Novel Catalytic Methods for Efficient Radiolabeling of Un-activated Arene Compounds Supplement

摘要 正电子发射断层扫描(PET)是一项功能强大、发展迅速的技术，在其中扮演着关键的角色 在医学成像方面，包括阿尔茨海默病的研究。尽管PET有着不同寻常的前景 由于缺乏有效和简单的标记，PET试剂在许多情况下的可用性受到限制 方法修饰具有生物活性的小分子/药物。基于高度创新的光氧化还原系统 根据Nicewicz小组的描述，Li、Wu和Nicewicz在直接芳烃C-H上取得了第一个突破 用18F进行氟化-允许将药物直接转化为PET试剂；随后是Snar放射性氟化 可精确控制芳香族底物上的放射性氟化位置。这种新方法确实为我们提供了 可以接触到以前具有挑战性或不可能合成的试剂。基于亲核的芳香族 我们刚刚开发的替代物，在合成用于突触的创新的PET试剂方面取得了初步成功 密度成像。在美国，影响着600万人的阿尔茨海默病(AD)越来越被视为一种 从临床前AD发展到轻度认知障碍(MCI)，再到AD的恶性肿瘤。因为 突触对认知功能至关重要，突触丢失被认为是一种很有前途的预后标志 在AD患者中。因此，监测体内突触密度的能力对阿尔茨海默病患者很重要 管理层。基于突触密度成像的关键需求和我们的初步成功，我们将验证 新制剂在正常动物和AD动物在此补充。这种方法的成功不仅可以导致 用于AD患者的新的PET试剂，但由于更简单和温和，也增加了PET试剂的可用性 反应条件。这里提出了两个目标。在目标1中，我们将建立18F-UCB的放射化学 突触密度成像试剂。为了让代理商以低成本广泛应用于现场，我们将 还为我们的UCB试剂开发了基于LED光的合成方法。在目标2中，我们将描述敏感度 我们的18F-UCB制剂在正常和AD小鼠中的应用。总而言之，光氧化还原反应是一种全新的方法 在芳香族化合物中加入[18F]F。温和的条件加上很容易到达 所需的前体将允许前所未有地获得新型芳香族[18F]PET示踪剂，用于 神经学。本附录的目标是开发和验证用于成像突触丢失的创新的PET试剂 在AD模型中，基于我们新开发的标记方法。

Abstract Positron emission tomography (PET) is a powerful and rapidly developing technology that plays key roles in medical imaging, including the research of Alzheimer’s disease. Despite the exceptional promise of PET imaging, the availability of PET agents is limited in many situations due to the lack of efficient and simple labeling methods to modify biologically active small molecules/drugs. Based on the highly innovative photoredox systems described by the Nicewicz group, Li, Wu and Nicewicz have made the first breakthrough on direct arene C–H fluorination with 18F- that allows direct conversion of drugs to PET agents; followed by SNAr radiofluorination that could precisely control the radiofluorination position on aromatic substrates. This new method indeed provide us access to agents that are previously challenging or impossible to synthesize. Based on the Nucleophilic Aromatic Substitution we just developed, initial success was made on the synthesis of innovative PET agents for synapse density imaging. Affecting 6 million people in the USA, Alzheimer’s disease (AD) is increasingly viewed as a malignancy that progressed from preclinical AD, to mild cognitive impairment (MCI), and to AD. Because synapses are crucial for cognitive function, synaptic loss has been observed as a promising prognosis marker in AD patients. The ability to monitor synaptic density in vivo would therefore be important in AD patient management. Based on the critical need of synapse density imaging and our initial success, we will validate the new agents in normal and AD animals in this supplement. The success of this approach could not only lead to new PET agents for AD patients, but also increase the availability of the PET agent due to simpler and milder reaction conditions. Two aims are proposed here. In Aim 1, we will establish the radiochemistry of 18F-UCB agents for synapse density imaging. In order to make the agent widely available to the field with low cost, we will also develop LED light based synthetic method for our UCB agents. In Aim 2, we will characterize the sensitivity of our 18F-UCB agent in normal and AD mice. In summary, photoredox reactions are entirely new methods for the incorporation of [18F]F into aromatic compounds. The mild conditions coupled with easy access to the required precursors will allow for the unprecedented access to novel aromatic [18F] PET tracers for use in neurology. The goal of this supplement is to develop and validate innovative PET agents to image synaptic loss in AD model based on our newly developed labeling method.