Evaluation of breast cancer resistance protein function in hepatobiliary and renal excretion using PET with 11C-SC-62807

Abstract

A quantitative PET imaging method was used to assess the in vivo kinetics of hepatobiliary and renal excretion of the breast cancer resistance protein (Bcrp) substrate 11C-SC-62807 in mice. Methods: Serial abdominal PET scans were collected in wild-type and Bcrp knockout (Bcrp-/-) mice after intravenous injection of 11C-SC-62807. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after radiotracer administration. Dynamic PET data were analyzed to determine the canalicular and brush-border efflux clearances in the liver and kidney (CL int,bile,liver and CLint,urine,kidney, respectively). Results: SC-62807 is an in vitro substrate of mouse Bcrp and human BCRP. Radioactivity associated with 11C-SC-62807 was predominantly found in the blood, liver, bile, and urine 30 min after administration. Both biliary and urinary excretion of radioactivity was markedly lower in Bcrp-/- mice than in wild-type mice, suggesting greater systemic exposure in Bcrp -/- mice. Both the CLint,bile,liver and the CL int,urine,kidney were significantly lower in Bcrp-/- mice (74% ± 10% and 99% ± 1% lower than controls, respectively). We also found that 11C-SC-62807 is a substrate of the organic anion-transporting polypeptides OATP1B1 and OATP1B3 in vitro. Conclusion: The present study demonstrated that Bcrp plays a significant role in the efflux of 11C-SC-62807 in mouse liver and kidney. We also demonstrated the feasibility of PET using 11C-SC-62807 to study the activity of BCRP in humans. Copyright © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.