18F-Difluoromethylation: The Missing Link in Radiochemistry for Positron Emission Tomography

“物理科学对促进生命科学的重要性从未像现在这样重要”，人们不断需要新的化学来编程、理解和控制功能。这一建议符合这一背景，通过在放射化学领域的创新在分子成像中的应用。正电子发射断层扫描(PET)是一种对活组织和器官进行功能和定量分子成像的独特方式。PET扫描可以询问体内的生物过程，促进药物发现和实验医学，使早期临床试验成为可能，并指导临床实践(例如，癌症和神经疾病的诊断、分期和治疗反应)。与计算机断层扫描(CT)或磁共振成像(MRI)等其他诊断测试相结合，这项技术可以帮助例如诊断癌症、评估癫痫、阿尔茨海默病和冠状动脉疾病。由于PET是一种依赖于伽马射线发射的核医学程序，因此需要少量的放射性物质，称为放射性药物(放射性示踪剂)来进行这些研究。这种放射性物质必须在专门的实验室中制备，该实验室使用回旋加速器产生的正电子发射放射性同位素，如经常使用的18F，进行放射化学。由于18F的半衰期很短(不到两个小时)，所涉及的化学成分是具有挑战性的。世界各地的许多小组一直在不懈地开发新的放射化学转化，以形成碳-18F或碳-[18F]CF3键，因为它们在新陈代谢方面是强健的，F和CF3基团经常出现在药物中。然而，药物化学家最近发现，二氟甲基(CF2H)基团具有特殊的性质，可以极大地有利于提高药物的疗效，这一发现促进了对创造性放射化学的需求，不仅构建碳-[18F]CF2H键，而且构建氧-[18F]CF2H、硫-[18F]CF2H和氮-[18F]CF2H键以及其他具有CF2基序的分子，例如二氟环丙烷。解决这些问题的统一战略将是理想的，特别是如果它使用容易获得的起始材料的话。这正是我们打算通过这个项目实现的目标。我们建议开发新型的18F-二氟甲基化试剂，我们仔细选择了这些试剂，因为它们能够释放出一种高活性的18F标记的二氟卡宾物种，该物种可以与一系列容易获得的18F-二氟甲基化前体反应。这些试剂将导致PET应用中最需要的新型放射化学转化的发明，特别是各种杂原子-氢插入以及过渡金属介导的交叉偶联反应。这些新颖的放射合成将在英国和世界上广泛使用的一系列自动化平台上进行。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迅速转化为临床立即使用以改善患者保健并最终制造新的诊断或放射配体非常重要。为了在这个项目的时间框架内展示CF2H基团在放射性示踪剂开发中的价值，我们还建议举例说明，由于代谢放射性脱氟而表现不佳的18F-放射性示踪剂可以通过引入[18F]CF2H取代基来拯救；这对所有对PET成像感兴趣的科学家来说都是一个令人兴奋的前景。

"The importance of the physical sciences to advance life sciences has never been greater" and novel chemistry is continuously needed to program, understand and control function. This proposal fits within this context through innovation in the field of radiochemistry for applications in molecular imaging.Positron-emission tomography (PET) is a unique modality for functional and quantitative molecular imaging of living tissues and organs. PET scans can 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 such as computed tomography (CT) or magnetic resonance imaging (MRI), this technology can facilitate for example the diagnosis of cancer, evaluate epilepsy, Alzheimer's disease and coronary artery disease. Since PET is a type of nuclear medicine procedure relying on the emission of gamma rays, a tiny amount of a radioactive substance, called a radiopharmaceutical (radioactive tracer) is required to perform these studies. This radioactive substance must be prepared in a specialised laboratory that performs radiochemistry with a cyclotron-produced positron emitting radioisotope such as 18F, which is often used. Since the half-life of 18F is short (just under two hours), the chemistry involved is challenging. Many groups around the world have worked relentlessly to develop novel radiochemical transformations to form a carbon-18F or a carbon-[18F]CF3 bond because these are metabolically robust, and both the F and CF3 groups are frequently encountered in pharmaceutical drugs. Medicinal chemists have however recently discovered that the difluoromethyl group (CF2H) group has specific properties that can be hugely beneficial to improve the efficacy of pharmaceuticals, a discovery that has fuelled the demand for inventive radiochemistry to construct not only carbon-[18F]CF2H bonds but also oxygen-[18F]CF2H, sulfur-[18F]CF2H and nitrogen-[18F]CF2H bonds as well as other molecules with a CF2 motif, for example difluorinated cyclopropanes. A unified strategy to solve these problems would be ideal especially if it makes use of starting materials that are readily accessible. This is exactly what we intend to achieve with this project.We propose to develop novel 18F-difluoromethylation reagents that we have carefully selected for their ability to release a highly reactive 18F-labelled difluorocarbene species that can react with a range of readily available precursors for 18F-difluoromethylation. These reagents will lead to the invention of novel radiochemical transformations that are most needed for PET applications, specifically various heteroatom-hydrogen insertions as well as cross-coupling reactions mediated by transition metals. These novel radiosyntheses will be performed on a range of automated platforms that are 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 use to improve patient healthcare, and eventually manufacturing of new diagnostics or radioligands. In order to demonstrate within the timeframe of this project the value of the CF2H group in radiotracer development, we also propose to exemplify that 18F-radiotracers known to underperform because of metabolic radiodefluorination can be rescued by introducing an [18F]CF2H substituent; this is an exciting prospect for all scientists interested in PET imaging.