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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, Jeroen Verhoeven UGent, Lindsey Devisscher UGent, Hans Van Vlierberghe UGent, Christian Vanhove UGent and Filip De Vos UGent (2017) PLOS ONE. 12(3).
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.
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author
organization
alternative title
Synthesis, in vitro and in vivo evaluation of 3 beta-[F-18]fluorocholic acid for the detection of drug-induced cholestasis in mice
year
type
journalArticle (original)
publication status
published
subject
keyword
WHOLE-BODY DISTRIBUTION, INDUCED LIVER-INJURY, BILE-ACIDS, HEPATOBILIARY, TRANSPORTERS, OATP, POLYPEPTIDE, RECEPTOR, BOSENTAN, BIODISTRIBUTION, RADIOSYNTHESIS
journal title
PLOS ONE
PLoS One
volume
12
issue
3
article number
e0173529
pages
14 pages
Web of Science type
Article
Web of Science id
000396073700013
ISSN
1932-6203
DOI
10.1371/journal.pone.0173529
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
8516440
handle
http://hdl.handle.net/1854/LU-8516440
date created
2017-03-31 05:41:11
date last changed
2017-04-18 08:49:14
@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 ({\textrangle}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},
  keyword      = {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 3\ensuremath{\beta}-[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},
}

Chicago
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).
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).
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).
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.