We require a Mn complex that possesses relaxivity ( r 1 = (Δ1/T 1) normalized to mM contrast agent) that is comparable or better than GBCAs.

metastases) or OATP under-expressing cells (primary liver cancers), are rendered conspicuously hypo-intense against normal liver during the delayed phase.Ī number of design criteria must be met in developing a suitable Mn complex for liver-specific imaging. 22, 23 Malignancies, which are comprised of non-OATP expressing cells (ie. 38 Both liver tumors and benign abnormalities such as focal nodular hyperplasia can be avidly enhanced by contrast agents during the arterial, venous, or extracellular phases of distribution, but OATP-mediated hepatocellular uptake enables differential diagnosis during what is referred to as the delayed phase (15–60 min post injection) when the blood signal is diminished but liver enhancement is strong. The liver specificity of Gd-DTPA-EOB and Gd-BOPTA is imparted by peripheral lipophilic functional groups that promote recognition by organic anion transporting peptides (OATPs) that are abundantly expressed on the cell membranes of hepatocytes lining biliary sinusoids. 37Ī new liver-specific agent should be a direct replacement for the GBCA standard of care. 36 Unlike Gd, Mn is a trace nutritional element that the human body can incorporate or excrete as required, avoiding concerns of long-term accumulation. Mn 2+ is one of the few ions that can generate MRI contrast that is comparable to Gd 3+. We posit that a Mn complex is the most likely GBCA alternative to succeed as a clinically viable agent. 34, 35 In this regard, we sought to develop a Gd-free liver-specific contrast agent. 24– 33 Considerably less effort has been placed on developing Gd-free liver-specific agents despite the fact that liver cancer and metastatic liver disease are among the leading causes of cancer related death. Most research to date has focused on developing extracellular agents. The rising concerns over GBCA safety have underscored a pressing urgency to develop Gd-free MRI contrast agents.

Differential diagnosis cannot be made using ultrasound imaging, CT, or contrast-free MRI. 22, 23 There are no liver specific macrocyclic GBCAs or iodinated computed tomography (CT) contrast agents. 19– 21 EMA has allowed two acyclic agents, Gd-DTPA-EOB and Gd-BOPTA, to remain available but according to the EMA 2017 statement these agents are now restricted “to be used for liver scans because they are taken up in the liver and meet an important diagnostic need.” 15 Liver-specific agents enable high-sensitivity detection of liver metastases, differential diagnosis of malignant tissue from benign abnormalities, and staging of hepatocellular lesions. 15– 18 However, long-term Gd retention is also documented in patients that have exclusively received macrocyclic GBCAs. 10– 15 In 2017, the FDA announced a new class warning for all GBCAs and the European Medicines Agency suspended marketing authorizations for three of the five Gd-based agents comprised of acyclic chelators, which are more prone to Gd release than the class of agents comprised of macrocyclic chelators ( Figure S1). benefit of GBCAs in response to well-documented safety concerns related to long-term Gd retention. 1– 9 However, regulatory agencies are currently re-assessing the risk vs. Gd-based MRI contrast agents (GBCAs) are heavily relied upon for the radiologic diagnosis of tissue and vascular abnormalities.

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