Development of a PET probe for the imaging of COX-2 expression in cancers

Pacelli, Anna

Biological sciences
May 2015

Thesis or dissertation

© 2015 Anna Pacelli. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

The COX-2 isozyme is overexpressed in several kinds of cancer, including colorectal, lung, breast, and oesophageal cancer. High levels of COX-2 are usually associated with poor prognosis and advanced disease. Furthermore, studies have suggested that co-administering COX-2 inhibitors along with classic chemotherapy can improve disease outcome. Therefore, COX-2 is an attractive PET imaging biomarker for patient stratification.

A first library of potential COX-2 inhibitors with a 5,5-diphenyl hydantoin core was synthesised and screened for its affinity for COX isozymes. This structure was chosen for its novelty, its potential to improve the biodistribution of the tracer, due its lipophilicity, and its possible in vivo metabolic stability.

However, these compounds showed no affinity for COX-2, therefore its further development into PET probes was no longer pursued.

A second library with a 1,5-diphenyl imidazole structure was designed and synthesised, based on previous literature data with optimistic IC50 values for COX inhibition. A candidate for fluorine-18 radiolabelling was identified, therefore nitro and trimethyl ammonium triflate precursors were synthesised. A variety of conditions were tested for the fluorine-18 radiolabelling reactions, which identified the trimethyl ammonium precursor as a better choice. Further experiments, however, are needed in order to fully optimise the conditions of the reaction and to calculate the specific activity.

In conclusion, two libraries of potential COX-2 inhibitors were designed, synthesised and tested in order to develop a PET imaging probe. A possible compound was identified, precursors were synthesised and radiolabelled with fluorine-18 in a variety of conditions, though further tests are necessary.

School of Biological, Biomedical and Environmental Sciences, The University of Hull
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