Design of Mn(1,4-DO2A) derivatives as stable and inert contrast agents for magnetic resonance imaging

Manganese(II) is considered a valuable alternative to gadolinium(III) in developing contrast agents (CAs) for magnetic resonance imaging (MRI). However, due to the labile nature of common Mn(II) complexes, designing ligands that enable stable and inert complexation is essential before clinical application. Mn(1,4-Et4DO2A) bearing four ethyl groups, is found to have a log K_MnL as high as 17.86, together with a pMn of 7.52 at pH 7.4. Kinetically, Mn(1,4-Et4DO2A) is approximately 20 times more inert than Mn(1,4-DO2A) in the presence of a 25-fold excess of Zn(II) at pH 6.0 and 37 °C, with the incorporation of a benzoic group to one pendant arm extending the half-life time (t_1/2) to around 22 hours. Its r₁ is measured as 2.34 and 2.20 mM⁻¹ s⁻¹ at 310 K and 1.5 and 3.0 T, respectively, representing an approximate 50% increase compared to Mn(1,4-DO2A). Mn(1,4-Et4DO2A) shows hepatic preference in mice, and its efficacy in diagnosing orthotopic hepatocellular carcinoma (HCC) is also confirmed.