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Drug-induced cholestasis is a liver disorder that might be caused by interference of drugs with the hepatobiliary bile acid transporters. It is important to identify this interference early on in drug development. In this work,  Positron Emission Tomography  (PET)-imaging with a  18 F labeled bile acid analogue was introduced to detect disturbed hepatobiliary transport of bile acids.    Methods  3β-[ 18 F]fluorocholic acid ([ 18 F]FCA) was prepared by nucleophilic substitution of a mesylated precursor with [ 18 F]fluoride, followed by deprotection with sodium hydroxide. Transport of [ 18 F]FCA was assessed  in vitro  using CHO-NTCP, HEK-OATP1B1, HEK-OATP1B3 transfected cells and BSEP & MRP2 membrane vesicles. Investigation of [ 18 F]FCA metabolites was performed with primary mouse hepatocytes. Hepatobiliary transport of [ 18 F]FCA was evaluated  in vivo  in wild-type, rifampicin and bosentan pretreated FVB-mice by dynamic μPET scanning.    Results  Radiosynthesis of [ 18 F]FCA was achieved in a moderate radiochemical yield (8.11 ± 1.94%; non-decay corrected; n = 10) and high radiochemical purity (>99%). FCA was transported by the basolateral bile acid uptake transporters NTCP, OATP1B1 and OATP1B3. For canalicular efflux, BSEP and MRP2 are the relevant bile acid transporters. [ 18 F]FCA was found to be metabolically stable.  In vivo , [ 18 F]FCA showed fast hepatic uptake (4.5 ± 0.5 min to reach 71.8 ± 1.2% maximum % ID) and subsequent efflux to the gallbladder and intestines (93.3 ± 6.0% ID after 1 hour). Hepatobiliary transport of [ 18 F]FCA was significantly inhibited by both rifampicin and bosentan.    Conclusion  A  18 F labeled bile acid analogue, [ 18 F]FCA, has been developed that shows transport by NTCP, OATP, MRP2 and BSEP. [ 18 F]FCA can be used as a probe to monitor disturbed hepatobiliary transport  in vivo  and accumulation of bile acids in blood and liver during drug development.

Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice