50 s−1mM−1 was determined at 25 MHz for the protein-bound paramagnetic complex. This value is lower than the maximal relaxivity predicted for a paramagnetic center totally immobilized at the surface of the protein.