Novel Radiochemistry with Fluorine-18

该提议研究了短寿命正电子发射器氟-18 （18F）的新型放射化学，旨在(1)开发用于正电子发射断层扫描(PET)/荧光（FL）双成像探针的荧光“点击”化学策略，以及(2)使用钯介导的交叉偶联化学用于18F的化学选择性肽和蛋白质标记。该提案涉及18F的基础放射化学，可用于高灵敏度和准确检测体内疾病生物标志物的新型显像剂。我们将首先用18F探索几种荧光“点击”化学概念，以制备新型双成像探针，这些探针本质上结合了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)各种18f标记的四唑与烯烃的光点击化学，作为光触发的生物正交连接方法，形成荧光吡唑啉环加合物，(b)铜(I)介导的各种18f标记的3-叠氮香豆素与炔之间的1,3-偶极环加成反应，得到荧光三唑香豆素。(c)将18f标记的和弱荧光的烷基修饰的苯并噻唑衍生物与含叠氮化合物进行点击化学反应，形成放射性标记的和荧光的“点击”加合物，以及(d)使用18f标记的sydnone报告物作为高荧光性无铜点击连接化学的新型构建块，以制备双PET/FL成像探针。该项目的第二部分将开发创新的钯介导放射化学，用于将18F结合到肽和蛋白质中。我们将利用不同的交叉偶联策略，对含18F的多肽和蛋白质中的几种天然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位点特异性修饰，包括使用18F标记的醋酸烯丙酯和碳化烯丙酯作为新的18F标记的构建块，用于酪氨酸残基的Tsuji-Trost反应，以及半胱氨酸残基与4-[18F]氟碘苯的氟芳基化反应。在多肽和蛋白质中安装烯烃、炔或芳基硼酸基序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。根据mirozaki - heck、Sonogashira和Suzuki-Miyaura化学，这将使随后的钯介导的与4-[18F]氟碘苯的交叉偶联反应能够形成各自的4-[18F]氟化化合物，作为新型PET显像剂。这两个项目部分都可以带来新型PET显像剂，用于无创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进程。因此，该提案对加拿大人有重大的好处。

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.