Currently, there exists no accurate, noninvasive clinical imaging method to detect living bacteria in vivo. Our goal is to provide a positron emission tomography (PET) method to image infection by targeting bacteria-specific metabolism. Standard of care methodologies detect morphologic changes, image immunologic response to infection, or employ invasive tissue sampling with associated patient morbidity. These strategies, however, are not specific for living bacteria and are often inadequate to detect bacterial infection during fever workup. As such, there is an unmet clinical need to identify and validate new imaging tools suitable for noninvasive, in vivo (PET) imaging of living bacteria. We have shown that d-[methyl-11C]methionine (d-[11C]Met) can distinguish active bacterial infection from sterile inflammation in a murine infection model and is sensitive to both Gram-positive and Gram-negative bacteria. Here, we report an automated and >99% enantiomeric excess (ee) synthesis of d-[11C]Met from a linear d-homocysteine precursor, a significant improvement over the previously reported synthesis utilizing a d-homocysteine thiolactone hydrochloride precursor with approximately 75-85% ee. Furthermore, we took additional steps toward applying d-[11C]Met to infected patients. d-[11C]Met was subject to a panel of clinically relevant bacterial strains and demonstrated promising sensitivity to these pathogens. Finally, we performed radiation dosimetry in a normal murine cohort to set the stage for translation to humans in the near future.

中文翻译：

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d- [甲基-11C]蛋氨酸的高对映体过量环内合成，用作细菌感染中的正电子发射断层显像示踪剂。

当前，尚不存在用于检测体内活细菌的准确，无创的临床成像方法。我们的目标是通过针对细菌的新陈代谢提供一种正电子发射断层扫描（PET）方法来对感染进行成像。标准的护理方法论可检测形态变化，对感染的图像免疫反应，或采用侵入性组织取样以及相关的患者发病率。但是，这些策略并非针对活细菌，并且通常不足以检测发烧后的细菌感染。因此，对于鉴定和验证适用于活细菌的非侵入性，体内（PET）成像的新成像工具的临床需求尚未得到满足。我们已经表明，在鼠类感染模型中，d- [甲基-11C]蛋氨酸（d- [11C] Met）可以区分活动性细菌感染和无菌性炎症，并且对革兰氏阳性和革兰氏阴性细菌均敏感。在这里，我们报道了从线性d-高半胱氨酸前体自动合成> 99％的d- [11C] Met的对映体过量（ee）的自动化方法，相对于先前报道的使用d-高半胱氨酸硫代内酯盐酸盐前体的合成，其合成有约75％的显着改进-85％ee。此外，我们还采取了其他步骤将d- [11C] Met应用于感染的患者。d- [11C] Met受一组临床相关细菌菌株的影响，并显示出对这些病原体的有希望的敏感性。最后，