Development of Prodrug Tracers for Functional Imaging of P-glycoprotein

Kerstin Sander^a*, Eva Galante^a, David Dickens^b, Mathew Robson^c, Adam Badar^d, Matthias Koepp^e, Erik Årstad^a

^a Institute of Nuclear Medicine, University College Hospital, 235 Euston Road (T-5), London NW1 2BU, UK; ^b The Wolfson Centre for Personalised Medicine, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, 1-5 Brownlow Street, Liverpool L69 3GL, UK; ^c Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK; ^d Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6BT, UK; ^e Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. * email: k.sander@ucl.ac.uk

Multiple drug resistance (MDR) is a major clinical challenge for the successful treatment of many prevalent diseases of the central nervous system (CNS). Inadequate access of CNS drugs to their targets is apparently caused by the overexpression and/or overactivity of multidrug transporters located at the blood-brain barrier (BBB).¹ In order to evaluate the role of the efflux pump p-glycoprotein (p-gp) in the development of MDR and moreover, to provide a diagnostic tool to quantify p-gp turnover, prodrug tracers for dynamic imaging by positron-emission tomography (PET) are being developed.

                       Illustration of the metabolite extrusion method

According to the metabolite extrusion method (MEM; see figure), a prodrug tracer will passively diffuse the BBB. Fast oxidative metabolism will provide a tracer that is being trapped in the CNS and can only be extruded by active transport by the efflux pump p-gp (see figure). Hence, the clearance of radioactivity over time from the CNS can be directly related to p-gp function.²

New p-gp substrates and their corresponding potential prodrugs have been synthesised and investigated in an in vitro screening. New metabolic pairs have been successfully identified. Selected compounds have been labelled with fluorine-18 and investigated in vivo in biodistribution experiments. The compounds exhibit excellent initial brain uptake in mice as well as a washout profile that clearly hints at the applicability of these compounds as p-gp prodrug tracers.

References: ¹ Tate SK et al. Expert Opin Pharmacother 2007, 8, 1441-1449; ² Kannan P et al. Clin Pharmacol Ther 2009, 86, 368-377.