Fluorine Radioisotopes; Membrane Transport Proteins; Blood-Brain Barrier; Fluorine Radioisotopes/chemistry; Membrane Transport Proteins/metabolism; Positron-Emission Tomography/methods; Positron-Emission Tomography; Molecular Medicine; Drug Discovery
Abstract :
[en] Increased activity of efflux transporters, e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), at the blood-brain barrier is a pathological hallmark of many neurological diseases, and the resulting multiple drug resistance represents a major clinical challenge. Noninvasive imaging of transporter activity can help to clarify the underlying mechanisms of drug resistance and facilitate diagnosis, patient stratification, and treatment monitoring. We have developed a metabolically activated radiotracer for functional imaging of P-gp/BCRP activity with positron emission tomography (PET). In preclinical studies, the tracer showed excellent initial brain uptake and clean conversion to the desired metabolite, although at a sluggish rate. Blocking with P-gp/BCRP modulators led to increased levels of brain radioactivity; however, dynamic PET did not show differential clearance rates between treatment and control groups. Our results provide proof-of-concept for development of prodrug tracers for imaging of P-gp/BCRP function in vivo but also highlight some challenges associated with this strategy.
Disciplines :
Chemistry Radiology, nuclear medicine & imaging
Author, co-author :
Sander, Kerstin; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Galante, Eva; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Gendron, Thibault ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique-nucléaire ; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Yiannaki, Elena; ‡Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K
Patel, Niral; §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Kalber, Tammy L; §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Badar, Adam; §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Robson, Mathew; ∥Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Johnson, Sean P; ∥Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Bauer, Florian; ⊥Department of Medicinal Chemistry, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
Mairinger, Severin; #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria
Stanek, Johann; #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria
Wanek, Thomas; #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria
Kuntner, Claudia; #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria
Kottke, Tim; ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
Weizel, Lilia; ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
Dickens, David; ○The Wolfson Centre for Personalised Medicine, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Block A Waterhouse Buildings, 1-5 Brownlow Street, Liverpool L69 3GL, U.K
Erlandsson, Kjell; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Hutton, Brian F; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Lythgoe, Mark F; §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Stark, Holger; ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
Langer, Oliver; ●Department of Clinical Pharmacology, Medical University of Vienna, Waehringer-Guertel 18-20, A-1090 Vienna, Austria
Koepp, Matthias; ◆Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, U.K
Årstad, Erik; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K ; ‡Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K
FP7 - 201380 - EURIPIDES - EUropean Research initiative to develop Imaging Probes for early In-vivo Diagnosis and Evaluation of response to therapeutic Substances
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