TK-based Infection Imaging

描述（由申请人提供）： 具有抗生素耐药性的传染病被认为是最紧迫的全球健康问题。感染的早期发现是必要的，以尽快开始抗生素治疗。感染在体内的空间定位通常决定治疗。空间定位在诊断中也很重要，例如，在确定疼痛的关节假体是否感染或仅仅松动，或者在发烧的患者中的血管移植物是否确实感染并需要切除时。我们已经开发出一种适用于大多数细菌和许多病毒的感染成像的特定技术。该方法使用细菌和病毒胸苷激酶（TK）底物的放射性标记核苷类似物。在进入细胞后，这些化合物被磷酸化，捕获并浓缩在含有TK酶的细胞内。我们已经成功地证明了在动物模型和有限的临床研究中对各种细菌物种进行成像的能力。我们还能够借助病毒TK对感染γ疱疹病毒的肿瘤进行成像。目前感染成像的最新技术涉及从患者分离和标记白细胞并重新给予它们的费力过程。该技术通常提供假阳性（无菌炎症），并且繁琐且效率低下。标记白细胞的新兴临床替代品，特别是对于中轴骨骼的慢性感染，是正电子发射断层扫描与[18 F]氟脱氧葡萄糖（FDG-PET）。我们的技术直接对细菌进行放射性标记和成像。我们预计，我们的技术将提供一种可行的替代感染成像的方式，但只在一个有限的临床应用中进行了测试：肌肉骨骼感染。在这项提案中，我们将进一步研究肌肉骨骼感染，比较这种新方法的FDG-PET，同时试图确定我们的技术的灵敏度，特别是特异性。为了确定特异性，我们将对一组患有类风湿性关节炎（一种无菌形式的关节炎）的患者进行成像。我们还将通过研究一小群可能患有肺部感染的患者（目标2），将我们的方法扩展到一个新的临床适应症。迄今为止，我们一直使用的显像剂是2 '-氟-2'-脱氧-1-2-D-阿拉伯呋喃糖基-5- [124 I]碘尿嘧啶（[124 I]FIAU），用于PET联合计算机断层扫描（PET/CT）。除了使用[124 I]FIAU执行前两个目标外，第三个目标将涉及以自动化方式合成用18 F标记的相应材料，以最终过渡到[18 F]FIAU。我们可能最终在未来的研究中使用18F标记的材料。我们相信，这个项目将有助于建立这种基于核苷的成像技术作为一种新的替代成像感染。 公共卫生相关性： 目前对感染进行成像的方法是繁琐的并且缺乏特异性。我们已经开发出一种方法，使用正电子发射断层扫描（PET），直接放射性标记和图像的细菌凭借的细菌胸苷激酶（TK）酶，它可以与[124 I]FIAU标记。我们将比较这种基于TK的技术与新兴的临床标准FDG-PET在定位肌肉骨骼和肺部感染的特异性方面的差异，并将自动合成我们的放射性氟化成像剂。

DESCRIPTION (provided by applicant): Infectious disease with antibiotic resistance is considered the most imperative global health problem. Early detection of infection is necessary to institute antibiotic therapy as soon as possible. The spatial localization of infection within the body often dictates treatment. Spatial localization is also important in diagnosis, for example, in determining whether a painful joint prosthesis is infected or merely loose or whether a vascular graft in a patient presenting with fever is indeed infected and needs excision. We have developed a specific technique for the imaging of infection that is applicable to most bacteria and many viruses. The method uses radiolabeled nucleoside analogs that are substrates of bacterial and viral thymidine kinases (TKs). Upon entering the cell, these compounds are phosphorylated, trapped and concentrated within cells harboring the TK enzyme. We have successfully demonstrated the ability to image a variety of bacterial species both in animal models and in a limited clinical study. We have also been able to image tumors infected with gamma herpesviruses by virtue of the viral TK. The current state-of-the-art for imaging infection involves a laborious process of isolating and tagging leukocytes from a patient and re-administering them. That technique often provides false positives (sterile inflammation) and is cumbersome and inefficient. The emerging clinical replacement for tagged leukocytes, particularly for chronic infections of the axial skeleton, is positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET). Our technique radiolabels and images bacteria directly. We anticipate that our technique will provide a viable alternative to the way infection is imaged, but have only tested it in one, limited, clinical application: musculoskeletal infection. In this proposal we will further study musculoskeletal infection, comparing this new method to FDG-PET, while attempting to determine the sensitivity and especially the specificity of our technique. To determine specificity we will image a cohort of patients with rheumatoid arthritis, a sterile form of joint inflammation. We will also extend our method to one new clinical indication by studying a small cohort of patients with possible pulmonary infection (Aim 2). The imaging agent that we have been using to date has been 2'-fluoro-2'-deoxy-1-2-D-arabinofuranosyl-5- [124I]iodouracil ([124I]FIAU) for PET combined with computed tomography (PET/CT). In addition to performing the first two aims using [124I]FIAU, the third aim will involve synthesis of the corresponding material labeled with 18F in an automated fashion to enable an eventual transition to [18F]FIAU. We may ultimately use the 18F- labeled material in future studies. We believe that this project will help to establish this nucleoside-based imaging technique as a new alternative for imaging infection. PUBLIC HEALTH RELEVANCE: Current methods to image infection are cumbersome and suffer from lack of specificity. We have developed a method that uses positron emission tomography (PET) that directly radiolabels and images bacteria by virtue of the bacterial thymidine kinase (TK) enzyme, which can be tagged with [124I]FIAU. We will compare this TK- based technique with the emerging clinical standard, FDG-PET, in terms of specificity for localizing musculoskeletal and pulmonary infection and will automate the synthesis of a radiofluorinated version of our imaging agent.