Validation of hepatobiliary transport PET imaging in liver function assessment : evaluation of 3β-[18F]FCA in mouse models of liver disease

Abstract Recently, our research group reported on the development of 3β-[ 18 F]Fluorocholic acid (3β-[ 18 F]FCA), a 18 F labeled bile acid to detect drug interference with the bile acid transporters (drug-induced cholestasis). It was hypothesized that 3β-[ 18 F]FCA could also be used as a non-invasive tool to monitor (regional) liver function in vivo in different liver diseases through altered expression of bile acid transporters. Methods Hepatobiliary transport of 3β-[ 18 F]FCA was evaluated in four murine liver disease models. Acute liver injury was induced by oral gavage of an acetaminophen (APAP) overdose (300 mg/kg). Chronic cholangiopathy and non-alcoholic steatohepatitis (NASH) were induced by feeding mice 3,5-diethoxycarbonyl- 1,4-dihydrocollidine (DDC) diet or methionine and choline deficient (MCD) diet, respectively. Hepatocellular carcinoma (HCC) was evoked by intraperitoneal injection of 35 mg/kg diethylnitrosamine (DEN) once a week for 23 weeks. Gene expression of the murine bile acid transporters was determined by RT-qPCR. Results Hepatobiliary transport of 3β-[ 18 F]FCA was not significantly altered after an APAP overdose. Mice fed the DDC or MCD diet showed impaired transport of 3β-[ 18 F]FCA compared to baseline, which was associated with altered expression of the bile acid transporters ntcp, oatp4 and mrp2. After recovery from DDC- and MCD-induced liver injury, 3β-[ 18 F]FCA parameters returned to baseline. Global hepatobiliary transport of 3β-[ 18 F]FCA in HCC bearing mice was not significantly different compared to control mice. However, HCC lesions showed reduced hepatic uptake of the tracer (tumor-to-background: 0.45 ± 0.13), which was in line with decreased in expression of basolateral bile acid uptake transporters nctp and oatp4 in tumor tissue. Conclusion 3β-[ 18 F]FCA is a useful tool to assess and longitudinally follow-up liver function in several mouse models for liver diseases that are associated with altered expression of the bile acid transporters. These results point towards the (pre)clinical utility of 3β-[ 18 F]FCA as a PET tracer to monitor altered liver functionality in patients with chronic liver diseases.