Manganese-Based Contrast Agents for Magnetic Resonance Imaging of Liver Tumors: Structure–Activity Relationships and Lead Candidate Evaluation

Gd-based MRI contrast agents (GBCAs) have come under intense regulatory scrutiny due to concerns of Gd retention and delayed toxicity. Three GBCAs comprising acyclic Gd chelates, the class of GBCA most prone to Gd release, are no longer marketed in Europe. Of particular concern are the acyclic chelates that remain available for liver scans, where there is an unmet diagnostic need and no replacement technology. To address this concern, we evaluated our previously reported Mn-based MRI contrast agent, Mn-PyC3A, and nine newly synthesized derivatives as liver specific MRI contrast agents. Within this focused library the transient liver uptake and rate of blood clearance are directly correlated with log P. The complex Mn-PyC3A-3-OBn emerged as the lead candidate due to a combination of high relaxivity, rapid blood clearance, and avid hepatocellular uptake. Mn-PyC3A-3-OBn rendered liver tumors conspicuously hypo-intense in a murine model and is wholly eliminated within 24 h of injection.