Evaluation of a Novel Infection PET Diagnostic

新型感染 PET 诊断的评估

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要细菌感染，例如假体关节、骨骼（骨髓炎）和心脏瓣膜（感染性瓣膜）的感染心内膜炎）很难诊断和治疗，是死亡率、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，以检测和定位人体细菌病原体。此类放射性示踪剂将区分不同的病原体群体，用作非侵入性诊断和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。我们合成了对氨基苯甲酸的氟18标记衍生物2-氟-4- 氨基苯甲酸（[18F]F-PABA）是一种新型放射性示踪剂，可被细菌选择性吸收，包括临床- 金黄色葡萄球菌的相关菌株，包括 MRSA。我们已经证明 [18F]F-PABA 在 S. 疾病动物模型中的金黄色葡萄球菌感染，并且可以量化细菌负荷作为化疗的函数。值得注意的是，与临床上广泛使用的方法不同，[18F]F-PABA 可以区分细菌感染和炎症。 PET 示踪剂 2-脱氧-2-[18F]氟-D-葡萄糖 ([18F]FDG)。第一阶段 STTR 的目的是验证 [18F]F- PABA 在临床前感染模型中进行研究，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金黄色葡萄球菌并对其进行成像感染，并且这种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，我们将进行剂量测定研究，以评估预计人体剂量引起的辐射暴露。我们还将证明 19F-PABA 在 100 倍人类预期剂量下不会表现出任何不利影响小鼠剂量。因此，我们将证明放射性示踪剂剂量造成的辐射负担和毒性根据 FDA 的数据，建议进行临床研究处于可接受的范围内。我们已经开发了适合人体研究的 [18F]F-PABA 的 cGMP 合成方法，该 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。