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Evaluation of new PET tracers for receptor tumour imaging

Miranda, Cecília


Cecília Miranda


Chris Cawthorne


PET imaging can be used to non-invasively characterise biological processes at the molecular and cellular levels. The oestrogen receptor (ER) and progesterone receptor (PR) are important biomarkers in the diagnosis, prognosis and follow-up of the therapeutic response of breast cancer. Determination of the status of these receptors has become the standard of care in the treatment of hormone positive breast cancer, and currently the most widely used technique for their assessment is immunohistochemistry (IHC), however, this invasive technique has several limitations e.g. the lack of a well-defined and reproducible cut-off value for positivity/unsuitability for the assessment of metastatic lesions. The ability of ER and PR to bind ligands provides a suitable target for the development of imaging agents, in this work a focused library of non-steroidal PR ligands was synthesized based on the Tanaproget pharmacophore. The lead radiotracer, 18F-fluoropyridine was further assessed by in vitro and in vivo assays. 18F-Fluoropyridine in vitro uptake was showed to be receptor-mediated, however the in vivo imaging in hormone treated mice showed significant tracer defluorination.
The CXCR4 chemokine receptor and its natural ligand CXCL12 have essential physiological roles including cell trafficking for organogenesis at the embryonic development stage. They also have an established role in tumorigenesis with CXCR4 being overexpressed in range of cancers with aggressive phenotypes. Therefore, it is of high interest to develop non-invasive methods to identify tumour sites with higher CXCR4 expression levels and identify the likelihood of disease progression. The goal of this work was to characterise a number of novel CXCR4 antagonists to assess their potential application as PET imaging radiotracers for imaging CXCR4 expression levels in vivo. In this study, novel restricted CXCR4 macrocyclic compounds synthesized by Archibald and co-workers, Cu2CB-Bicyclam and CuCB-Bicyclam were tested and shown to be potent CXCR4 antagonists, with improved characteristics in comparison with the clinically approved AMD3100 and related compound AMD3465. [64Cu]CuCB-Bicyclam was shown to bind specifically and with high affinity to CXCR4. The in vivo PET/CT imaging showed that [64Cu]CuCB-Bicyclam has excellent characteristics for imaging CXCR4 and is able to detect variations in CXCR4 receptor density. Additionally, the tracer was proved to be stable both in vitro and in vivo.
Characterisation of [64Cu]Cu2CB-Bicyclam as a potential PET radioligand showed that there were some issues with the radiolabelling process and purification, and further optimization must be undertaken. In order to characterise Cu2CB-Bicyclam and CuCB-Bicyclam as potential CXCR4 binding drugs, a comparative study between these novel compounds as CXCR4 ligands and the known compound AMD3100 and AM3465 by evaluating their blocking capability in murine liver. Across all CXCR4 ligands tested, Cu2CB-Bicyclam and CuCB-Bicyclam were shown to have the highest affinity for CXCR4.
Synthesis of a gallium-68 derivative was also evaluated, and it was found that the structural modification requires further optimisation as an unexpected decrease in binding affinity towards CXCR4 receptor was observed.


Miranda, C. (2018). Evaluation of new PET tracers for receptor tumour imaging. (Thesis). University of Hull

Thesis Type Thesis
Publication Date 2018-11
Deposit Date Feb 8, 2023
Publicly Available Date Feb 8, 2023
Keywords Biological Sciences


Thesis (6.2 Mb)

Copyright Statement
© 2018 Cecília Miranda. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

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