Synthesis, in vitro and in vivo evaluation of 3β-18Ffluorocholic acid for the detection of drug-induced cholestasis in miceReportar como inadecuado

Synthesis, in vitro and in vivo evaluation of 3β-18Ffluorocholic acid for the detection of drug-induced cholestasis in mice - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.


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 18F labeled bile acid analogue was introduced to detect disturbed hepatobiliary transport of bile acids.


3β-18Ffluorocholic acid 18FFCA was prepared by nucleophilic substitution of a mesylated precursor with 18Ffluoride, followed by deprotection with sodium hydroxide. Transport of 18FFCA was assessed in vitro using CHO-NTCP, HEK-OATP1B1, HEK-OATP1B3 transfected cells and BSEP and MRP2 membrane vesicles. Investigation of 18FFCA metabolites was performed with primary mouse hepatocytes. Hepatobiliary transport of 18FFCA was evaluated in vivo in wild-type, rifampicin and bosentan pretreated FVB-mice by dynamic μPET scanning.


Radiosynthesis of 18FFCA 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. 18FFCA was found to be metabolically stable. In vivo, 18FFCA 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 18FFCA was significantly inhibited by both rifampicin and bosentan.


A 18F labeled bile acid analogue, 18FFCA, has been developed that shows transport by NTCP, OATP, MRP2 and BSEP. 18FFCA 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.

Autor: Stef De Lombaerde , Sara Neyt, Ken Kersemans, Jeroen Verhoeven, Lindsey Devisscher, Hans Van Vlierberghe, Christian Vanhove, Fili



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