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。早期发现感染是必要的，以便尽快进行抗生素治疗。感染在体内的空间定位往往决定了治疗。空间定位在诊断中也很重要，例如，确定疼痛的关节假体是感染还是仅仅是松动，或者发烧患者的血管移植物是否确实感染并需要切除。我们已经开发出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，是细菌和病毒胸腺嘧啶激酶（TKs）的底物。进入细胞后，这些化合物被磷酸化，被困住并浓缩在含有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多种细菌进行成像的能力。利用病毒TK，我们也能够对伽玛疱疹病毒感染的肿瘤进行成像。目前最先进的感染成像技术涉及从患者身上分离和标记白细胞并重新给药的繁琐过程。这种技术通常会产生误报（无菌炎症），而且操作繁琐且效率低下。在临床上，标记白细胞的新替代品，特别是对于轴骨的慢性感染，是使用[18F]氟脱氧葡萄糖（FDG-PET）的正电子发射断层扫描。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为感染成像提供一种可行的替代方法，但目前只在一个有限的临床应用中进行了测试：肌肉骨骼感染。在本研究中，我们将进一步研究肌肉骨骼感染，将这种新方法与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，我们将对一组类风湿关节炎患者进行成像，类风湿关节炎是一种无菌的关节炎症。我们还将通过研究一组可能患有肺部感染的患者，将我们的方法扩展到一个新的临床适应症（目的2）。迄今为止，我们一直使用的显像剂是2'-氟-2'-脱氧-1-2- d -阿拉伯呋喃基-5- [124I]碘脲嘧啶（[124I]FIAU），用于PET联合计算机断层扫描（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化方式合成相应的标有18F的材料，以实现最终过渡到[18F]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成像感染的新选择。

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.