A PET Diagnostic for Imaging Bacterial Infection

项目总结 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)很难诊断和治疗，是死亡率、发病率和医疗保健的主要原因 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。这种放射性示踪剂 将作为一种非侵入性诊断，准确识别细菌感染并告知细菌载量 在化疗期间，从而确定和改善传染病患者的治疗结果。 我们合成了一种新的放射性示踪剂CC-001，它可以被细菌选择性地摄取，包括临床上 金黄色葡萄球菌相关菌株。我们已经证明CC-001在金黄色葡萄球菌的部位聚集 感染是一种软组织感染的疾病模型。值得注意的是，CC-001可以区分细菌感染和 炎症不同于临床广泛使用的PET示踪剂2-脱氧-2-[18F]氟-D-葡萄糖([18F]FDG)。该对象 这项研究的第一阶段是在感染的临床前模型中验证CC-001，并在准备中进行研究 提交一份研究用的新药。在目标1中，我们将演示CC-001可以检测和成像S。 在感染性心内膜炎的临床前模型中发现金黄色葡萄球菌，这种放射性示踪剂可以量化细菌负荷作为 抗生素治疗的作用。在目标2中，我们将进行剂量学研究，以评估计划的 与临床相关的人体剂量的辐射暴露。我们还将演示CC-001不会显示 在小鼠身上的任何不良反应都是人类计划剂量的100倍和1000倍。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所造成的负担和毒性在可接受的范围内 范围基于美国食品和药物管理局的数据。这一第一阶段的STTR将为 第二阶段，我们将收集更多的临床前数据，并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.