Liver Specific Manganese Based MRI Contrast Agent

Project SummaryAbstract Hepatocellular carcinomaHCCis the second most common cause of cancer death worldwide and HCC mortality is increasing at a faster rate than any other cancerMetastatic liver disease occurs with greater frequency than HCC and is also associated with high mortality ratesThere is a significant survival benefit associated with early detection of liver tumorsHoweverthe liver specific gadoliniumGdbased MRI contrast agentsGBCAswhich are the radiologic standard of care for diagnoses of liver malignances do not optimally meet clinical needs and have come under intense regulatory scrutiny over concerns of Gd retention and delayed Gd associated toxicityThe two GBCAs used for liver imagingGd EOB DTPA and Gd BOPTAbelong to the class of GBCAs comprised of acyclic chelatorswhich are associated with the highest risk of Gd releaseThe European Medicines Agency suspended the marketing authorizations for theacyclic extracellular fluid GBCAsbut allowed the GBCAs used for liver specific imaging to remain available for restricted use in liver scans because these agents satisfy the need for diagnosis of liver cancer and metastatic liver diseaseGd EOB DTPA and GdBOPTA provide initial dynamic phase enhancement of hypervascular structuresand subsequently accumulate in hepatocytes via the action of organic anion transporter peptidesOATPsresulting in hepatocellular enhancement on delayed phase imagingThe different contrasts observed in lesions during dynamic and delayed phase imaging enable differential diagnosis of liver malignancies from commonbenign abnormalitiesHoweverthe dynamic enhancement of delayed phase lesions is poor with Gd EOB DTPA compared to GdBOPTAbut the delayed phase enhancement with Gd BOPTA is lower than with Gd EOBDTPA and is performedhour post injectionlimiting patient throughputOur solution to these problems is to develop a Gdfree liver specific contrast agent with optimized dynamic and delayed phase contrast propertiesReveal Pharmaceuticals has demonstrated that the extracellular manganeseMnbased contrast agent RVPaka Mn PyC Aprovides equivalent extracellular contrast to GBCAsdoes not release free Mnionand is more effectively eliminated from the body than GBCAsIn this FastTrack application we will develop OATP targeted contrast agents that utilize the chemically stablehigh relaxivity Mn PyC A core for liver specific imagingIn Phase I we will identify a lead candidate and demonstrate strongconspicuous enhancement of liver tumors in humanized OATP knock in miceIn Phase II we will perform lead optimization with respect to relaxivitypharmacokineticssafetyand liver image contrastand select a development candidateDCfor ultimate clinical translationWe will validate our DC in rat and rabbit models of liver cancerand evaluate its safety in ratsWe will develop a scalablecost effective synthesis of the DC for technology transfer to a cGMP manufacturer Project Narrative Liver cancer is the second most common cause of cancer death worldwide and the frequency of liver cancer mortality is increasing at a faster rate than another other cancerOther common cancersbreastcolorectalmelanomaalso metastasize to the liverCurrent liver specific MRI contrast agents have high sensitivity to detect disease but have technical limitations and all utilize the toxic metal ion gadoliniumThis FastTrack application focuses on addressing this need by creating a technically superior liver specific contrast agent that does not contain gadolinium