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

摘要 正电子发射断层扫描（PET）是一种功能强大且发展迅速的技术， 在医学成像方面，包括阿尔茨海默病的研究。尽管PET有着非凡的前景， 由于缺乏有效和简单的标记，PET试剂的可用性在许多情况下受到限制 修饰生物活性小分子/药物的方法。基于高度创新的光氧化还原系统 Li，Wu和Nicewicz首次在直接芳烃C-H上取得了突破性进展 用18F进行放射性核素显像--允许药物直接转化为PET试剂;然后进行SNAr放射性核素显像， 可以精确控制芳香底物上的放射性位置。这种新方法确实为我们提供了 获得以前具有挑战性或不可能合成的试剂。基于亲核芳香族 我们刚刚开发的替代品，在合成用于突触的创新PET试剂方面取得了初步成功 密度成像影响美国600万人的阿尔茨海默病（AD）越来越被视为一种 从临床前AD进展到轻度认知障碍（MCI）和AD的恶性肿瘤。因为 突触对认知功能至关重要，突触丢失已被观察为有希望的预后标志物 在AD患者中。因此，在体内监测突触密度的能力在AD患者中是重要的 管理基于突触密度成像的迫切需要和我们的初步成功，我们将验证 在正常和AD动物的新代理商在这个补充。这种方法的成功不仅可以导致 用于AD患者的新PET剂，而且由于更简单和更温和， 反应条件这里提出两个目标。目的一：建立18F-UCB的放射化学 用于突触密度成像的试剂。为了使代理商能够以低成本广泛应用于该领域，我们将 我们还开发了基于LED光的UCB试剂合成方法。在目标2中，我们将描述灵敏度 我们的18F-UCB剂在正常和AD小鼠中的作用。总之，光氧化还原反应是一种全新的方法， 将[18 F]F掺入芳族化合物中。温和的条件加上容易获得 所需的前体将允许前所未有地获得新型芳族[18F] PET示踪剂，用于 神经学这一补充的目标是开发和验证创新的PET剂成像突触损失 在AD模型的基础上，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.