Visible Light Promoted Fluorination for Application to PET Imaging

可见光促进氟化在 PET 成像中的应用

• 批准号: 9259364
• 负责人: Laura Keiko Ackerman
• 金额: $ 5.67万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259364
• 关键词: Attention; Benzoic Acids; Biological; Carbon; Carboxylic Acids; Cell Nucleus; Chemicals; Chemistry; Collaborations; Copper; Coupling; Detection; Development; Epoxy Compounds; Esters; Fluorides; Fluorine; Fluorouracil; Half-Life; Image; Imaging Techniques; In Situ; Label; Ligands; Light; Metals; Methodology; Methods; Neurodegenerative Disorders; Organic Chemistry; Oxidants; Oxidation-Reduction; Positron-Emission Tomography; Prevalence; Procedures; Radioactive; Radiochemistry; Radiopharmaceuticals; Reaction; Reaction Time; Reagent; Research; Salts; Source; System; Temperature; Transition Elements; Translating; Translations; Visible Radiation; catalyst; design; experimental study; metal complex; molecular imaging; physical property; radiotracer; success

Project Summary The incorporation of fluorine into molecules has been widely demonstrated to alter the physical properties as well as bioactivity of chemical compounds. While a variety of practical catalytic fluorination methods have been established for late-stage 19F chemistry there are relatively few practical methods for 18F that enable access to a broad scope of substrates. Conventional methods for accessing C-F bonds in radiochemistry are highly specialized for aliphatic compounds and utilize organometallic reagents or stoichiometric oxidants for aryl compounds. Ideally, a fluorination strategy would occur at room temperature and rely on abundant and stable organic substrates such as benzoic acids and inexpensive fluoride salts. Although cross- coupling methods are capable of promoting this type of reaction in the presence of a transition metal catalyst, a long-standing challenge, especially in aryl fluorination, is the effective reductive elimination of carbon-fluorine bonds from a low-valent transition metal complex. In this research strategy, we propose accessing a reactive, high-valent metal fluoride species with a photocatalyst, while still relying on convenient aryl starting materials. In addition to acting as an oxidant for the transition metal, we propose that the photocatalyst in its reduced state can activate an aryl ester for capture by the main transition metal catalyst. This ester can be easily made in situ or pre-synthesized from the corresponding carboxylic acid, making the procedure amenable to a radiochemist. The unification of a photoredox catalyst with a transition metal catalyst has precedent, however, has not yet been applied to fluorination chemistry. This dual catalytic system is predicted to enable the fluorination of Lewis basic and protic molecules under mild conditions. And, if successful, this reaction would provide the first example of light-driven synthesis of radiopharmaceuticals. Due to the prevalence of fluorine in bioactive molecules, the success of this chemistry with even 19F would represent a valuable advance in the field. Specific aim 1 discusses the design and optimization of the light promoted fluorination of activated aryl esters. Specific aim 2 presents the fluorination of activated aliphatic esters. And, specific aim 3 discusses the application of this methodlogy to the development of radiopharmaceuticals.

项目摘要 在分子中掺入氟已被广泛证明能改变物理性质。 化合物的性质和生物活性。而各种实用的催化 已建立了用于晚期~(19)F化学的氟化方法，相对较少 18F的实用方法，使其能够获得广泛的底物。传统型 放射化学中获得C-F键的方法对于脂肪族来说是高度专门化的 化合物，并利用有机金属试剂或化学计量氧化剂芳基化合物。 理想情况下，氟化策略将在室温下进行，并依赖于丰富和稳定的 有机底物，如苯甲酸和廉价的氟化盐。尽管克罗斯- 耦合方法能够在存在转变的情况下促进这类反应 金属催化剂是一个长期存在的挑战，特别是在芳基氟化反应中，是一种有效的还原剂。 从低价过渡金属络合物中消除碳-氟键。 在这项研究策略中，我们建议获取一种活性的、高价的金属氟化物物种 使用光催化剂，同时仍然依赖方便的芳基起始材料。除了表演之外 作为过渡金属的氧化剂，我们认为处于还原状态的光催化剂可以 激活芳基酯以被主过渡金属催化剂捕获。这种酯可以很容易地 由相应的羧酸原位制成或预先合成，使程序 服从放射化学家的。光氧化还原催化剂与过渡金属的统一性 催化剂已有先例，但尚未将其应用于氟化化学。这种双重奏 预测了催化体系能够使Lewis碱性和质子化分子在 条件温和。如果成功，这种反应将提供第一个光驱动的例子 放射性药物的合成。由于生物活性分子中氟的普遍存在， 这种化学反应的成功，即使是19F，也将代表着该领域的宝贵进步。特定的 目的1讨论活性芳基的光促进氟化反应的设计和优化 酯类化合物。具体目标2介绍了活化脂肪酸酯的氟化反应。和，具体目标3 讨论了这一方法学在放射性药物开发中的应用。