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首页> 外文期刊>Chemistry: A European journal >General method for the C-labeling of 2-arylpropionic acids and their esters: Construction of a PET tracer library for a study of biological events involved in COXs expression
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General method for the C-labeling of 2-arylpropionic acids and their esters: Construction of a PET tracer library for a study of biological events involved in COXs expression

机译：C-标记2-芳基丙酸及其酯的通用方法：构建PET示踪剂文库，用于研究与COXs表达有关的生物学事件

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Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate ~(11)C radionuclide into various 2-arylpropionic acids that have a common methylated structure, particularly among nonsteroidal antiinflammatory drugs (NSAIDs). Thus, we developed a novel ~(11)C-radiolabeling methodology based on rapid C[~(11)C] methylation by the reaction of [~(11)C]CH_3I with enolate intermediates generated from the corresponding esters under basic conditions. One-pot hydrolysis of the above [~(11)C]methylation products also allows the synthesis of desired ~(11)C-incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [ ~(11)C]Ibuprofen, [~(11)C]Naproxen, [~(11)C] Flurbiprofen, [~(11)C]Fenoprofen, [~(11)C]Ketoprofen, and [ ~(11)C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)-induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [ ~(11)C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general ~(11)C-labeling of 2-arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression.
机译：环氧合酶（COX）是前列腺素生物合成中的关键酶，可调节多种生物学功能，例如疼痛，发烧等。为了通过正电子发射断层扫描（PET）进行体内COX成像，我们开发了一种将〜（11）C放射性核素掺入具有共同甲基化结构的各种2-芳基丙酸中的方法，尤其是在非甾体抗炎药（NSAID）中。因此，我们通过在碱性条件下[〜（11）C] CH_3I与相应酯生成的烯醇酸酯中间体反应，开发了一种基于快速C [〜（11）C]甲基化的新颖〜（11）C放射性标记方法。上述[〜（11）C]甲基化产物的一锅水解也可以合成所需的〜（11）C结合的酸。我们证明了该方法在六种PET示踪剂[[（（11）C]布洛芬，[〜（11）C]萘普生，[〜（11）C]氟比洛芬，[〜（11）C]非诺洛芬）的合成中的效用，[〜（11）C]酮洛芬和[〜（11）C]洛索洛芬。值得注意的是，我们发现它们的甲酯特别适合用作研究神经炎症的放射菌。对脂多糖（LPS）引起的脑部炎症的大鼠进行的microPET研究清楚地表明，PET示踪剂的放射性积聚在炎症区域。在这些PET示踪剂中，通过阻断研究证明了[〜（11）C]酮洛芬甲酯的特异性。在大鼠大脑中进行的代谢物分析表明，甲酯最初是在大脑中吸收的，然后进行水解以形成相应酸的药理活性形式。因此，我们成功地将2-芳基丙酸及其甲酯作为NSAIDs的PET示踪剂进行了〜（11）C标记，从而构建了潜在有用的PET示踪剂库，用于体内成像涉及COXs表达的炎症。

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