Peter Mareski

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.

A new polysaccharide macromolecular contrast agent for MR imaging: Biodistribution and imaging characteristics

The aims of this study were to characterize certain physicochemical, pharmacokinetic, and enhancement properties of a new macromolecular contrast agent, carboxymethyl hydroxyethyl starch‐(Gd‐DO3A)35 [CMHES‐(Gd‐DO3A)35], consisting of a polysaccharide backbone covalently derivatized with multiple macrocyclic chelating groups for gadolinium. CMHES‐(Gd‐DO3A)35 has an average molecular weight of 72 kD and a plasma half‐time of 8.4 hours. T1 and T2 relaxivities are 14.1 ± 0.1 L mmol−1 • sec−1 and 17.8 ± 0.9 L mmol−1 • sec−1, respectively, for each gadolinium ion measured at 39°C and 20 Mhz; this T1 relaxivity is more than 4 times that of gadopentetate. Seven days after intravenous administration only relatively small amounts of gadolinium could be detected in blood or other tissues of rats. The compound was well tolerated in diagnostic dosages by all experimental animals. Magnetic resonance angiography performed within 1 hour of CMHES‐(Gd‐DO3A)35 administration showed a near‐constant and strong enhancement of blood in arteries and veins. Analysis of dynamic enhancement patterns of experimental tumors (MAT‐LyLu prostate cancer implanted in rats) following intravenous CMHES‐(Gd‐DO3A)35 administration yielded quantitative estimates of tumor plasma volume and microvessel permeability; the demonstrated hyperpermeability of tumor microvessels was easily distinguished from the absence of measurable microvascular permeability in non‐neoplastic soft tissues. J. Magn. Reson. Imaging 2000;11:694–701.