Tracer Development for the Imaging of Multidrug Resistance Associate Protein 1

Eva Galante^a*, Kerstin Sander^a, Matthias Koepp^b, Adam Badar^c, Erik Årstad^a
a Institute of Nuclear Medicine, University College Hospital, 235 Euston Road, London NW1 2BU, UK; ^b Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK; ^c Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, UK. ^* email: e.galante@ucl.ac.uk

Drug resistance is a major problem for the treatment of many neurological diseases,^1,2 such as epilepsy, as well as for cancer therapy. According to the 'drug transporter hypothesis' for drug resistance, the lack of response to drugs is at least in part caused by high expression of drug efflux pumps, which effectively prevents therapeutic drug concentrations to be reached in target tissues. Multidrug Resistance Associated Protein 1 (MRP1), is one of the main efflux pumps, and is known to extrude metabolites and foreign compounds, such as drugs, from the brain. The aim of this project is to develop 18F-labelled tracers for imaging of MRP1 function by dynamic PET as a tool to identify drug resistant patients and to evaluate novel treatment strategies. 

We are exploring a novel concept for tracer design based on formation of radioactive metabolites from prodrugs in vivo, and imaging of their excretion rate from tissues of interest (see figure). Using a 6-halo-purine scaffold, we have prepared a library of compounds, and labelled 5 derivatives with 18F. A lead tracer candidate has been indentified that undergoes rapid conversion to an "active" metabolite, which in turn can be used to monitor MRP1 function. The tracer is currently under evaluation using transgenic mice.

Illustration of the metabolite extrusion method

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