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

Abstract

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 vivoMRI 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)(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 vivoMRI study.