Evaluation of a Novel Infection PET Diagnostic

项目总结/文摘

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.