مرکز منطقه ای اطلاع رساني علوم و فناوري - Evaluating Hepatobiliary Transport with 18F-Labeled Bile Acids: The Effect of Radiolabel Position and Bile Acid Structure on Radiosynthesis and In Vitro and In Vivo Performance

Author/Authors :

Lombaerde, Stef De Ghent University - Ottergemsesteenweg - Ghent, Belgium , Kersemans, Ken Ghent University Hospital - Department of Nuclear Medicine - De Pintelaan - Ghent, Belgium , Neyt, Sara Ghent University - Ottergemsesteenweg - Ghent, Belgium , Verhoeven, Jeroen Ghent University - Ottergemsesteenweg - Ghent, Belgium , Vanhove, Christian Ghent University - Ghent, Belgium , De Vos, Filip Ghent University - Ottergemsesteenweg - Ghent, Belgium

Abstract :

An in vivo determination of bile acid hepatobiliary transport efciency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET-) imaging, a further understanding of the impact of 18-fuorine substitution on bile acid handling in vitro and in vivo can be of signifcance. Methods. A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fuoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fuorine atom (3β-[18F]FCA; 7β-[18F]FCA; 12β-[18F]FCA); a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3β-[18F]FGCA and 3β-[18F]FCDCA, resp.). Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (β=3 per group): hepatobiliary transport was monitored and compared to a reference tracer, namely, 3β-[18F]FCA. Results. Compounds 3β-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA were synthesized in moderate radiochemical yields (4–10% n.d.c.) and high radiochemical purity (>99%); 7β- [ 18F]FCA and 12β-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3β-FCA, 3β-FGCA, and 3β-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3β-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA displayed hepatobiliary transport with varying efciency. A slight yet signifcant diference in uptake and efux rate was noticed between the 3β-[18F]FCA and 3β-[18F]FCA epimers. Conjugation of 3β-[18F]FCA with glycine had no signifcant efect in vivo. Compound 3β-[18F]FCDCA showed a signifcantly slower hepatic uptake and efux towards gallbladder and intestines. Conclusion. A set of 18F labeled bile acids was synthesized that are substrates of the bile acid transportersin vitro and in vivo and can serve as PET-biomarkers for hepatobiliary transport of bile acids.