Introduction

Bacterial infections are a major problem in medicine, and the rapid and accurate detection of such infections is essential for optimal patient outcome. Bacterial infections can be diagnosed by nuclear imaging, but most currently available modalities are unable to discriminate infection from sterile inflammation. Bacteria-targeted positron emission tomography (PET) tracers have the potential to overcome this hurdle. In the present study, we compared three ¹⁸F-labelled PET tracers based on the clinically applied antibiotic vancomycin for targeted imaging of Gram-positive bacteria.

Methods

[¹⁸F]FB-NHS and [¹⁸F]BODIPY-FL-NHS were conjugated to vancomycin. The resulting conjugates, together with our previously developed [¹⁸F]PQ-VE1-vancomycin, were tested for stability, lipophilicity, selective binding to Gram-positive bacteria, antimicrobial activity and biodistribution. For the first time, the pharmacokinetic properties of all three tracers were compared in healthy animals to identify potential binding sites.

Results

[¹⁸F]FB-vancomycin, [¹⁸F]BODIPY-FL-vancomycin, and [¹⁸F]PQ-VE1-vancomycin were successfully synthesized with radiochemical yields of 11.7%, 2.6%, and 0.8%, respectively. [¹⁸F]FB-vancomycin exhibited poor in vitro and in vivo stability and, accordingly, no bacterial binding. In contrast, [¹⁸F]BODIPY-FL-vancomycin and [¹⁸F]PQ-VE1-vancomycin showed strong and specific binding to Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which was outcompeted by unlabeled vancomycin only at concentrations exceeding clinically relevant vancomycin blood levels. Biodistribution showed renal clearance of [¹⁸F]PQ-VE1-vancomycin and [¹⁸F]BODIPY-FL-vancomycin with low non-specific accumulation in muscles, fat and bones.

Conclusion

Here we present the synthesis and first evaluation of the vancomycin-based PET tracers [¹⁸F]BODIPY-FL-vancomycin and [¹⁸F]PQ-VE1-vancomycin for image-guided detection of Gram-positive bacteria. Our study paves the way towards real-time bacteria-targeted diagnosis of soft tissue and implant-associated infections that are oftentimes caused by Gram-positive bacteria, even after prophylactic treatment with vancomycin.

中文翻译：

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用于使用正电子发射断层扫描检测细菌感染的新型 18F-万古霉素示踪剂的合成和临床前评估

介绍

细菌感染是医学上的一个主要问题，快速准确地检测此类感染对于获得最佳患者治疗结果至关重要。细菌感染可以通过核成像来诊断，但目前大多数可用的方法无法区分感染和无菌炎症。针对细菌的正电子发射断层扫描（PET）示踪剂有可能克服这一障碍。在本研究中，我们比较了基于临床应用抗生素万古霉素的三种^{18 F标记PET示踪剂，用于革兰氏阳性菌的靶向成像。}

方法

[ ¹⁸ F]FB-NHS 和[ ¹⁸ F]BODIPY-FL-NHS 与万古霉素缀合。由此产生的缀合物与我们之前开发的[ ¹⁸ F]PQ-VE1-万古霉素一起进行了稳定性、亲脂性、与革兰氏阳性菌的选择性结合、抗菌活性和生物分布的测试。首次在健康动物中比较了所有三种示踪剂的药代动力学特性，以确定潜在的结合位点。

结果

成功合成了[ ¹⁸ F]FB-万古霉素、[ ¹⁸ F]BODIPY-FL-万古霉素和[ ¹⁸ F]PQ-VE1-万古霉素，放化收率分别为11.7%、2.6%和0.8%。 [ ¹⁸ F]FB-万古霉素表现出较差的体外和体内稳定性，因此不与细菌结合。相比之下，[ ¹⁸ F]BODIPY-FL-万古霉素和[ ¹⁸ F]PQ-VE1-万古霉素对革兰氏阳性菌表现出强烈且特异性的结合，包括耐甲氧西林金黄色葡萄球菌（MRSA），仅与未标记的万古霉素竞争。浓度超过临床相关的万古霉素血液浓度。生物分布显示[ ¹⁸ F]PQ-VE1-万古霉素和[ ¹⁸ F]BODIPY-FL-万古霉素的肾脏清除率，在肌肉、脂肪和骨骼中非特异性积累较低。

结论

^{在这里，我们介绍了基于万古霉素的 PET 示踪剂 [ 18} F]BODIPY-FL-万古霉素和 [ ¹⁸ F]PQ-VE1-万古霉素的合成和首次评估，用于图像引导检测革兰氏阳性菌。我们的研究为对软组织和植入物相关感染进行实时细菌靶向诊断铺平了道路，这些感染通常是由革兰氏阳性菌引起的，即使在使用万古霉素进行预防性治疗后也是如此。