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

Autor(en)

Chrysoula Vraka, Monika Dumanic, Teresa Racz, Florian Pichler, Cecile Philippe, Theresa Balber, Eva-Maria Klebermass, Karl-Heinz Wagner, Marcus Hacker, Wolfgang Wadsak, Markus Mitterhauser

Abstrakt

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(en)

Department für Ernährungswissenschaften, Institut für Anorganische Chemie

Externe Organisation(en)

Medizinische Universität Wien, Fachhochschule Wiener Neustadt

Journal

Nuclear Medicine and Biology

Band

60

Seiten

29-36

Anzahl der Seiten

8

ISSN

0969-8051

DOI

https://doi.org/10.1016/j.nucmedbio.2018.02.002

Publikationsdatum

05-2018

Peer-reviewed

Ja

ÖFOS 2012

104004 Chemische Biologie, 302054 Nuklearmedizin

Schlagwörter

ASJC Scopus Sachgebiete

Molecular Medicine, Radiology Nuclear Medicine and imaging, Cancer Research

Link zum Portal

https://ucris.univie.ac.at/portal/de/publications/a-new-method-measuring-the-interaction-of-radiotracers-with-the-human-pglycoprotein-pgp-transporter(e7f77160-c0b1-4bd6-9c24-15e86b94dfe4).html