Clinical translation of D-amino acid derived PET tracers for imaging spinalinfection

D-氨基酸衍生 PET 示踪剂用于脊髓感染成像的临床转化

• 批准号: 9750744
• 负责人: Michael Ohliger
• 金额: $ 50.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750744
• 关键词: Acute; Address; Amino Acids; Animal Model; Antibiotic Therapy; Bacteria; Bacterial Infections; Biopsy; Blinded; Cell Nucleus; Cells; Citrates; Clinical; Detection; Diagnosis; Discitis; Environment; Escherichia coli; Evaluation; Failure; Fever; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Human; Human body; Image; Imaging Techniques; Imaging technology; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Inpatients; Investigational Drugs; Joints; Lead; Leukocytes; Malignant Neoplasms; Mammalian Cell; Metabolic; Metabolic Pathway; Methionine; Methodology; Methods; Modality; Modeling; Morphology; Mus; Myositis; New Drug Approvals; Organism; Osteomyelitis; Outpatients; Patients; Peptidoglycan; Performance; Physicians; Positron-Emission Tomography; Preclinical Testing; Procedures; Process; Prosthesis; Rattus; Risk; Scanning; Specificity; Spinal; Stains; Sterility; Structure; Techniques; Therapeutic; Time; Tissue Sample; Tissues; Tracer; acute infection; analog; bacterial resistance; base; clinical practice; clinical translation; clinically relevant; clinically translatable; cohort; dosimetry; epidural space; first-in-human; fluorodeoxyglucose; human study; imaging modality; improved; in vivo; intervertebral disk degeneration; metabolic imaging; methicillin resistant Staphylococcus aureus; mimicry; pathogenic bacteria; pre-clinical; radiologist; radiotracer; recruit; research clinical testing; response; routine Bacterial stain; single photon emission computed tomography; small molecule; spine bone structure; standard of care; uptake; vertebra body

PROJECT SUMMARY: This proposal addresses a major challenge that radiologists and other physicians encounter frequently, namely distinguishing active infection from other processes in the human body. Existing clinical techniques target the host immune response, for example 111In SPECT white blood cell scanning or 18F-FDG PET. Although these modalities can sometimes be useful, they lack the specificity required to distinguish living bacteria from sterile inflammation, cancer, and other highly metabolic tissues. Therefore we are proposing a PET imaging technique that exploits metabolic pathways specific to bacteria, targeting both gram-positive and gram- negative organisms. We believe a technique that detects ALL or at least a majority of pathogenic bacteria will be most useful in clinical practice. Once an imaging abnormality has been identified as infection, tissue sampling, staining and culture may still be required. An imaging method that could distinguish active infection from frequent mimics, would instantly become the standard of care in a variety of inpatient and outpatient settings. In this proposal, we develop 18F and 11C tracers for positron emission tomography (PET) using D-Met derived tracers, and study them for the first time in human patients with spinal infections. We have identified 11C D-met as a radiotracer with (1) a simple, high-yield radiosynthesis (2) good in vivo stability (3) appropriate mimicry of the endogenous substrate (4) high rate of incorporation into bacterial peptidoglycan and (5) low uptake in background tissues. We will start by refining the synthesis of enantiopure 11C D-met, and investigating close structural relatives of 11C D-met for enhanced bacterial uptake (Specific Aim 1). We will then study our lead D-met tracer in compelling preclinical infection models, including models of vertebral osteomyelitis-discitis (Specific Aim 2). In Specific Aim 3, we will take all steps needed for an investigational new drug (IND) approval for our lead tracer, and study its performance in patients suffering from spinal infection.

项目总结: