Pharmaceutical Research

, Volume 30, Issue 5, pp 1240–1251 | Cite as

Design and Characterization of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transporter Activity

  • Diana Vivian
  • Kunrong Cheng
  • Sandeep Khurana
  • Su Xu
  • Valerie Whiterock
  • Drew Witter
  • Kimberley A. Lentz
  • Kenneth S. Santone
  • Jean-Pierre Raufman
  • James E. Polli
Research Paper



To synthesize a trifluorinated bile acid that can be used for 19F magnetic resonance imaging (MRI) of bile acid enterohepatic circulation, characterize its in vitro transporter affinity, stability, and 19F-MRI signal, and assess its ability to concentrate in the gallbladder of C57BL/6 mice.


Target compound CA-lys-TFA was synthesized and tested for affinity toward the apical sodium dependent bile acid transporter (hASBT) and the Na+/taurocholate cotransporting polypeptide (hNTCP). In a pilot study, fasted mice were gavaged with vehicle control, 150 mg/kg or 300 mg/kg CA-lys-TFA. CA-lys-TFA in gallbladder, liver and plasma at t = 5 h was quantified. Additionally, a 24-h time course (24 mice across eight time points) was studied using 50 mg/kg CA-lys-TFA.


CA-lys-TFA was a potent substrate of hASBT (Kt = 39.4 μM, normalized Vmax = 0.853) and hNTCP (Kt = 8.99 μM, normalized Vmax = 0.281). 19F MRI phantom imaging showed linear signal-concentration dependence. In vivo studies showed that rapid accumulation of CA-lys-TFA in the gallbladder was maximal within 4–7 h.


These findings suggest that CA-lys-TFA, a fluorinated non-radioactive bile acid analogue, has potential for use in MRI to measure in vivo bile acid transport and diagnose bile acid malabsorption and other conditions associated with impaired bile acid transport.


apical sodium-dependent bile acid transporter bile acid transport enterohepatic circulation fluorine MRI Na+/taurocholate cotransporting polypeptide 





bile acid malabsorption


cholic acid-trifluoroacetyl lysine


choloylglycine hydrolase


dulbecco’s modified Eagle medium


dimethyl formamide


dulbecco’s phosphate buffered saline


ethylenediaminetetraacetic acid


ethyl acetate


fetal bovine serum


fibroblast growth factor 19


fast low angle shot


human apical sodium-dependent bile acid transporter


hematoxylin and eosin


Hank’s balanced salt solution


O-benztriazol-1-yloxytris-1,1,3,3 tetra methyl uranium hexafluorophosphate


human embryonic kidney


Na+/taurocholate cotransporting polypeptide




irritable bowel syndrome


liquid chromatography/mass spectrometry


Madin-Darby canine kidney


multifluorinated bile acid


magnetic resonance imaging


number of average


aqueous boundary layer permeability


polyethylene glycol


positron emission tomography


phenylmethylsulfonyl fluoride


passive permeability




room temperature


substrate concentration


sodium-free buffer


simulated intestinal fluid with pancreatic enzymes




substrate flux



We acknowledge Dr. Kellie Hom for NMR help, Dr. Cinthia Drachenberg for histology analysis, and Dr. Werner Weitschies for donation of stably transfected hNTCP-HEK cells.

This work was supported by the National Institutes of Health [NIDDK T32 DK067872 Research Training in Gastroenterology; R21 DK093406, DK67530, and K08DKO81479].


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Diana Vivian
    • 1
  • Kunrong Cheng
    • 2
  • Sandeep Khurana
    • 2
  • Su Xu
    • 3
  • Valerie Whiterock
    • 4
  • Drew Witter
    • 4
  • Kimberley A. Lentz
    • 4
  • Kenneth S. Santone
    • 4
  • Jean-Pierre Raufman
    • 2
  • James E. Polli
    • 1
    • 5
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyUniversity of MarylandBaltimoreUSA
  2. 2.Department of Medicine, School of MedicineUniversity of MarylandBaltimoreUSA
  3. 3.Department of Diagnostic Radiology and Nuclear Medicine School of MedicineUniversity of MarylandBaltimoreUSA
  4. 4.Bristol Myers SquibbWallingfordUSA
  5. 5.School of PharmacyUniversity of MarylandBaltimoreUSA

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