Thermodynamic stability and kinetic inertness of MS-325, a new blood pool agent for magnetic resonance imaging

Stability constants were measured for complexes formed between a modified D TPA ligand and the metal ions Gd(III), Eu(III), Fe(III), Ca(II) Cu(II), and Zn(II) at 25 degreesC in 0.1 M NaClO4. The gadolinium complex of this liga nd is MS-325. a novel blood pool contrast agent for magnetic resonance imag ing currently undergoing clinical trials. Stability constants were determin ed by 4 different methods: direct pH titration, pH titration with competiti on by EDTA, competition with DTPA using an HPLC-MS detection system, and co mpetition with Eu(III) by monitoring equilibrium by luminsecence spectrosco py. The 1:1 stability constants, log beta (101) are the following: Gd, 22.0 6 (23.2 in 0.1 M Me4NCl): Eu, 22.21; Fe, 26.66; Ca, 10.45; Cu, 21.3; Zn, 17 .82. The exchange kinetics of the Gd complex, MS-325, with the radioactive tracer (EU)-E-152,154 were studied at 25 degreesC: in 0.1 M NaClO4. The exc hange reaction has acid-dependent and acid-independent terms. The rate expr ession is given by the following: R = k(a)[GdL][H](2) + k(b)[GdL][Gd][H] k(c)[GdL][Gd]. The rate constants were determined to be the following: ka = 1.84 x 10(6) M(-2)min(-1), k(b) = 2.87 x 10(3) M(-2)min(-1), k(c) = 3.72 x 10(-3) M(-1)min(-1). MS-325 is 2-3 times more stable than GdDTPA at pH 7.4 and is 10-100 times more kinetically inert.