title: Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography.
abstract: 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.
authors.affiliation: †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sander
authors.affiliation: †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K.
authors.forename: Eva
authors.initials: E
authors.lastname: Galante
authors.affiliation: †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K.
authors.forename: Thibault
authors.initials: T
authors.lastname: Gendron
authors.affiliation: ‡Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.
authors.forename: Elena
authors.initials: E
authors.lastname: Yiannaki
authors.affiliation: §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K.
authors.forename: Niral
authors.initials: N
authors.lastname: Patel
authors.affiliation: §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Kalber
authors.affiliation: §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K.
authors.forename: Adam
authors.initials: A
authors.lastname: Badar
authors.affiliation: ∥Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, U.K.
authors.forename: Mathew
authors.initials: M
authors.lastname: Robson
authors.affiliation: ∥Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, U.K.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Johnson
authors.affiliation: ⊥Department of Medicinal Chemistry, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Bauer
authors.affiliation: #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
authors.forename: Severin
authors.initials: S
authors.lastname: Mairinger
authors.affiliation: #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.affiliation: #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.affiliation: #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.affiliation: ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Kottke
authors.affiliation: ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Weizel
authors.affiliation: ○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.
authors.forename: David
authors.initials: D
authors.lastname: Dickens
authors.affiliation: †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K.
authors.forename: Kjell
authors.initials: K
authors.lastname: Erlandsson
authors.affiliation: †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Hutton
authors.affiliation: §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: ●Department of Clinical Pharmacology, Medical University of Vienna, Waehringer-Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.affiliation: ◆Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, U.K.
authors.forename: Matthias
authors.initials: M
authors.lastname: Koepp
authors.affiliation: †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.
authors.forename: Erik
authors.initials: E
authors.lastname: Årstad
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D026901:Membrane Transport Proteins