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

@article{Kawamura2010EvaluationOL,
  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},
  year={2010},
  volume={13},
  pages={152-160}
}
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… 
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54 Citations

Evaluation of the P-glycoprotein- and breast cancer resistance protein-mediated brain penetration of 11C-labeled topotecan using small-animal positron emission tomography.
[11C]sorafenib: radiosynthesis and preliminary PET study of brain uptake in P-gp/Bcrp knockout mice.
PET study on mice bearing human colon adenocarcinoma cells using [11C]GF120918, a dual radioligand for P-glycoprotein and breast cancer resistance protein
TLDR
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
TLDR
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
TLDR
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
TLDR
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
TLDR
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.
Assessment of cerebral P-glycoprotein expression and function with PET by combined [11C]inhibitor and [11C]substrate scans in rats.
Interaction of 11C-Tariquidar and 11C-Elacridar with P-Glycoprotein and Breast Cancer Resistance Protein at the Human Blood–Brain Barrier
TLDR
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.
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