Novel Radiochemistry with Fluorine-18

氟 18 的新型放射化学

• 批准号: RGPIN-2019-04504
• 负责人: Wuest, Frank
• 金额: $ 3.5万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761830
• 关键词: Novel; Radiochemistry; Fluorine; 18; Novel; Radiochemistry; Fluorine; 18

The proposal studies novel radiochemistry with short-lived positron emitter fluorine-18 (18F) directed to (1) the development of fluorogenic `click-on' chemistry strategies for positron emission tomography (PET)/fluorescence (FL) dual imaging probes and (2) the use of palladium-mediated cross-coupling chemistry for chemoselective peptide and protein labeling with 18F. The proposal concerns fundamental radiochemistry with 18F leading to novel classes of imaging agents for high sensitivity and accurate detection of disease biomarkers in vivo. We will first explore several fluorogenic `click-on' chemistry concepts with 18F to prepare novel classes of dual imaging probes which intrinsically combine the highly synergistic and complementary imaging advantages of PET and fluorescence imaging technology. Fluorogenic `click-on' labeling strategies will include (a) photo-click chemistry of various 18F-labeled tetrazoles with alkenes as a light-triggered bioorthogonal ligation method to form fluorescent pyrazoline cycloadducts, (b) copper(I)-mediated 1,3-dipolar cycloaddition reactions between various 18F-labeled 3-azidocoumarins with alkynes to give fluorescent triazolylcoumarins, (c) click chemistry of 18F-labeled and weakly fluorescent alkyne-decorated benzothiazole derivatives with azide-containing compounds to form radiolabeled and fluorescent `click-on' adducts, and (d) the use of 18F-labeled sydnone reporters as novel building blocks for highly fluorogenic copper-free click ligation chemistry to prepare dual PET/FL imaging probes. The second part of the project will develop innovative palladium-mediated radiochemistry for the site-specific incorporation of 18F into peptides and proteins. We will utilize different cross-coupling strategies for palladium-mediated modification of several natural and modified amino acid residues in peptides and proteins with 18F. Site-specific modification of peptides and proteins employing natural amino acid residues will include the use of 18F-labeled allyl acetates and allyl carbonates as novel 18F-labeled building blocks for Tsuji-Trost reactions with tyrosine residues, and [18F]fluoroarylation reactions of cysteine residues with 4-[18F]fluoroiodobenzene. Installation of alkene, alkyne or aryl boronic acid motifs into peptides and proteins will comprise chemoselective modifications of tyrosine residues through azo coupling chemistry. This will enable subsequent palladium-mediated cross-coupling reactions with 4-[18F]fluoroiodobenzene according to Mirozoki-Heck, Sonogashira, and Suzuki-Miyaura chemistry, respectively, to form respective 4-[18F]fluoroarylated compounds as novel PET imaging agents. Both project parts can lead to novel PET imaging agents for non-invasive and accurate detection of human disease biomarkers, and to further advance the process of drug development and evaluation through innovative dual imaging probes. Therefore, the proposal is of significant benefit to Canadians.

该建议研究具有短寿命的正电子发射器氟-18（18F）的新型放射化学，该研究指向（1）开发荧光发射层造影（PET）/荧光（FL）偶性成像探针的荧光“点击启动”化学策略，以及（2）使用palladium介导的跨跨化学效应的化学效果。该提案涉及基本放射化学，18F导致新型成像剂类型，以高灵敏度和体内准确检测疾病生物标志物。 我们将首先使用18F探索几种荧光“点击式”化学概念，以准备新的双重成像探针，从而结合了PET的高度协同和互补成像的优势和荧光成像技术。 Fluorogenic `click-on' labeling strategies will include (a) photo-click chemistry of various 18F-labeled tetrazoles with alkenes as a light-triggered bioorthogonal ligation method to form fluorescent pyrazoline cycloadducts, (b) copper(I)-mediated 1,3-dipolar cycloaddition reactions between various 18F-labeled 3-azidocoumarins with （c）（c）单击18F标记和荧光型炔烃的化学，含叠氮化物的化合物的化学性质，形成辐射式和荧光的“单击式构造”，以及（d）供应18f-Labegen的构造，并形成含叠岩无铜点击连接化学准备双PET/FL成像探针。 该项目的第二部分将开发创新的钯介导的放射化学，以将18F特定于肽和蛋白质的特定地点掺入。我们将利用不同的交叉偶联策略来钯介导的肽和蛋白质中的几种天然和改性氨基酸残基的修饰，其18F。采用天然氨基酸残基的肽和蛋白质的位点特异性修饰将包括使用18F标记的烯丙基乙酸盐和烯丙基碳酸盐作为新型的18F标记的构件，用于与酪氨酸残基的TSUJI-TROST块反应，以及[18F]与[18f] cyperue cysteine cysteine cysteine cysteine cysteine cysteene Rescenene cysteene cysteene Rescene cysteene cysteene cysteene cysteene cysteene Rescenene cysteene cysteene Rescene cypyob cysene consenne consene consenne consene consection。将烷烃，炔烃或芳基硼酸基序的安装到肽中，蛋白质将通过偶氮偶联化学构成酪氨酸残基的化学选择性修饰。这将使随后的钯介导的交叉偶联反应与4- [18F]氟二苯苯根据Mirozoki-Heck，Sonogashira和Suzuki-Miyaura化学分别形成相应的4- [18f]氟含液的富含氟糖化的宠物成分。这两个项目部分都可以导致新颖的宠物成像剂，以非侵入性和准确检测人类疾病生物标志物，并通过创新的双重成像探针进一步推进药物开发和评估的过程。因此，该提议对加拿大人有重大好处。