Thomas Frenzel PhD, Presenter: Employee, Bayer AG, Berlin, Germany

Hans J. Weinmann PhD, Abstract Co-Author: Employee, Bayer AG

With respect to NSF, a severe disorder possibly linked to MRI contrast media, the in-vivo stability of Gd-complexes has gained new interest. It is described best by the conditional stability constant Kcond at pH 7.5. In this study the stability of Gd-complexes was determined experimentally at pH 7.5 in order to rank them according to their stability

Investigated compounds: Gd-EDTA, Gadoversetamide, Gadodiamide, Gd-DTPA, Gadoxetate, Gadobenate, Gadofosveset, Gadoteridol, Gadobutrol and Gadoterate. Each Gd-complex (GdL1) was incubated with the free ligand of another chelate (L2), both at 1 mmol/L in buffer (MOPS 20 mM, pH 7.5) at 90°C to speed up the Gd-exchange. GdL1 + L2 -> m*GdL1 + (1-m)*GdL2 + (1-m)*L1 + m*L2. At equilibrium the Gd-fractions m and 1-m in both ligands are a measure for the relative complex stability of L1 and L2. Where possible the complementary pairs (GdL1 + L2; GdL2 + L1) were prepared. The Gd-exchange was followed by HPLC-ICP-MS until equilibrium was reached and m and 1-m were obtained from peak area analysis

Open chain ligands (DTPA-type): Even at 90°C the Gd-exchange at pH 7.5 is slow. When complementary pairs were investigated the same values for m were obtained, indicating that equilibrium was reached after several days. The following order could be established: Gd-EDTA Macrocyclic ligands (DOTA-type): Even after several days at 90°C the Gd-exchange at pH 7.5 is incomplete and equilibrium was not reached. This confirms the generally accepted concept that the kinetic inertness of this class of Gd-complexes is more important than the stability constant for their in-vivo stability

The experimental data are in good agreement with published data for Kcond with only minor changes in the ranking between Gadobenate, Gadopentetate and Gadoxetate for which reported Kcond are very similar

MRI contrast media differ in their propensity to release Gd to other chelating competitors (proteins, phosphate) in blood.

Frenzel, T, Weinmann, H, Stability of MRI Contrast Media at pH 7.5.  Radiological Society of North America 2007 Scientific Assembly and Annual Meeting, November 25 - November 30, 2007 ,Chicago IL. http://archive.rsna.org/2007/5008654.html