Novel Radiochemistry with Fluorine-18

该计划旨在(1)发展正电子发射体层析(PET)/荧光(FL)双成像探针的荧光点击化学策略；(2)将钯介导的交叉偶联化学用于18F标记化学选择性多肽和蛋白质。该提案涉及18F的基础放射化学，导致了用于体内疾病生物标记物的高灵敏度和准确检测的新型显像剂。*我们将首先用18F探索几个荧光点击的化学概念，以制备新型的双成像探针，它内在地结合了PET和荧光成像技术的高度协同和互补的成像优势。荧光点击标记策略将包括：(A)作为光触发生物正交连接方法的各种18F标记的四唑与烯烃的光点击化学，以形成荧光的吡唑啉环加成物，(B)铜(I)介导的各种18F标记的3-叠氮基香豆素与炔之间的1，3-偶极环加成反应，以得到荧光的三唑基香豆素，(C)18F标记的和弱荧光的炔修饰的苯并噻唑衍生物与叠氮化合物的点击化学，以形成放射性标记的和荧光点击的加合物，以及(D)使用18F标记的sydone报告作为高荧光无铜点击连接化学的新构建块来制备双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，用于将18F特定地掺入多肽和蛋白质中。我们将利用不同的交叉偶联策略对18F中肽和蛋白质中的几个天然氨基酸残基和修饰氨基酸残基进行钯介导的修饰。利用天然氨基酸残基对多肽和蛋白质进行定点修饰将包括使用18F标记的乙酸烯丙酯和烯丙基碳酸酯作为新的18F标记的构建块，用于与酪氨酸残基的Tsuji-Trost反应，以及半胱氨酸残基与4-[18F]氟碘苯的[18F]氟芳基化反应。将烯烃、炔烃或芳基硼酸基序安装到多肽和蛋白质中将包括通过偶氮偶联化学对酪氨酸残基进行化学选择性修饰。这将使随后的钯介导的交叉偶联反应分别与Mirozoki-Heck、Sonogashira和Suzuki-Miyaura化学的4-[18F]氟碘苯反应，形成各自的4-[18F]氟代芳基化合物作为新型PET显像剂。*这两个项目部分都可以导致新的PET显像剂，用于非侵入性和准确地检测人类疾病的生物标志物，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进程。因此，这项提议对加拿大人有重大好处。

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.