Evaluation of Limiting Brain Penetration Related to P-glycoprotein and Breast Cancer Resistance Protein Using [11C]GF120918 by PET in Mice

Purpose GF120918 has a high inhibitory effect on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). We developed [ 11 C]GF120918 as a positron emission tomography (PET) probe to assess if dual modulation of P-gp and BCRP is useful to evaluate brain penetration. Procedures PET studies using [ 11 C]GF120918 were conducted on P-gp and/or Bcrp knockout mice as well as wild-type mice. Results In PET studies, the AUC brain [0–60 min] and K 1 value in P-gp/Bcrp knockout mice were nine- and 26-fold higher than that in wild-type mice, respectively. These results suggest that brain penetration of [ 11 C]GF120918 is related to modulation of P-gp and BCRP and is limited by two transporters working together. Conclusions PET using [ 11 C]GF120918 may be useful for evaluating the function of P-gp and BCRP. PET using P-gp/Bcrp knockout mice may be an effective method to understand the overall contributions the functions of P-gp and BCRP.