Synthesis and Testing of diaryl sulphide based Fluorine-18 Radiotracers for Positron Emission Tomography of Hypoxic Tumours

© 2019 Lee Wenn ChongHypoxia is a critical physiological marker demonstrated in a variety of cancers, imaging it will provide valuable insight into prognosis and treatment. However, the slow kinetics of [18F]FMISO(1.2) means that there is a 2 hour delay between injection and imaging for patients. Fluorine-18 labelled Chloroethyl sulfoxides [18F]SO101 and [18F]SO201 were shown to have both faster kinetics and higher contrast compared to [18F]FMISO(1.2) in a rat model of ischemic stroke. Perceived toxicity from the nitrogen mustard analogues in [18F]SO101 and [18F]SO201 lead to structural changes resulting in [18F]SO501. [18F]SO501 demonstrated good uptake into hypoxic SK-RC-52 tumours while also clearing from muscle, giving good contrast and therefore high-quality images, however it had a low radiochemical yield of 2.5% making it impractical for routine clinical application. Structural changes were made to the base compound [18F]SO501 in order to adapt it to a different method of radiolabelling in an attempt to increase the RCY while maintaining its selectivity for hypoxic tissue. The modifications made included the introduction of a propargyl group for click chemistry, variable length PEG groups and alterations to the ester group from an ethyl ester to an isopropyl ester and in one case doing away with it entirely. Six different diaryl-sulfoxide radiolabelled compounds were synthesised for this project [18F]2.16, [18F]2.26, [18F]2.36, [18F]2.43, [18F]2.53 and [18F]2.63 from their respective diaryl-sulfoxide precursors 2.15, 2.25, 2.35, 2.42, 2.52 and 2.62. After in-vivo imaging in SK-RC-52 tumours xenografted onto BALB/c nude mice the most promising tracer [18F]2.16, which had the best tumour to muscle ratio of 1.6 at 60 minutes and 2.1 at 110min, underwent metabolism studies involving Rat S9 liver fractions