TK-based Infection Imaging

描述(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卫生问题。及早发现感染对于尽快实施抗生素治疗是必要的。感染在体内的空间定位往往决定了治疗方法。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感染还是仅仅松动，或者出现发烧症状的患者的血管移植物是否确实受到感染需要切除。我们已经开发了一种特殊的感染成像技术，适用于大多数细菌和许多病毒。该方法使用放射性标记的核苷类似物，作为细菌和病毒胸苷激酶(TKS)的底物。一旦进入细胞，这些化合物就被磷酸化，捕获并浓缩在含有TK酶的细胞中。我们已经在动物模型和有限的临床研究中成功地展示了成像各种细菌物种的能力。我们也已经能够通过病毒TK对感染了伽马疱疹病毒的肿瘤进行成像。目前最先进的成像感染包括从患者身上分离和标记白细胞并重新给药的繁琐过程。这项技术经常提供假阳性(无菌炎症)，而且繁琐且效率低下。[18F]氟代脱氧葡萄糖正电子发射断层扫描(FDG-PET)是标记白细胞的新兴临床替代品，特别是对于中轴骨的慢性感染。我们的技术可以直接对细菌进行无线电标记和成像。我们预计，我们的技术将为感染成像提供一种可行的替代方法，但只在一个有限的临床应用中进行了测试：肌肉骨骼感染。在这项建议中，我们将进一步研究肌肉骨骼感染，将这一新方法与FDG-PET进行比较，同时试图确定我们技术的敏感性，特别是特异性。为了确定特异性，我们将对类风湿性关节炎患者进行成像，类风湿性关节炎是一种无菌的关节炎症形式。我们还将通过研究一小部分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。到目前为止，我们一直使用的显像剂是2‘-氟-2’-脱氧-1-2-D-阿拉伯呋喃葡萄糖-5-[124I]碘尿嘧啶([124I]FIAU)，用于PET/CT。除了使用[124I]FIAU实现前两个目标外，第三个目标将涉及以自动方式合成相应的18F标记材料，以使最终能够过渡到[18F]FIAU。我们最终可能会在未来的研究中使用18F标记的材料。我们相信，该项目将有助于建立这种基于核苷的成像技术，作为一种新的成像感染替代方案。 与公共卫生相关：目前成像感染的方法繁琐，缺乏特异性。我们开发了一种使用正电子发射断层扫描(PET)的方法，通过细菌胸苷激酶(TK)酶直接对细菌进行放射性标记和成像，该酶可以用[124I]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方面的特异性，并将自动合成我们的显像剂的放射性氟化版本。

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.