2. Academic Validation
  3. A new method measuring the interaction of radiotracers with the human P-glycoprotein (P-gp) transporter

A new method measuring the interaction of radiotracers with the human P-glycoprotein (P-gp) transporter

  • Nucl Med Biol. 2018 May;60:29-36. doi: 10.1016/j.nucmedbio.2018.02.002.
Chrysoula Vraka 1,  Monika Dumanic 2,  Teresa Racz 2,  Florian Pichler 3,  Cecile Philippe 2,  Theresa Balber 4,  Eva-Maria Klebermass 2,  Karl-Heinz Wagner 5,  Marcus Hacker 2,  Wolfgang Wadsak 6,  Markus Mitterhauser 7
Affiliations

Affiliations

  • 1 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department for Nutritional Science, University of Vienna, Vienna, Austria.
  • 2 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
  • 3 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Engineering, University of Applied Sciences Wiener Neustadt, Austria.
  • 4 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Pharmaceutical Technology and Biopharmaceuticals (PTB), University of Vienna, Vienna, Austria.
  • 5 Department for Nutritional Science, University of Vienna, Vienna, Austria.
  • 6 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Inorganic Chemistry, University of Vienna, Vienna, Austria; CBmed, Graz, Austria.
  • 7 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Pharmaceutical Technology and Biopharmaceuticals (PTB), University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria. Electronic address: markus.mitterhauser@meduniwien.ac.at.
PMID: 29529532 DOI: 10.1016/j.nucmedbio.2018.02.002
Abstract

In drug development, biomarkers for cerebral applications have a lower success rate compared to cardiovascular drugs or tumor therapeutics. One reason is the missing blood brain barrier penetration, caused by the tracer's interaction with efflux transporters such as the P-gp (MDR1 or ABCB1). Aim of this study was the development of a reliable model to measure the interaction of radiotracers with the human efflux transporter P-gp in parallel to the radiolabeling process. LigandTracer® Technology was used with the wildtype cell line MDCKII and the equivalent cell line overexpressing human P-gp (MDCKII-hMDR1). The method was evaluated based on established PET tracers with known interaction with the human P-gp transporter and in nanomolar concentration (15 nM). [11C]SNAP-7941 and [18F]FE@SNAP were used as P-gp substrates by comparing the real-time model with an uptake assay and μPET images. [11C]DASB [11C]Harmine, [18F]FMeNER,[18F]FE@SUPPY and [11C]Me@HAPTHI were used as tracers without interactions with P-gp in vitro. However, [11C]Me@HAPTHI shows a significant increase in SUV levels after blocking with Tariquidar. The developed real-time kinetic model uses directly PET tracers in a compound concentration, which is reflecting the in vivo situation. This method may be used at an early stage of radiopharmaceutical development to measure interactions to P-gp before conducting animal experiments.

Keywords

ABCB1; MDR1; P-gp-substrate; PET tracer; efflux transporter.

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