N-(4-[18F]fluorobenzyl)cholylglycine, a potential tracer for positron emission tomography of enterohepatic circulation and drug-induced inhibition of ileal bile acid transport. A proof-of-concept PET/CT study in pigs

Abstract

Introduction: Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for bile acids to function as detergents and signal carriers. Perturbation of the EHC by disease or drugs may lead to serious and life-threatening liver and gastrointestinal disorders. In this proof-of-concept study in pigs, we investigate the potential of N-(4-[¹⁸F]fluorobenzyl)cholylglycine ([¹⁸F]FBCGly) as tracer for quantitative positron emission tomography (PET) of the EHC of conjugated bile acids.

Methods: The biodistribution of [¹⁸F]FBCGly was investigated by PET/CT in domestic pigs following intravenous and intraileal administration of the tracer. Hepatic kinetics were estimated from PET and blood data using a 2-tissue compartmental model and dual-input of [¹⁸F]FBCGly. The ileal uptake of [¹⁸F]FBCGly was investigated with co-injection of nifedipine and endogenous cholyltaurine. Dosimetry was estimated from the PET data using the Olinda 2.0 software. Blood, bile and urine samples were analyzed for possible fluorine-18 labelled metabolites of [¹⁸F]FBCGly.

Results: [¹⁸F]FBCGly was rapidly taken up by the liver and excreted into bile, and underwent EHC without being metabolized. Both nifedipine and endogenous cholyltaurine inhibited the ileal uptake of [¹⁸F]FBCGly. The flow-dependent hepatic uptake clearance was estimated to median 1.2 mL blood/min/mL liver tissue. The mean residence time of [¹⁸F]FBCGly in hepatocytes was 4.0 ± 1.1 min. Critical organs for [¹⁸F]FBCGly were the gallbladder wall (0.94 mGy/MBq) and the small intestine (0.50 mGy/MBq). The effective dose for [¹⁸F]FBCGly was 36 μSv/MBq.

Conclusion: We have shown that [¹⁸F]FBCGly undergoes EHC in pigs without being metabolized and that its ileal uptake is inhibited by nifedipine and endogenous bile acids. Combined with our previous findings in rats, we believe that [¹⁸F]FBCGly has potential as PET tracer for assessment of EHC of conjugated bile acids under physiological conditions as well as conditions with perturbed hepatic and ileal bile acid transport.

Keywords: Apical sodium-dependent bile acid transporter; Drug inhibition; Hepatic transport; Ileum; Liver; Molecular imaging.