Novel PET Radiotracers for Imaging Infection

项目概要/摘要 我们计划的长期目标是开发可用于非侵入性PET成像的放射性示踪剂， 检测和定位人体内的细菌病原体。这种放射性示踪剂将区分不同的病原体 人群，作为非侵入性诊断，并告知化疗期间的细菌负荷， 确定并改善对传染病患者的治疗。虽然这种方法最终将 适用于任何感染剂，目前的建议是集中在发展成像剂， 金黄色葡萄球菌，这是导致皮肤和软组织感染，骨髓炎，传染性 心内膜炎、菌血症和器械相关感染。骨髓炎和心内膜炎，这是感染 骨和心脏瓣膜以及人工关节感染特别难以检测， 由于它们在人体中的位置，限制了临床样品的可用性，并且是一个主要的 发病率、死亡率和经济成本的原因。通常需要手术干预，而不适当的 广谱抗生素的使用导致了额外的问题，例如微生物组的破坏。虽然 非侵入性成像是检测和诊断感染的有前途的方法， 缺乏敏感性和特异性，在许多情况下无法区分感染和炎症。在 此外，目前正在开发的PET感染示踪剂也不被S.金黄色葡萄球菌，患有 差的信号背景比，或尚未在S.金黄色葡萄球菌感染模型。在 在此建议中，我们描述了氟-18标记的2-氟-4-氨基苯甲酸（[18F]F-PABA）的评价， 一种新型的放射性示踪剂，它被细菌选择性地吸收。我们已经证明，[18 F]F-PABA积累在 S.金黄色葡萄球菌软组织感染的动物模型，并可以区分细菌感染， 炎症在目标1中，我们将确定[18 F]F-PABA对临床相关的S菌株成像的能力。 金黄色葡萄球菌，并评估[18 F]F-PABA监测感染进展和定量细菌 抗生素治疗期间的负担。在目标2中，我们将确定[18F]F-PABA检测和成像S的能力。 金黄色葡萄球菌在两种临床相关的感染模型，骨髓炎和感染性心内膜炎。在目标3中， 确定哪些细菌物种可以吸收[18F]F-PABA，包括那些对靶向药物具有抗性的细菌。 叶酸生物合成，确定F-PABA在细菌细胞中的命运，以了解分子因素 控制F-PABA在细菌中的积累，并确定提高 [18F]F-PABA成像感染。

Project Summary/Abstract The long-term goal of our program is to develop radiotracers that can be used for non-invasive PET imaging to detect and localize bacterial pathogens in humans. Such radiotracers will distinguish between different pathogen populations, serve as non-invasive diagnostics and inform on bacterial load during chemotherapy, thereby identifying and improving treatment of patients with infectious diseases. While this approach will ultimately be applicable to any infectious agent, the current proposal is focused on the development of imaging agents for Staphylococcus aureus, which is the leading cause of skin and soft tissue infections, osteomyelitis, infective endocarditis, bacteremia and device-related infections. Osteomyelitis and endocarditis, which are infections of bones and heart valves, respectively, as well as prosthetic joint infections, are particularly difficult to detect and diagnose due to their location in the human body which limits the availability of clinical samples, and are a major cause of morbidity, mortality and financial costs. Surgical intervention is often required, and the inappropriate use of broad spectrum antibiotics leads to additional problems such as disruption of the microbiome. Although non-invasive imaging is a promising approach for detecting and diagnosing infection, current clinical methods lack sensitivity and specificity, in many cases being unable to distinguish infection from inflammation. In addition, current PET infection tracers under development either are not taken up by S. aureus, suffer from poor signal-to-background ratios, or have not been extensively evaluated in S. aureus infection models. In this proposal, we describe the evaluation of fluorine-18 labeled 2-fluoro-4-aminobenzoic acid ([18F]F-PABA), a novel radiotracer that is selectively taken up by bacteria. We have shown that [18F]F-PABA accumulates at the site of S. aureus soft tissue infection in an animal model of disease and can distinguish bacterial infection from inflammation. In Aim 1 we will determine the ability of [18F]F-PABA to image clinically relevant strains of S. aureus and assess the ability of [18F]F-PABA to monitor the progression of infection and to quantify bacterial burden during antibiotic therapy. In Aim 2 we will determine the ability of [18F]F-PABA to detect and image S. aureus in two clinically-relevant models of infection, osteomyelitis and infective endocarditis. In Aim 3 we will determine which bacterial species can take up [18F]F-PABA including those that are resistant to drugs that target folate biosynthesis, determine the fate of F-PABA in bacteria cells in order to understand the molecular factors that control F-PABA accumulation in bacteria, and identify structural modifications that improve the ability of [18F]F-PABA to image infection.