A new method measuring the interaction of radiotracers with the human P-glycoprotein (P-gp) transporter
- Author(s)
- Chrysoula Vraka, Monika Dumanic, Teresa Racz, Florian Pichler, Cecile Philippe, Theresa Balber, Eva-Maria Klebermass, Karl-Heinz Wagner, Marcus Hacker, Wolfgang Wadsak, Markus Mitterhauser
- 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 (R) 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). [C-11]SNAP-7941 and [F-18]FE@SNAP were used as P-gp substrates by comparing the real-time model with an uptake assay and mu PET images. [C-11]DASB [C-11]Harmine, [F-18]FMeNER,[F-18]FE@SUPPY and [C-11] Me@HAPTHI were used as tracers without interactions with P-gp in vitro. However, [C-11]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. (C) 2018 Elsevier Inc. All rights reserved.
- Organisation(s)
- Department of Nutritional Sciences, Department of Inorganic Chemistry
- External organisation(s)
- Medizinische Universität Wien, Fachhochschule Wiener Neustadt, Centre for Biomarker Research in Medicine – CBmed GmbH, Ludwig Boltzmann Intitute Applied Diagnostics
- Journal
- Nuclear Medicine and Biology
- Volume
- 60
- Pages
- 29-36
- No. of pages
- 8
- ISSN
- 0969-8051
- DOI
- https://doi.org/10.1016/j.nucmedbio.2018.02.002
- Publication date
- 02-2018
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104004 Chemical biology, 302054 Nuclear medicine
- Keywords
- ASJC Scopus subject areas
- Molecular Medicine, Radiology Nuclear Medicine and imaging, Cancer Research
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/e7f77160-c0b1-4bd6-9c24-15e86b94dfe4