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click-on化学策略，以及(2)使用钯介导的交叉偶联化学用于化学选择性肽和蛋白质标记18F。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。

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.