Late-Stage C-H Iodination: Applications Towards Radiopharmaceutical Synthesis

Fluorine can be highly advantageous in pharmaceutical and agrochemical compounds as its presence can dramatically alter chemical and biological properties, including stability, lipophilicity and bioavailability. Indeed, 30-40% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine. As natural fluoroorganic compounds are extremely rare, major advances rely heavily on synthetic organic chemistry. Positron Emission Tomography (PET) is a noninvasive diagnostic tool enabling the study of biochemical and physiological processes following administration of a radiopharmaceutical. Among all PET radioisotopes, 18F is the most widely used and clinically relevant radionuclide. Due to their short half-lives, PET radioisotopes must typically be incorporated into tracer molecules at a late stage of the overall synthesis process. Therefore, the development of efficient and fast reactions allowing the late-stage incorporation of fluorine is crucial in drug discovery. This is the central objective of this proposal. At Janssen Pharmaceuticals, a new C-H iodination reaction was recently discovered allowing the introduction of an iodine atom onto a broad range of leads, pharmaceuticals, and biomolecules, including peptides and carbohydrates. This method provides a synthetic handle which enables a wide range of diversification. Herein, we shall combine this late stage CH iodination chemistry with labelling technologies to extend the diversification of bioactive molecules to positronemitting fluorine-containing groups such as 18F, CF18F, CF2 18F and XCF2 18F groups for applications in PET. The proposal will focus firstly on developing new methods for the labelling of iodine-containing small molecules followed by the introduction of 18F-motifs onto biologics. This latter application is highly challenging as labelling must be achieved under remarkably mild conditions. Through work funded by the EPSRC and in maintained EPSRC research areas (medical imaging and chemical biology), Gouverneur has developed a Cu-mediated fluoro-deboronation capable of installing fluorine-18 in (pre)clinically relevant compounds, a method used by radiochemists worldwide. This chemistry has led to new 18F-radiotracers for applications in the clinic (eg 18F-olaparib for DNA damage imaging), an important advance to improve the quality of life for cancer patients. This outcome reflects the importance of innovative methodologies and 18F-radiochemistry for healthcare. This proposal merging expertise from academia and industry will ensure that our strength is maintained in molecular imaging including the manufacturing of radiopharmaceuticals/diagnostics. These activities can make a direct impact on society by strengthening the portfolio of healthcare technologies for patient's care. Late stage functionalisation will be at the core of the studentship and will provide extensive training in synthesis, catalysis, high-throughput screening, mechanism elucidation, radiochemistry, and medicinal chemistry. The three-month placement at Janssen Pharmaceutica will offer direct exposure to a dynamic industrial environment that believes in diverse backgrounds to drive innovation and success, and in a culture of collaboration. The company has superb facilities and has identified precision medicine as a high priority aim. This proposal will contribute to achieving this vision of personalised health outcomes.