18F-Fluorodeamination through Pyridinium Salts: Innovation, Mechanism, and User Guidelines

通过吡啶盐进行 18F-氟脱氨：创新、机制和用户指南

• 批准号: EP/Y001931/1
• 负责人: Veronique Gouverneur
• 金额: $ 75.33万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY001931%2F1
• 关键词: 18F; Fluorodeamination; through; Pyridinium; Salts

"The importance of the physical sciences to advance life sciences has never been greater", and inventive chemistry is continuously needed to program, understand and control function. This proposal fits within this context with innovation in the field of radiochemistry to advance molecular imaging. Positron-emission tomography (PET) is a functional and quantitative molecular imaging technology to interrogate biological processes in vivo, facilitate drug discovery and experimental medicine, enable early-stage clinical trials, and guide clinical practice (e.g. cancer and neurological disorders diagnosis, staging, and response to treatment). Combined with other diagnostic tests, this technology can facilitate for example the diagnosis of cancer, evaluate epilepsy, Alzheimer's disease and coronary artery disease. PET scans are routinely performed in the clinic and to support pharmaceutical drug discovery programs. A radiopharmaceutical (radioactive tracer) is required to perform these scans because the technique relies on the emission of gamma rays. These radioactive molecules must be prepared in specialist laboratories that performs radiochemistry with a cyclotron-produced positron emitting radioisotope such as commonly used 18F. Since the half-life of 18F is short (just under 110 minutes), the chemistry involved is challenging. Many groups including our laboratory have focused on novel radiochemical transformations for 18F-labelling because fluorine substitution is frequently encountered in pharmaceutical drugs. Labelling strategies that make use of ubiquitous precursors are the most sought-after, especially if these precursors are amenable to divergent radiochemistries. This is exactly what we will achieve with this project. We propose to develop novel 18F-radiochemistries using ubiquitous primary amines to accelerate PET ligand and radiopharmaceutical discovery. Our strategy consists of converting amines into pyridinium salts that are highly versatile synthetic intermediates acting either as electrophiles or as redox-active precursors. This rich reactivity profile offers the possibility to access a large diversity of 18F-labelled molecules through either direct 18F-fluorination or 18F-fluoroalkylation/arylation from primary amines. Such radiochemistry will streamline access to molecules that are either difficult to label or not possible to label with current technologies. All labelling reactions will be performed on an automated platform that is widely used in the UK and in the world. This aspect of the project is very important to ensure rapid translation of the novel radiochemistry proposed from a research laboratory to the clinic for immediate impact and use to improve patient healthcare, and ultimately for the manufacturing of new PET diagnostics or radioligands.

“物理科学对推动生命科学的重要性从未如此重要”，并且不断需要创造性的化学来编程、理解和控制功能。该提案符合放射化学领域创新的背景，以推进分子成像。正电子发射断层扫描 (PET) 是一种功能性定量分子成像技术，可用于探究体内生物过程、促进药物发现和实验医学、实现早期临床试验并指导临床实践（例如癌症和神经系统疾病的诊断、分期和治疗反应）。与其他诊断测试相结合，该技术可以促进癌症的诊断、评估癫痫、阿尔茨海默病和冠状动脉疾病。 PET 扫描在诊所常规进行，用于支持药物发现计划。执行这些扫描需要放射性药物（放射性示踪剂），因为该技术依赖于伽马射线的发射。这些放射性分子必须在专业实验室中制备，使用回旋加速器产生的正电子发射放射性同位素（例如常用的 18F）进行放射化学。由于 18F 的半衰期很短（不到 110 分钟），因此所涉及的化学反应具有挑战性。包括我们实验室在内的许多团队都专注于 18F 标记的新型放射化学转化，因为氟取代在药物中经常遇到。利用普遍存在的前体的标记策略是最受欢迎的，特别是如果这些前体适合不同的放射化学。这正是我们将通过这个项目实现的目标。我们建议利用普遍存在的伯胺开发新型 18F 放射化学，以加速 PET 配体和放射性药物的发现。我们的策略包括将胺转化为吡啶鎓盐，吡啶鎓盐是高度通用的合成中间体，可充当亲电子试剂或氧化还原活性前体。这种丰富的反应性特征提供了通过伯胺直接 18F-氟化或 18F-氟烷基化/芳基化获得多种 18F 标记分子的可能性。这种放射化学将简化对难以标记或无法用现有技术标记的分子的获取。所有标记反应都将在英国和世界各地广泛使用的自动化平台上进行。该项目的这一方面对于确保将研究实验室提出的新型放射化学快速转化为临床以产生直接影响并用于改善患者医疗保健，并最终用于制造新的 PET 诊断或放射性配体非常重要。