Novel Radiochemistry with Fluorine-18

该提案研究了具有短寿命正电子发射体氟-18（18F）的新型放射化学，其目的是（1）开发用于正电子发射断层扫描（PET）/荧光（FL）双重成像探针的荧光点击化学策略，以及（2）使用钯介导的交叉偶联化学进行18F的化学选择性肽和蛋白质标记。该提案涉及使用18F的基础放射化学，从而产生新型成像剂，用于体内疾病生物标志物的高灵敏度和准确检测。* 我们将首先利用18 F探索几种荧光点击化学概念，以制备新型双成像探针，其本质上联合收割机了PET和荧光成像技术的高度协同和互补成像优势。荧光"点击“标记策略将包括（a）各种18 F-标记的四唑与烯烃的光点击化学，作为光触发生物正交连接方法，以形成荧光吡唑啉环加合物，（B）各种18 F-标记的3-叠氮基香豆素与炔之间的铜（I）介导的1，3-偶极环加成反应，以得到荧光三唑基香豆素，（c）18F标记的和弱荧光的炔修饰的苯并噻唑衍生物与含叠氮化物的化合物的点击化学反应，以形成放射性标记的和荧光的点击加合物，和（d）使用18F-标记的悉尼酮报道分子作为高荧光无铜点击连接化学的新型结构单元，以制备双重PET/FL成像探头。* 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定点掺入肽和蛋白质中。我们将利用不同的交叉偶联策略，用18 F对肽和蛋白质中的几个天然和修饰的氨基酸残基进行钯介导的修饰。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标记的乙酸烯丙酯和碳酸烯丙酯作为新型18F标记的结构单元，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、炔或芳基硼酸基序安装到肽和蛋白质中将包括通过偶氮偶联化学对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-[18 F]氟碘苯分别根据Mirozoki-Heck，Sonogashira和Suzuki-Miyaura化学，以形成相应的4-[18 F]氟芳基化化合物作为新的PET成像剂。这两个项目部分都可以产生新型PET成像剂，用于非侵入性和准确检测人类疾病生物标志物，并通过创新的双成像探针进一步推进药物开发和评估过程。因此，该提案对加拿大人有很大的好处。

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.