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)(H₂O)]•nH₂O (L = L1-L6) are described. Except for the case of L1, all Gd-complexes exhibit greatly enhanced R₁ relaxivity. Highest R₁ reaches up to 12.9 mM^-1 s^-1 for [Gd(L2)(H₂O)]. 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)(H ₂O)] as an MRI contrast agent. Thermodynamic stability constants, conditional stability constants, and the pM values demonstrate higher stability of [Gd(L)(H₂O)]•nH₂O (L = L1-L6) than Omniscan® under physiological conditions. The MTT assay performed on these complexes reveals cytotoxicity as low as that for Omniscan® in the concentration range required to obtain intensity enhancement in the in vivo MRI study.