Repurposing 99mTc-1 mebrofenin as a probe for molecular imaging of hepatocyte 2 transporters.

Hepatocyte transporters control the hepatobiliary elimination of many drugs, metabolites and endogenous substances. Hepatocyte transporter function is altered in several pathophysiological situations and can be modulated by certain drugs, with a potential impact for pharmacokinetics and drug-induced liver injury. Development of substrate probes with optimal properties for selective and quantitative imaging of hepatic transporters remains a challenge. [99mTc]mebrofenin has been used for decades for hepatobiliary scintigraphy, but the specific transporters controlling its liver kinetics have been characterized more recently. These include sinusoidal influx transporters (organic anion-transporting polypeptides, OATP) responsible for hepatic uptake of [99mTc]mebrofenin, and efflux transporters (multidrug resistance-associated proteins, MRP) mediating its canalicular (liver-to-bile) and sinusoidal (liver-to-blood) excretion. Pharmacokinetic modeling enables molecular interpretation of [99mTc]mebrofenin scintigraphy data, thus offering a widely available translational method to investigate transporter-mediated drug-drug interactions in vivo. [99mTc]mebrofenin allows for phenotyping transporter activity at the different poles of hepatocytes as a biomarker of liver function.