Difluorocarbene: Synthesis, Reactivity and Applications for PET Imaging

正电子发射断层扫描(PET)是一种非侵入性的定量成像技术，可以在计算机断层扫描(CT)或磁共振成像(MRI)未发现异常证据的情况下，或在疾病发生结构变化之前，检测出症状前身体组织的生化变化。这项技术有助于研究人员了解疾病，并可以帮助临床医生为个别患者选择最佳治疗方案，前提是有合格的生物标记物可用。PET无与伦比的敏感性使这项技术也适合于解决肿瘤学、心脏病学、神经科学和炎症性疾病药物开发的基本问题。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上的广泛使用以及氟替代在药物发现中的重要性。18F的短半衰期(110分钟)决定了对基于晚期氟化的方案的偏好。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，因为它是发展[18F]放射性示踪剂探针分子所必需的。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上进行的化学反应的独特行为，以获得比活度足够高的产品，需要对标有短半衰期放射性核素的材料进行化学转化和产品净化的效率和速度[18F]。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标记含有CF3和CF2基序的分子，这些基序通常存在于药物候选和生物标记物中。该项目以固体公布的初步数据为基础，利用二氟卡宾和容易获得的[18F]氟化物的反应性，与容易获得的前体和辅助试剂结合使用。重点是发展[18F]放射性示踪化学方法，这些方法是通用的，易于在分子之间转换，以推动英国和国外的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.