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 output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1240-1251
Number of pages12
JournalPharmaceutical Research
Volume30
Issue number5
DOIs
StatePublished - May 2013

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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