Evaluation of a Novel Infection PET Diagnostic

项目摘要/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)很难诊断和治疗，是死亡、发病率和死亡率的主要原因。 医疗保健费用。因此，我们计划的长期目标是发展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区分不同的病原体群体，作为非侵入性诊断和 告知化疗期间的细菌载量，从而识别和改进患者的治疗 传染病。我们合成了对氨基苯甲酸的氟-18标记的衍生物2-氟-4- 氨基苯甲酸([18F]F-PABA)是一种新型的放射性示踪剂，临床上可选择性地被细菌摄取。 金黄色葡萄球菌相关菌株，包括耐甲氧西林金黄色葡萄球菌。结果表明，[18F]F-PABA在S。 金黄色葡萄球菌感染在动物模型中的疾病，并可以量化细菌载量作为化疗的功能。 值得注意的是，与广泛使用的临床应用不同，[18F]F-PABA可以区分细菌感染和炎症 2-脱氧-2-[18F]氟-D-葡萄糖([18F]FDG)。此第一阶段STTR的目的是验证[18F]F- PABA在临床前感染模型中，并进行研究，为IND提交做准备。在目标1中，我们 将证明[18F]F-PABA可以在假体周围关节的临床前模型中检测和成像金黄色葡萄球菌 这种放射性示踪剂可以量化抗生素治疗过程中的细菌载量。在《目标2》中，我们 将进行剂量学研究，以评估预计的人体剂量造成的辐射暴露。我们 还将证明，19F-PABA在100倍于预计的人体内没有表现出任何不良影响 小鼠体内的剂量。因此，我们将展示由放射性示踪剂剂量引起的辐射负荷和毒性 根据FDA的数据，建议用于临床研究的药物在可接受的范围内。我们已经这么做了 开发了一种适合人体研究的cGMP合成[18F]F-PABA，这一第一阶段的STTR将为 我们将把放射性示踪剂转化为人体的第二阶段STTR的方法。

Project Summary/Abstract Bacterial infections such as those of prosthetic joints, bones (osteomyelitis) and heart valves (infective endocarditis) are difficult to 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 thus to develop positron emission tomography (PET) radiotracers that can be used for non-invasive PET imaging to detect and localize bacterial pathogens in humans. Such radiotracers will distinguish between different pathogen populations, serve as non-invasive diagnostics and inform on bacterial load during chemotherapy, thereby identifying and improving treatment of patients with infectious diseases. We have synthesized a fluorine-18 labeled derivate of p-aminobenzoic acid, 2-fluoro-4- aminobenzoic acid ([18F]F-PABA), a novel radiotracer that is selectively taken up by bacteria including clinically- relevant strains of S. aureus including MRSA. We have shown that [18F]F-PABA accumulates at the site of S. aureus infection in an animal model of disease, and can quantify bacterial load as a function of chemotherapy. Significantly, [18F]F-PABA 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 [18F]F- PABA in a preclinical model of infection and perform studies in preparation for an IND submission. In Aim 1 we will demonstrate that [18F]F-PABA can detect and image S. aureus in a preclinical model of periprosthetic joint infection 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 radiation exposure caused by a projected human dose. We will also demonstrate that 19F-PABA does not display any adverse effects at 100-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 FDA. We have already developed a cGMP synthesis of [18F]F-PABA suitable for human studies, and this Phase I STTR will pave the way for a Phase II STTR in which we will translate the radiotracer into humans.