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

Abstract

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.

Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups

“…Solutions contained 0.4 mM Fe(III) complex and 4.5 % (w/v) HSA (0.7 mM). The binding percentages were measured by using ICP-MS to analyze the Fe concentration in the unbound complex solutions after HSA incubation (Table 1) [20,37,42,44,60]. The protein binding for Fe(L3)(OH 2 ) was higher (75%) than for Fe(L1)(OH 2 ) (37%) or Fe(L2) (11%).…”

“…There has been much progress in the development of Mn(II) complexes as MRI probes [9][10][11][12][13]. However, despite the prominent role of iron in human biology, there are significantly fewer studies on Fe(III)-based contrast agents [14][15][16][17][18][19][20].…”

“…Lipophilic and anionic complexes tend to bind more tightly to human serum albumin (HSA) [37,[40][41][42][43]. Structure-activity studies show that aryl groups and anionic substitutents increase HSA binding and influence the pharmacokinetics of Gd(III) and Mn(II) contrast agents [7,20,37,44]. Moreover, interaction of contrast agents with cell membrane receptor proteins may influence the clearance pathway in animals.…”

“…Moreover, interaction of contrast agents with cell membrane receptor proteins may influence the clearance pathway in animals. For example, contrast agents that are taken up by organic anionic receptors on hepatocytes clear through the hepatobiliary route and are used for liver imaging [20,22,45,46].…”

Integration of gadolinium in nanostructure for contrast enhanced‐magnetic resonance imaging

“…Among the contrast agents, MRI CAs are safer when compared to those used in X‐ray/CT scans and nuclear medicine. The commonly used CAs in Ce‐MRI includes Gd 3+ , Mn 2+ , and Fe 3+ complexes (Gale & Caravan, ; Thanh Nguyen, Pitchaimani, Ferrel, Thakkar, & Aryal, ; Wahsner et al, ; Wang et al, ). Among these CAs, the majority of Ce‐MRI is attributed to GBCAs due to their bright contrast due to its high magnetic moment, better thermodynamic, and kinetic stability in‐vivo (Gizzatov et al, ; Schroeder, Clarke, Neubauer, & Tyler, ).…”