Evaluation of limiting brain penetration related to P-glycoprotein and breast cancer resistance protein using [(11)C]GF120918 by PET in mice.
OBJECTIVE
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.


METHODS
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.
Kawamura
Kazunori
K
Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. kawamur@nirs.go.jp
Yamasaki
Tomoteru
T
Konno
Fujiko
F
Yui
Joji
J
Hatori
Akiko
A
Yanamoto
Kazuhiko
K
Wakizaka
Hidekatsu
H
Takei
Makoto
M
Kimura
Yuichi
Y
Fukumura
Toshimitsu
T
Zhang
Ming-Rong
MR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000166:Acridines / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D049268:Positron-Emission Tomography; D016339:Spectrometry, Mass, Fast Atom Bombardment; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000166:Acridines; D002250:Carbon Radioisotopes; D044005:Tetrahydroisoquinolines; C083501:Elacridar