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

Stef De Lombaerde (UGent) , Sara Neyt (UGent) , Ken Kersemans (UGent) , Jeroen Verhoeven (UGent) , Lindsey Devisscher (UGent) , Hans Van Vlierberghe (UGent) , Christian Vanhove (UGent) and Filip De Vos (UGent)
(2017) PLOS ONE. 12(3).
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Abstract
Introduction : 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 F-18 labeled bile acid analogue was introduced to detect disturbed hepatobiliary transport of bile acids. Methods : 3 beta-[F-18]fluorocholic acid ([F-18]FCA) was prepared by nucleophilic substitution of a mesylated precursor with [F-18]fluoride, followed by deprotection with sodium hydroxide. Transport of [F-18]FCA was assessed in vitro using CHO-NTCP, HEK-OATP1B1, HEK-OATP1B3 transfected cells and BSEP & MRP2 membrane vesicles. Investigation of [F-18]FCA metabolites was performed with primary mouse hepatocytes. Hepatobiliary transport of [F-18]FCA was evaluated in vivo in wild-type, rifampicin and bosentan pretreated FVB-mice by dynamic mu PET scanning. Results : Radiosynthesis of [F-18] 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. [F-18]FCA was found to be metabolically stable. In vivo, [F-18]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 [F-18]FCA was significantly inhibited by both rifampicin and bosentan. Conclusion : A F-18 labeled bile acid analogue, [F-18]FCA, has been developed that shows transport by NTCP, OATP, MRP2 and BSEP. [F-18]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.
Keywords
WHOLE-BODY DISTRIBUTION, INDUCED LIVER-INJURY, BILE-ACIDS, HEPATOBILIARY, TRANSPORTERS, OATP, POLYPEPTIDE, RECEPTOR, BOSENTAN, BIODISTRIBUTION, RADIOSYNTHESIS

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MLA
De Lombaerde, Stef, Sara Neyt, Ken Kersemans, et al. “Synthesis, in Vitro and in Vivo Evaluation of 3β-[18F]fluorocholic Acid for the Detection of Drug-induced Cholestasis in Mice.” PLOS ONE 12.3 (2017): n. pag. Print.
APA
De Lombaerde, S., Neyt, S., Kersemans, K., Verhoeven, J., Devisscher, L., Van Vlierberghe, H., Vanhove, C., et al. (2017). Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice. PLOS ONE, 12(3).
Chicago author-date
De Lombaerde, Stef, Sara Neyt, Ken Kersemans, Jeroen Verhoeven, Lindsey Devisscher, Hans Van Vlierberghe, Christian Vanhove, and Filip De Vos. 2017. “Synthesis, in Vitro and in Vivo Evaluation of 3β-[18F]fluorocholic Acid for the Detection of Drug-induced Cholestasis in Mice.” Plos One 12 (3).
Chicago author-date (all authors)
De Lombaerde, Stef, Sara Neyt, Ken Kersemans, Jeroen Verhoeven, Lindsey Devisscher, Hans Van Vlierberghe, Christian Vanhove, and Filip De Vos. 2017. “Synthesis, in Vitro and in Vivo Evaluation of 3β-[18F]fluorocholic Acid for the Detection of Drug-induced Cholestasis in Mice.” Plos One 12 (3).
Vancouver
1.
De Lombaerde S, Neyt S, Kersemans K, Verhoeven J, Devisscher L, Van Vlierberghe H, et al. Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice. PLOS ONE. 2017;12(3).
IEEE
[1]
S. De Lombaerde et al., “Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice,” PLOS ONE, vol. 12, no. 3, 2017.
@article{8516440,
  abstract     = {Introduction : 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 F-18 labeled bile acid analogue was introduced to detect disturbed hepatobiliary transport of bile acids. 
Methods : 3 beta-[F-18]fluorocholic acid ([F-18]FCA) was prepared by nucleophilic substitution of a mesylated precursor with [F-18]fluoride, followed by deprotection with sodium hydroxide. Transport of [F-18]FCA was assessed in vitro using CHO-NTCP, HEK-OATP1B1, HEK-OATP1B3 transfected cells and BSEP & MRP2 membrane vesicles. Investigation of [F-18]FCA metabolites was performed with primary mouse hepatocytes. Hepatobiliary transport of [F-18]FCA was evaluated in vivo in wild-type, rifampicin and bosentan pretreated FVB-mice by dynamic mu PET scanning. 
Results : Radiosynthesis of [F-18] 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. [F-18]FCA was found to be metabolically stable. In vivo, [F-18]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 [F-18]FCA was significantly inhibited by both rifampicin and bosentan. 
Conclusion : A F-18 labeled bile acid analogue, [F-18]FCA, has been developed that shows transport by NTCP, OATP, MRP2 and BSEP. [F-18]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.},
  articleno    = {e0173529},
  author       = {De Lombaerde, Stef and Neyt, Sara and Kersemans, Ken and Verhoeven, Jeroen and Devisscher, Lindsey and Van Vlierberghe, Hans and Vanhove, Christian and De Vos, Filip},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  keywords     = {WHOLE-BODY DISTRIBUTION,INDUCED LIVER-INJURY,BILE-ACIDS,HEPATOBILIARY,TRANSPORTERS,OATP,POLYPEPTIDE,RECEPTOR,BOSENTAN,BIODISTRIBUTION,RADIOSYNTHESIS},
  language     = {eng},
  number       = {3},
  pages        = {14},
  title        = {Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice},
  url          = {http://dx.doi.org/10.1371/journal.pone.0173529},
  volume       = {12},
  year         = {2017},
}

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