Evaluation of a Novel Infection PET Diagnostic

项目总结/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 医疗保健费用。因此，我们计划的长期目标是开发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，用作非侵入性诊断， 告知化疗期间的细菌负荷，从而识别和改善患者的治疗 传染病本文合成了一种氟-18标记的对氨基苯甲酸衍生物2-氟-4- 氨基苯甲酸（[18F]F-PABA），一种新型放射性示踪剂，可被细菌选择性吸收，包括临床上- S.金黄色葡萄球菌包括MRSA。我们已经证明[18 F]F-PABA在S. 金黄色葡萄球菌感染的动物疾病模型，并可以量化细菌负荷作为化疗的函数。 值得注意的是，[18F]F-PABA可以区分细菌感染和炎症，这与广泛使用的临床诊断不同。 PET示踪剂2-脱氧-2-[18 F]氟-D-葡萄糖（[18 F]FDG）。本阶段I STTR的目的是验证[18 F]F- PABA在临床前感染模型中的应用，并进行研究，为IND提交做准备。在目标1中， 将证明[18 F]F-PABA可以检测和成像S。金黄色葡萄球菌在假体周围关节的临床前模型中 感染，并且该放射性示踪剂可以量化细菌负荷作为抗生素治疗的函数。在目标2中， 将进行剂量测定研究，以评估预计人体剂量造成的辐射照射。我们 还将证明，19 F-PABA在100倍于人类预期的剂量下不会显示任何不良影响。 小鼠剂量。因此，我们将表明，放射性示踪剂剂量引起的辐射负荷和毒性 根据FDA的数据，拟定用于临床研究的剂量在可接受范围内。我们已经 开发了适合人体研究的[18F]F-PABA的cGMP合成，这一I期STTR将为 第二阶段STTR的方式，我们将把放射性示踪剂转化为人类。

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.