Evaluation of Limiting Brain Penetration Related to P-glycoprotein and Breast Cancer Resistance Protein Using [11C]GF120918 by PET in Mice
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GF120918 has a high inhibitory effect on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). We developed [11C]GF120918 as a positron emission tomography (PET) probe to assess if dual modulation of P-gp and BCRP is useful to evaluate brain penetration.
PET studies using [11C]GF120918 were conducted on P-gp and/or Bcrp knockout mice as well as wild-type mice.
In PET studies, the AUCbrain[0–60 min] and K1 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 [11C]GF120918 is related to modulation of P-gp and BCRP and is limited by two transporters working together.
PET using [11C]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.
Key wordsPositron emission tomography (PET) P-glycoprotein (P-gp) Breast cancer resistance protein (BCRP) Carbon-11 GF120918 Elacridar
- 22.Gilday JP, Moody D (2004) Process for the preparation of 4-(3′-chlorp-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy) quinazoline. PCT Int Appl WO/2004/024703 A1Google Scholar
- 32.Zhou L, Schmidt K, Nelson FR, Zelesky V, Troutman MD, Feng B (2009) The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in mice. Drug Metab Dispos 37:946–955CrossRefPubMedGoogle Scholar