N-(4-[ 18 F]fluorobenzyl)cholylglycine, a novel tracer for PET of enterohepatic circulation of bile acids: Radiosynthesis and proof-of-concept studies in rats.

INTRODUCTION: Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for regulation of intracellular concentrations of bile acids and their function as detergents and signal carriers. Only few bile acid-derived imaging agents have been synthesized and hitherto none have been evaluated for studies of EHC. We hypothesized that N-(4-[18 F]fluorobenzyl)cholylglycine ([18 F]FBCGly), a novel fluorine-18 labeled derivative of endogenous cholylglycine, would be a suitable tracer for PET of the EHC of conjugated bile acids, and we report here a radiosynthesis of [18 F]FBCGly and a proof-of-concept study by PET/MR in rats.

METHODS: A radiosynthesis of [18 F]FBCGly was developed based on reductive alkylation of glycine with 4-[18 F]fluorobenzaldehyde followed by coupling to cholic acid. [18 F]FBCGly was investigated in vivo by dynamic PET/MR in anesthetized rats; untreated or treated with cholyltaurine or rifampicin. Possible in vivo metabolites of [18 F]FBCGly were investigated by analysis of blood and bile samples, and the stability of [18 F]FBCGly towards enzymatic de-conjugation by Cholylglycine Hydrolase was tested in vitro.

RESULTS: [18 F]FBCGly was produced with a radiochemical purity of 96% ± 1% and a non-decay corrected radiochemical yield of 1.0% ± 0.3% (mean ± SD; n = 12). PET/MR studies showed that i.v.-administrated [18 F]FBCGly underwent EHC within 40-60 min with a rapid transhepatic transport from blood to bile. In untreated rats, the radioactivity concentration of [18 F]FBCGly was approximately 15 times higher in bile than in liver tissue. Cholyltaurine and rifampicin inhibited the biliary secretion of [18 F]FBCGly. No fluorine-18 metabolites of [18 F]FBCGly were observed.

CONCLUSION: We have developed a radiosynthesis of a novel fluorine-18 labeled bile acid derivative, [18 F]FBCGly, and shown by PET/MR that [18 F]FBCGly undergoes continuous EHC in rats without metabolizing. This novel tracer may prove useful in PET studies on the effect of drugs or diseases on the EHC of conjugated bile acids.