Novel PET Radiotracers for Imaging Infection

项目摘要/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 作为非侵入性诊断，并在化疗期间告知细菌载量，从而 识别和改进传染病患者的治疗。虽然这种方法最终将是 适用于任何感染剂，目前的建议集中在开发用于 金黄色葡萄球菌，是皮肤和软组织感染、骨髓炎、感染性疾病的主要原因 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 骨骼和心脏瓣膜，以及假体关节感染，分别特别难发现和 由于它们在人体内的位置限制了临床样本的可获得性，是诊断的主要原因 发病率、死亡率和财务成本的原因。通常需要手术干预，而不适当的 使用广谱抗生素会导致其他问题，如破坏微生物群。虽然 非侵入性成像是一种很有前途的检测和诊断感染的方法，目前的临床方法 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……里面 此外，目前正在开发的PET感染示踪剂也没有被金黄色葡萄球菌摄取，遭受 信号背景比差，或者在金黄色葡萄球菌感染模型中没有得到广泛的评估。在……里面 在这个建议中，我们描述了氟-18标记的2-氟-4-氨基苯甲酸([18F]F-PABA)的评价。 能被细菌选择性摄取的新型放射性示踪剂。我们已经证明了[18F]F-PABA在 在疾病的动物模型中金黄色葡萄球菌软组织感染的部位，并可以区分细菌感染和 发炎。在目标1中，我们将确定[18F]F-PABA成像临床相关菌株的能力。 并评估[18F]F-PABA监测感染进展和量化细菌的能力 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。 在两种临床相关的感染模型--骨髓炎和感染性心内膜炎中发现金黄色葡萄球菌。在《目标3》中，我们将 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药性的细菌 叶酸生物合成，确定F-PABA在细菌细胞中的去向以了解分子因素 控制F-PABA在细菌中的积累，并确定提高 [18F]F-PABA对影像感染的影响。

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.