Gd-complexes of DTPA-bis(amide) conjugates of tranexamic acid and its esters with high relaxivity and stability for magnetic resonance imaging

The synthesis and the characterization of a series of DTPA-bis(amide) conjugates of tranexamic acid (L1), its esters (L2- L6), and their Gd(III) complexes of the type [Gd(L)(H(2)O)] center dot nH(2)O (L = L1-L6) are described. Except for the case of L1, all Gd-complexes exhibit greatly enhanced R(1) relaxivity. Highest R1 reaches up to 12.9 mM(-1) s(-1) for [Gd(L(2))(H(2)O)]. Such high relaxivity is reflected in the intensity enhancement of the in vivo MRI study on H-ras transgenic mice bearing hepatic tumor when employing [ Gd( L2)( H2O)] as an MRI contrast agent. Thermodynamic stability constants, conditional stability constants, and the pM values demonstrate higher stability of [Gd(L)(H(2)O)] center dot nH(2)O (L = L1-L6) than Omniscan (R) under physiological conditions. The MTT assay performed on these complexes reveals cytotoxicity as low as that for Omniscan (R) in the concentration range required to obtain intensity enhancement in the in vivo MRI study.