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

后期 C-H 碘化：在放射性药物合成中的应用

• 批准号: 2604930
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2604930
• 关键词: Late; Stage; Iodination; Applications; Towards

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.

氟在药物和农业化学化合物中非常有利，因为它的存在可以显着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) 是一种无创诊断工具，可用于研究放射性药物给药后的生化和生理过程。在所有PET放射性同位素中，18F是应用最广泛且与临床相关的放射性核素。由于半衰期短，PET 放射性同位素通常必须在整个合成过程的后期阶段加入示踪分子中。因此，开发有效且快速的反应以允许氟的后期掺入对于药物发现至关重要。这是本提案的中心目标。杨森制药公司最近发现了一种新的 C-H 碘化反应，可以将碘原子引入到多种先导化合物、药物和生物分子（包括肽和碳水化合物）上。该方法提供了一种合成手柄，可实现广泛的多样化。在此，我们将这种后期CH碘化化学与标记技术相结合，将生物活性分子的多样化扩展到正电子发射含氟基团，例如18F、CF18F、CF2 18F和XCF2 18F基团，以用于PET中的应用。该提案将首先侧重于开发标记含碘小分子的新方法，然后将 18F 基序引入生物制剂中。后一种应用极具挑战性，因为标记必须在非常温和的条件下实现。通过 EPSRC 资助的工作以及在 EPSRC 维护的研究领域（医学成像和化学生物学），Gouverneur 开发了一种铜介导的氟脱硼，能够在（前）临床相关化合物中安装氟 18，这是全世界放射化学家使用的一种方法。这种化学反应导致新型 18F 放射性示踪剂应用于临床（例如用于 DNA 损伤成像的 18F 奥拉帕尼），这是改善癌症患者生活质量的重要进步。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。该提案融合了学术界和工业界的专业知识，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用于患者护理的医疗保健技术组合来对社会产生直接影响。后期功能化将是学生的核心，并将提供合成、催化、高通量筛选、机制阐明、放射化学和药物化学方面的广泛培训。在杨森制药公司为期三个月的实习将让您直接接触充满活力的工业环境，该环境相信多元化的背景可以推动创新和成功，并具有协作文化。该公司拥有一流的设施，并将精准医疗作为首要目标。该提案将有助于实现个性化健康结果的愿景。