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

氟在制药和农用化合物中非常有利，因为它的存在可以极大地改变化学和生物特性，包括稳定性、亲脂性和生物利用度。事实上，市场上30-40%的农用化学品和20%的药品都含有氟。由于天然含氟有机化合物极为罕见，重大进展在很大程度上依赖于合成有机化学。正电子发射断层扫描（PET）是一种非侵入性诊断工具，可以研究放射性药物治疗后的生化和生理过程。在所有PET放射性同位素中，18F是应用最广泛和临床相关的放射性核素。由于其半衰期短，PET放射性同位素通常必须在整个合成过程的后期阶段并入示踪分子中。因此，开发有效和快速的反应，使氟的后期掺入在药物发现中至关重要。这是本建议的中心目标。在杨森制药公司，最近发现了一种新的碳氢碘化反应，允许将碘原子引入到广泛的铅、药物和生物分子上，包括肽和碳水化合物。这种方法提供了一个综合处理，可以实现广泛的多样化。在此，我们将把这种晚期CH碘化化学与标记技术结合起来，将生物活性分子的多样性扩展到18F、CF18F、CF2 18F和XCF2 18F等正电子发射含氟基团，以应用于PET。该提案将首先侧重于开发用于标记含碘小分子的新方法，然后将18f基序引入生物制剂。后一种应用是非常具有挑战性的，因为标签必须在非常温和的条件下完成。通过EPSRC资助的工作和EPSRC持续的研究领域（医学成像和化学生物学），Gouverneur开发了一种cu介导的氟-deboronation，能够在（预）临床相关的化合物中安装氟-18，这是世界各地放射化学家使用的一种方法。这种化学反应导致了用于临床应用的新型18f放射性示踪剂（例如用于DNA损伤成像的18F-olaparib），这是提高癌症患者生活质量的重要进展。这一结果反映了创新方法和18f放射化学对医疗保健的重要性。该提案将学术界和工业界的专业知识结合起来，将确保我们在分子成像（包括放射性药物/诊断的制造）方面保持优势。这些活动可以通过加强患者护理的医疗保健技术组合，对社会产生直接影响。后期功能化将是学生的核心，并将在合成，催化，高通量筛选，机制阐明，放射化学和药物化学方面提供广泛的培训。在杨森制药为期三个月的实习将提供直接接触一个充满活力的工业环境，相信多元化的背景推动创新和成功，并在合作的文化。该公司拥有一流的设备，并将精准医疗确定为优先目标。这一建议将有助于实现这一个性化健康结果的愿景。

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.