Evaluation of a Novel Infection PET Diagnostic

新型感染 PET 诊断的评估

• 批准号: 10020585
• 负责人: PETER J TONGE
• 金额: $ 0.45万
• 依托单位: CHRONUS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-21 至 2020-03-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020585
• 关键词: 4-Aminobenzoic Acid; Adverse effects; Animal Disease Models; Antibiotic Resistance; Antibiotic Therapy; Bacteria; Bacterial Infections; Biopsy; Blood Tests; C-reactive protein; Clinical; Clinical Research; Communicable Diseases; Cyclic GMP; Data; Development; Diagnosis; Diagnostic; Dose; Erythrocyte Sedimentation Rate; Evaluation; Financial cost; Fluorine; Goals; Health; Health Care Costs; Heart Valves; Human; Human body; Image; Incidence; Infection; Infective endocarditis; Inflammation; Inflammatory Response; Joint Prosthesis; Joints; Label; Licensing; Location; Maximum Tolerated Dose; Medical; Modeling; Monitor; Morbidity - disease rate; Mus; Nosocomial Infections; Orthopedics; Osteomyelitis; Outcome; Patients; Pharmacologic Substance; Phase; Population; Positron-Emission Tomography; Pre-Clinical Model; Preparation; Radiation; Radiation exposure; Radiolabeled; Radiometry; Rattus; Rodent Model; Serum; Signal Transduction; Site; Small Business Technology Transfer Research; Soft Tissue Infections; Staphylococcus aureus; Staphylococcus aureus infection; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Tracer; Translating; Triceps Brachii Muscle; United States; base; bone; chemotherapy; clinically relevant; commercial application; commercialization; cost; data submission; dosimetry; fluorodeoxyglucose; human imaging; imaging study; implant associated infection; implantable device; improved; innovation; joint infection; methicillin resistant Staphylococcus aureus; mortality; mouse model; noninvasive diagnosis; novel; pathogen; pathogenic bacteria; pre-clinical; programs; radiochemical; radiotracer; response; response biomarker; tool; uptake

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.

项目摘要/摘要 细菌感染，例如假体关节，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） 可用于非侵入性宠物成像的放射性示例可检测和定位人类中的细菌病原体。 这种放射性示例将区分不同的病原体种群，作为非侵入性诊断和 在化学疗法期间告知细菌负荷，从而确定和改善患者的治疗 传染病。我们已经合成了P-氨基苯甲酸，2-氟-4--的氟-18标记的衍生物 氨基苯甲酸（[18F] F-PABA），这是一种新型的放射性示踪剂，被细菌选择性地吸收，包括临床上 - 包括MRSA在内的金黄色葡萄球菌的相关菌株。我们已经表明，[18F] F-PABA积聚在S的位置。 在疾病的动物模型中，金黄色葡萄球菌感染可以定量细菌负荷作为化学疗法的函数。 值得注意的是，[18F] F-PABA可以将细菌感染与炎症区分开，与广泛使用的临床不同 宠物示踪剂2-脱氧-2- [18F]氟-D-葡萄糖（[18F] FDG）。该阶段I sttr的对象是验证[18f] f- PABA在感染和进行研究的临床前模型中，以准备IND提交。在目标1中我们 将证明[18F] F-PABA可以检测和图像S.金黄色 感染，这种放射性示踪剂可以与抗生素治疗的函数定量细菌负荷。在目标2中我们 将进行剂量测定研究，以评估预计人剂量引起的辐射暴露。我们 还将证明19f-paba不会在100倍的预计人中表现出任何不利影响 小鼠的剂量。因此，我们将证明辐射负担和毒性是由radiotracer剂量引起的 根据FDA的数据，临床研究提出的临床研究范围内。我们已经 开发了适用于人类研究的[18F] F-PABA的CGMP合成，这一阶段I将铺平 对于II期STTR，我们将将放射性示踪剂转化为人类。