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

Stef De Lombaerde; Lindsey Devisscher; Jeroen Verhoeven; Sara Neyt; Hans Van Vlierberghe; Christian Vanhove; Filip De Vos

doi:10.1016/j.nucmedbio.2018.12.001

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

Nucl Med Biol. 2019 Jan-Feb:68-69:40-48. doi: 10.1016/j.nucmedbio.2018.12.001. Epub 2018 Dec 8.

Authors

Stef De Lombaerde¹, Lindsey Devisscher², Jeroen Verhoeven³, Sara Neyt³, Hans Van Vlierberghe², Christian Vanhove⁴, Filip De Vos³

Affiliations

¹ Faculty of Pharmaceutical Sciences, Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium. Electronic address: stef.delombaerde@ugent.be.
² Ghent University Hospital, Gastroenterology and Hepatology, Ghent, Belgium.
³ Faculty of Pharmaceutical Sciences, Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium.
⁴ IBiTech-MEDISIP-INFINITY, Ghent University, Ghent, Belgium.

PMID: 30595544
DOI: 10.1016/j.nucmedbio.2018.12.001

Abstract

Recently, our research group reported on the development of 3β-[¹⁸F]Fluorocholic acid (3β-[¹⁸F]FCA), a ¹⁸F labeled bile acid to detect drug interference with the bile acid transporters (drug-induced cholestasis). It was hypothesized that 3β-[¹⁸F]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-[¹⁸F]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-[¹⁸F]FCA was not significantly altered after an APAP overdose. Mice fed the DDC or MCD diet showed impaired transport of 3β-[¹⁸F]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-[¹⁸F]FCA parameters returned to baseline. Global hepatobiliary transport of 3β-[¹⁸F]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-[¹⁸F]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-[¹⁸F]FCA as a PET tracer to monitor altered liver functionality in patients with chronic liver diseases.

Keywords: Bile acid; Liver; Liver disease; PET.

Publication types

Validation Study

MeSH terms

Animals
Biliary Tract / diagnostic imaging*
Biliary Tract / metabolism*
Biological Transport
Cholic Acids*
Disease Models, Animal
Liver / diagnostic imaging*
Liver / metabolism
Liver / physiopathology*
Liver Diseases / diagnostic imaging*
Liver Diseases / metabolism
Liver Diseases / physiopathology*
Male
Mice
Positron-Emission Tomography / methods*

Substances

3beta-(18F)FCA
Cholic Acids