Convergent 18F-Radiochemistry for Positron Emission Tomography

Imaging is a multidisciplinary research area. Positron emission tomography (PET), a non-invasive molecular imaging technique, relies on the availability of radiolabeled probes for molecular-level diagnostics [early diseases state detection], biological research [fundamental understanding of complex biological processes] and drug discovery [control of diseases]. PET can revolutionise these fields but its impact is limited by the worldwide shortage of skills needed to design and produce the radiotracers. This project supervised by Professor V. Gouverneur (University of Oxford - Chemistry Department), Dr Ian Newington and Dr Rajiv Bhalla (GE Healthcare Medical Diagnostics) will provide the opportunity to acquire these skills. Rapid progress in PET imaging is restricted by the cost, speed, and efficiency of radiosynthetic methods to access radiolabeled probes. 18F is identified as one of the radionuclides of choice due to its half-life of 110 mins, which allows for multistep radiosyntheses and commercial distribution. Currently, radiochemists select the site of 18F-radiolabeling to fit existing radiosynthetic methods, an approach that could be detrimental for rapid progress in PET probe discovery. 18F-Radio-retrosynthetic routes used to date are based on linear sequences of transformations designed with the aim of introducing the 18F-label ideally in the last step or as late as possible. This becomes increasingly difficult to implement when the probe is structurally complex or highly functionalised. Academics, industrialists and clinicians interested in PET-based imaging are in need of a wider range of structurally diverse radiotracers, which are currently not accessible using existing 18F-radiolabelling methods. The central proposition advanced here is that 18F-radiochemistry will benefit from convergent synthetic tactics assembling in one step a 18F-labelled component with two or more reactants simultaneously. Using this new radiochemistry, high value radiotracers will be prepared rapidly for applications in diagnostics or drug development. To validate this new conceptual framework, we selected multicomponent reactions (MCR) because these highly convergent atom- and step-economic procedures can deliver structurally diverse and complex molecules in a single step by reacting more than two substrates simultaneously. This class of reactions is attractive because the 18F-labeled precursor become integrated in the intrinsic structure of the probe and offers the possibility to introduce the 18F-label on different positions of the target probe without the need to redesign the overall radiosynthetic route. This chemistry will be validated with the preparation of targets not accessible by direct nucleophilic fluorination, for example electron rich 18F-aromatic motif. After proof of concept examining the value of 18F-labelled components for so-called 'radio-MCRs', further studies will aim at expanding the range of radio-MCRs suitable for 18F-labeling as well as the pool of radioactive building blocks and at mapping the various possible combinations of non-labeled and labeled components. Since the development of novel MCRs inclusive of asymmetric transformations is such an active area of research, a tantalizing range of opportunities emerges for the synthesis of structurally complex 18F-labeled PET tracers but also to access biomarkers for other imaging modalities. This work will establish that the inclusion of more convergent retro-radiosynthetic approach in the context of 18F-indirect labelling can greatly expand the range of 18F-labeled radiotracers made accessible for PET. This proposal represents a conceptual advance that would enlarge dramatically the scope of 18F-prosthetic group radiochemistry and provide immense benefit to diagnostics and drugs development.