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: 9974516
• 负责人: Michael Ohliger
• 金额: $ 54.02万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974516
• 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.

项目概要： 该提案解决了放射科医生和其他医生经常遇到的一个主要挑战，即 将活动性感染与人体内的其他过程区分开来。现有的临床技术针对 宿主免疫应答，例如111 In SPECT白色血细胞扫描或18 F-FDG PET。虽然这些 尽管这些方法有时是有用的，但它们缺乏区分活细菌和无菌细菌所需的特异性。 炎症、癌症和其他高代谢组织。因此，我们提出了PET成像 一种利用细菌特有代谢途径的技术，针对革兰氏阳性和革兰氏阳性， 阴性微生物。我们相信，一种检测到ALL或至少大部分致病菌的技术， 在临床实践中最有用。一旦成像异常被确定为感染， 可能仍然需要取样、染色和培养。一种可以区分活动性感染的影像学方法 从频繁的模仿，将立即成为各种住院和门诊的护理标准， 设置. 在这个建议中，我们开发了18F和11 C示踪剂的正电子发射断层扫描（PET）使用D-Met衍生 示踪剂，并首次在脊柱感染的人类患者中研究它们。我们已经鉴定出11 C D-蛋氨酸 作为放射性示踪剂，具有（1）简单、高产率的放射性合成（2）良好的体内稳定性（3）适当的模拟 内源性底物（4）掺入细菌肽聚糖的速率高，和（5） 背景组织我们将从优化对映体纯11 C D-met的合成开始， 11 C D-met的结构相关物，用于增强细菌摄取（具体目标1）。我们会研究我们的线索 D-met示踪剂在引人注目的临床前感染模型中的应用，包括脊椎骨髓炎-脊椎炎模型 （具体目标2）。在具体目标3中，我们将采取研究新药（IND）所需的所有步骤 批准我们的铅示踪剂，并研究其在脊柱感染患者中的性能。