It is well accepted that drug transporters play a pivotal role in hepatobiliary excretion of anionic drugs, in which drug-drug interactions and genetic polymorphisms are known to cause variations. However, PET probes for in vivo functional characterization of these transporters have not been established yet. We used PET to investigate hepatic uptake and subsequent canalicular efflux of 11 C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester [(15R)-11 C-TIC-Me)] in healthy subjects. Methods: Serial PET scans of the abdominal region in healthy male subjects were obtained with or without the organic anion-transporting polypeptide (OATP) inhibitor rifampicin after intravenous injection of (15R)-11 C-TIC-Me as a radiotracer. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots of data collected for 2-10 min and for 10-30 min after tracer administration for the determination of tissue uptake clearance and biliary efflux clearance, respectively. Results: After rapid hydrolysis in blood, the acid form-11 C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin [(15R)-11 C-TIC]-accumulated in the liver (37% of the dose by 17 min), and the radioactivity was then excreted into the bile (6.2% by 30 min). Rifampicin (600 mg by mouth), a potent OATP inhibitor, significantly reduced the radioactivity excreted into the bile (by 44%) by inhibiting both uptake (by 45%) and subsequent canalicular efflux (by 62%). (15R)-11 C-TIC is an in vitro substrate of OATP1B1 and OATP1B3, and clinically relevant concentrations of rifampicin inhibited uptake by OATP1B1 and OATP1B3. These results demonstrated that in humans, (15R)-11 C-TIC-associated radioactivity is excreted into the bile by organic anion transport systems. Conclusion: We demonstrated that PET image analysis with (15R)-11 C-TIC-Me is useful for investigating variations in OATP function in the human hepatobiliary transport system.

We developed a pravastatin derivative, sodium (3R,5R)-3,5-dihydroxy-7-((1S,2S,6S,8S)-6-hydroxy-2-methyl-8-((1-[ 11 C]-(E)-2-methyl-but-2-enoyl)oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoate ([ 11 C]DPV), as a positron emission tomography (PET) probe for noninvasive measurement of hepatobiliary transport, and conducted pharmacokinetic analysis in rats as a feasibility study for future clinical study. Transport activities of DPV in freshly isolated rat hepatocytes and rodent multidrug resistance-associated protein 2 (rMrp2; human, MRP2)-expressing membrane vesicles were similar to those of pravastatin. Rifampicin diminished the uptake of DPV and pravastatin by the hepatocytes, with similar inhibition potency. [11 C]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [ 11 C]DPV occurred negligibly in human hepatocytes during a 90-minute incubation. After intravenous injection, [11 C]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CL uptake,liver and CL uptake,kidney ) were blood-flow-limited (73.6 6 4.8 and 24.6 6 0.6 ml/min per kilogram, respectively). Systemic elimination of [ 11 C]DPV was delayed in rifampicin-treated rat and an Mrp2-deficient mutant rat, Eisai hyperbilirubinemic mutant rat (EHBR). Rifampicin treatment decreased both CL uptake,liver and CL uptake,kidney of [ 11 C]DPV by 30% (P , 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CL int,bile ) of [ 11 C]DPV, which was 12.2 6 1.5 ml/min per kilogram in the control rat, decreased by 60% and 89% in rifampicin-treated rat and EHBR (P , 0.05), respectively. These results indicate that [

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An efficient method for the synthesis of benzimidazo[1,2-a]quinolines under transition-metal-free conditions has been developed through a cascade reaction involving sequential aromatic nucleophilic substitution and intramolecular Knoevenagel condensation reactions. This method is applicable for the synthesis of a wide range of benzimidazo[1,2-a]quinoline derivatives from readily available 2-fluoroarylaldehyde and benzimidazole substrates.

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