Difluorocarbene: Synthesis, Reactivity and Applications for PET Imaging

正电子发射断层扫描（PET）是一种非侵入性定量成像技术，可以在计算机断层扫描（CT）或磁共振成像（MRI）未检测到异常证据或疾病发生结构变化之前检测身体组织的症状前生化变化。这项技术可以帮助研究人员了解疾病，并可以帮助临床医生为个体患者选择最佳治疗方案，前提是有合格的生物标志物可用。PET无与伦比的灵敏度使得这项技术也适用于解决肿瘤学、心脏病学、神经科学和炎症性疾病药物开发的基础问题。最常用的正电子发射放射性同位素之一是18F，部分原因是[18F]氟脱氧葡萄糖在临床中的广泛使用以及氟取代在药物发现中的重要性。18F的短半衰期（110分钟）决定了基于晚期氟化的方案的优先选择。所有形式的[18F]放射性示踪剂成像的基础技术是[18F]放射性示踪剂化学，因为它是[18F]放射性示踪剂探针分子开发所必需的。放射性示踪化学是一门独特的学科，需要特殊的反应、设备、技术、理解和培训。它的独特性源于在示踪剂水平尺度上进行的化学反应的独特行为，以获得足够高的比活性产物，以及对用短半衰期放射性核素（如[18F]）标记的材料进行化学转化和产品纯化时对效率和速度的需求。该项目的目的是开发新的[18F]放射化学，以期获得目前难以或不可能制备的急需的[18F]放射性示踪剂。我们提出了几种方法来[18F]标记在候选药物和生物标志物中常见的含有CF3和CF2基序的分子。该项目以已公布的可靠初步数据为基础，利用二氟化苯和易于获得的[18F]氟与现成的前体和助试剂结合使用的反应性。重点是发展[18F]多用途且易于从分子转化到分子的放射性示踪化学方法，以推动英国和国外PET成像领域的发展。

Positron Emission Tomography (PET) is a non-invasive quantitative imaging technology that can detect pre-symptomatic biochemical changes in body tissues where no evidence of abnormality from computed tomography (CT) or Magnetic Resonance Imaging (MRI) are detectable or before structural changes occur from disease. This technology helps researchers understanding diseases and can assist clinicians in the selection of the best treatment for an individual patient, provided that competent biomarkers are available. The unrivalled sensitivity of PET makes this technique also suitable to address questions fundamental to drug development for oncology, cardiology, neurosciences and inflammatory diseases. One of the most commonly used positron-emitting radioisotopes is 18F, in part due to the extensive use of [18F]fluorodeoxyglucose in the clinic and the importance of fluorine substitution in the context of drug discovery. The short half-life of 18F (110 min) dictates a preference for protocols based on late stage fluorination. The enabling technology that underlies all forms of [18F]radiotracer imaging is [18F]radiotracer chemistry, because it is required for the development of [18F]radiotracer probe molecules. Radiotracer chemistry is a unique discipline that demands special reactions, equipment, techniques, understanding, and training. Its uniqueness stems from the unique behavior of chemical reactions conducted at the tracer-level scale to obtain products of sufficiently high specific activity, the need for efficiency and speed associated with performing chemical transformations and product purifications on materials that are labeled with short half-life radionuclides such as [18F]. The aim of this project is to develop new [18F]radiochemistry with the view to access much needed [18F]radiotracers currently difficult or not possible to prepare. We propose several methods to [18F]label molecules containing CF3 and CF2 motifs commonly found in pharmaceutical drug candidates and biomarkers. The project based on solid published preliminary data exploits the reactivity of difluorocarbene and easily accessible [18F]fluoride used in combination with readily available precursors and co-reagents. The emphasis is on the development of [18F]radiotracer chemistry methods that are versatile and easy to translate from molecule to molecule to advance the field of PET imaging in the UK and abroad.