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

  title={Evaluation of Limiting Brain Penetration Related to P-glycoprotein and Breast Cancer Resistance Protein Using [11C]GF120918 by PET in Mice},
  author={Kazunori Kawamura and Tomoteru Yamasaki and Fujiko Konno and Joji Yui and Akiko Hatori and Kazuhiko Yanamoto and Hidekatsu Wakizaka and Makoto Takei and Yuichi Kimura and Toshimitsu Fukumura and Ming-Rong Zhang},
  journal={Molecular Imaging and Biology},
PurposeGF120918 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.ProceduresPET studies using [11C]GF120918 were conducted on P-gp and/or Bcrp knockout mice as well as wild-type mice.ResultsIn PET studies, the AUCbrain[0–60 min] and K1 value in P-gp/Bcrp knockout mice were nine- and 26-fold… 
PET study on mice bearing human colon adenocarcinoma cells using [11C]GF120918, a dual radioligand for P-glycoprotein and breast cancer resistance protein
A PET study combining the administration of [11C]GF 120918 with unlabeled GF120918 may be a useful tool for evaluating the functions of P-glycoprotein and BCRP in tumors.
Assessing the Functional Redundancy between P-gp and BCRP in Controlling the Brain Distribution and Biliary Excretion of Dual Substrates with PET Imaging in Mice
PET data provide evidence for redundancy between P-gp and BCRP in controlling both the brain distribution and biliary excretion of dual P- gp/BCRP substrates and highlight the utility of PET as an upcoming tool to assess the effect of transporters on drug disposition at a whole-body level.
P-Glycoprotein and Breast Cancer Resistance Protein at the Human Blood-Brain Barrier
Brain PET signal corrected for radioactivity in vasculature was very low, and low levels of radiolabeled metabolites were detected in plasma at time points up to 60 min after injection of 11 Ctariquidar or 11 C-elacridar, and the 2T4K model provided better data fits than the 1T2K model.
Interaction of HM30181 with P-glycoprotein at the murine blood-brain barrier assessed with positron emission tomography.
Tariquidar and Elacridar Are Dose-Dependently Transported by P-Glycoprotein and Bcrp at the Blood-Brain Barrier: A Small-Animal Positron Emission Tomography and In Vitro Study
Low intracellular accumulation of ELC and TQD at nanomolar concentrations and increased uptake at micromolar concentrations are confirmed and shows that microdoses can behave pharmacokinetically differently from MDT-inhibitory doses if a compound interacts with MDTs.
A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer
Among the tested radiotracers, [11C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp, and merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours.
Interaction of 11C-Tariquidar and 11C-Elacridar with P-Glycoprotein and Breast Cancer Resistance Protein at the Human Blood–Brain Barrier
Both tracers were unable to visualize cerebral Pgp density, most likely because of insufficiently high binding affinities in relation to the low density of Pgp in human brain, and may find use as a new class of radiotracers to study the interplay of PGP and BCRP at the human BBB in limiting brain uptake of dual substrates.


P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of Topotecan
To improve the brain penetration of such compounds for targeting intracranial malignancies in patients, it will be essential to use potent inhibitors of both drug transporters.
Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats.
Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan.
Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs, and it is proposed that strategic application of BCRP inhibitors may lead to more effective oral chemotherapy with topotecan or other B CRP substrate drugs.
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
It is shown that P-gp and Bcrp at BBB function synergistically to limit the brain penetration of shared substrates and clearly demonstrate that BCRp impairs the brain Penetration of its substrates.
Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs.
Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood-brain barrier.
The defective P-gp in the mutant mdr1a(-/-) mice was associated with increased abcg2 mRNA at the BBB and a greater export of prazosin and mitoxantrone from the brain, as measured in the P-GP-deficient mice versus the wild-type mice.
Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C.
A new tetracyclic analogue of FTC, Ko143, is evaluated as a practical inhibitor of BCRP, proving highly active for increasing the intracellular drug accumulation and reversing Bcrp1/BCRP-mediated multidrug resistance.
Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins.
  • A. Schinkel, U. Mayer, P. Borst
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
Mdr1a/1b (-/-) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs.
Drug transport across the blood-brain barrier and the impact of breast cancer resistance protein (ABCG2).
The purpose of this review is to summarise the findings of the various studies assessing the expression profile of ABCG2 at the BBB, to provide an overview on the current research being undertaken to identify specificABCG2 inhibitors with therapeutic benefit, and to critically assess the functional role of ABCg2 on drug transport across theBBB.
A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors
GF120918 is an MDR converter with only minimal side effects at a dose level yielding concentrations able to convert the action of P-glycoprotein in vitro.