A PET Diagnostic for Imaging Bacterial Infection

项目摘要 细菌感染，如假体关节、骨骼（骨髓炎）和心脏瓣膜（感染性 心内膜炎）难以诊断和治疗，并且是死亡率、发病率和卫生保健的主要原因 成本我们计划的长期目标是开发一种正电子发射断层扫描（PET）放射性示踪剂， 可用于非侵入性PET成像，以检测和定位人体内的细菌病原体。这个放射性示踪剂 将作为一种非侵入性诊断，以准确识别细菌感染，并告知细菌负荷 在化疗期间，从而识别和改善感染性疾病患者的治疗结果。 我们已经合成了一种新的放射性示踪剂，CC-001，它被细菌选择性地吸收，包括临床上 金黄色葡萄球菌的相关菌株。我们已经证明CC-001在S.金黄色 在软组织感染疾病模型中的感染。值得注意的是，CC-001可以区分细菌感染和 与广泛使用的临床PET示踪剂2-脱氧-2-[18 F]氟-D-葡萄糖（[18 F]FDG）不同，对象 该I期STTR的目的是在感染的临床前模型中验证CC-001，并在制备中进行研究。 用于研究性新药申报。在目标1中，我们将证明CC-001可以检测和成像S。 金黄色葡萄球菌在感染性心内膜炎的临床前模型中，这种放射性示踪剂可以量化细菌负荷， 抗生素治疗的作用。在目标2中，我们将进行剂量测定研究，以评估预计的 临床相关人体剂量的辐射暴露。我们还将证明CC-001不显示 在小鼠中，100和1000倍于预计人体剂量的任何不良反应。因此，我们将证明辐射 建议用于临床研究的放射性示踪剂剂量产生的负荷和毒性在可接受范围内 范围基于美国食品和药物管理局的数据。第一阶段短期技术研究将为 II期STTR，我们将收集额外的临床前数据，随后过渡到临床试验。

PROJECT SUMMARY Bacterial infections such as those of prosthetic joints, bones (osteomyelitis) and heart valves (infective endocarditis) are difficult to diagnose and treat, and are a major cause of mortality, morbidity and health care costs. The long-term goal of our program is to develop a positron emission tomography (PET) radiotracer that can be used for non-invasive PET imaging to detect and localize bacterial pathogens in humans. This radiotracer will serve as a non-invasive diagnostic to accurately identify bacterial infections and inform on bacterial load during chemotherapy, thereby identifying and improving treatment outcomes of patients with infectious diseases. We have synthesized a novel radiotracer, CC-001, that is selectively taken up by bacteria including clinically relevant strains of Staphylococcus aureus. We have shown that CC-001 accumulates at the site of S. aureus infection in a soft tissue infection model of disease. Significantly, CC-001 can distinguish bacterial infection from inflammation unlike the widely used clinical PET tracer 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). The object of this Phase I STTR is to validate CC-001 in a preclinical model of infection and perform studies in preparation for an investigational new drug submission. In Aim 1 we will demonstrate that CC-001 can detect and image S. aureus in a preclinical model of infective endocarditis and that this radiotracer can quantify bacterial load as a function of antibiotic treatment. In Aim 2 we will perform dosimetry studies in order to assess the projected radiation exposure at a clinically relevant human dose. We will also demonstrate that CC-001 does not display any adverse effects at 100 and 1000 times the projected human dose in mice. Thus, we will show that radiation burden and toxicity resulting from the dose of radiotracer proposed for clinical studies is within the acceptable range based on data from the U.S Food and Drug Administration. This Phase I STTR will pave the way for a Phase II STTR in which we will gather additional preclinical data and subsequently transition into clinical trials.