TY - JOUR
T1 - Design and characterization of a novel fluorinated magnetic resonance imaging agent for functional analysis of bile acid transporter activity
AU - Vivian, Diana
AU - Cheng, Kunrong
AU - Khurana, Sandeep
AU - Xu, Su
AU - Whiterock, Valerie
AU - Witter, Drew
AU - Lentz, Kimberley A.
AU - Santone, Kenneth S.
AU - Raufman, Jean Pierre
AU - Polli, James E.
N1 - Funding Information:
This work was supported by the National Institutes of Health [NIDDK T32 DK067872 Research Training in Gastroenterology; R21 DK093406, DK67530, and K08DKO81479].
PY - 2013/5
Y1 - 2013/5
N2 - 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.
AB - 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.
KW - Na+/taurocholate cotransporting polypeptide
KW - apical sodium-dependent bile acid transporter
KW - bile acid transport
KW - enterohepatic circulation
KW - fluorine MRI
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U2 - 10.1007/s11095-012-0963-6
DO - 10.1007/s11095-012-0963-6
M3 - Article
C2 - 23319170
AN - SCOPUS:84876488722
SN - 0724-8741
VL - 30
SP - 1240
EP - 1251
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 5
ER -