Development of a PET radioligand targeting angiogenesis for oncology applications

Brocklesby, Kayleigh Louise

March 2016

Thesis or dissertation

© 2016 Kayleigh Louise Brocklesby. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

All tumours must become vascularised in order to survive and metastasise, and initiate angiogenesis through the dysregulated and uncontrolled release of pro-angiogenic factors. Such uncontrolled angiogenesis leads to highly disordered and abnormal vasculature and is widely recognised as a hallmark of cancer. The major angiogenic pathway hyper-activated in cancer is the VEGF-VEGFR₂ signalling system. Anti-angiogenic therapies have been developed, but there is no accepted way of determining which patients will respond. The development of a molecular imaging probe targeting VEGFR₂ through the use of PET represents one way to achieve this. Currently, there are no PET imaging probes which exhibit the required characteristics. Therefore, the initial focus of this project was to synthesise novel probes based around existing suitable pharmacophores. Initial libraries focusing on urea or indole motifs, lacked either routes to a radiolabelling precursor or selectivity on biological testing, and were abandoned. A third library based around the only known selective VEGFR₂ inhibitor 5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol 98, ZM323881, was developed. Synthesis of 98 proceeded via the Dimroth rearrangement in three steps, with a shorter synthesis time, use of less toxic reagents and easier purification than published methods. Initial kinase profiling revealed 98 also targeted closely related kinases; VEGFR₁, VEGFR₃, RET, PDGFRα. Known inhibitor 98 and closely related analogue 4-fluoro-5-((7- (4-fluorobenzyl)oxy))quinazoline-4-yl)amino)-2-methylphenol 101 exhibited activity against VEGFR₂, 4.75 nM and 7.5 nM respectively. The quinazoline focused library was selected for radiolabelling. Initial radiolabelling revealed a debenzylation reaction occurring, to produce 4-(2-fluoro-5-hydroxy-4-methylphenyl)amino quinazolin-7-ol 166 during the radiolabelling reaction. Radiolabelling analogue 7-(benzyloxy)-N-(4-bromo—fluorophenyl)quinazolin-4-amine 123, via the Dimroth rearrangement was troublesome and requires more optimisation, due the presence of the de-cyanation by-product. Initial biological testing presented in this thesis does not rule out the quinazoline library from its use as a PET imaging agent and further in vitro characterisation is required.

Hull York Medical School, The University of Hull and the University of York
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