Exceptional stability of a Gd-free extracellular fluid MRI contrast agent based on manganese porphyrin

Metal-ligand stability plays a central role in medicinal bioinorganic chemistry, as it impacts not only the efficacy but also the safety profiles of metal-based therapeutic and diagnostic agents. Gadolinium-based contrast agents (GBCAs) have been widely applied in clinical magnetic resonance imaging (MRI) scans for decades to enhance the detection of otherwise hardly visible diseases. However, evidence of metal dissociation from Gd chelates in vivo have raised safety concerns and led to the withdrawals of several clinically approved GBCAs in recent years. Here we report an exceptionally high stability of Mn(III)tetracarboxylporphyrin (MnTCP), a Gd-free extracellular fluid CA with high MRI contrast enhancement efficiency at clinic magnetic fields. The stability of MnTCP was systematically investigated under challenging conditions known to cause metal dissociation or transmetallation of GBCAs, as well as most other chelated metal complexes. The kinetic inertness of MnTCP was demonstrated at low pH and high temperature, and no sign of metal dissociation was observed. Incubation of MnTCP with excess of various endogenous metal ions, as well as metal chelators also did not cause any observable transmetalation under neutral or acidic conditions up to 50 days. Moreover, MnTCP is highly stable against reduction by endogenous species, preventing the formation of labile Mn(II)-complex. These findings are consistent with in vivo and intracellular behaviors of MnTCP observed in previous studies. The abnormally high stability of this tetradentate coordination complex can be attributed to structural rigidity, aromaticity and strong metal-ligand orbital interactions.