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

项目总结： 这项建议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其他过程区分开来。现有的临床技术针对的是 宿主免疫反应，例如111In SPECT白细胞扫描或18F-FDG PET。尽管这些 模式有时是有用的，它们缺乏区分活细菌和无菌细菌所需的特异性 炎症、癌症和其他高度代谢的组织。因此，我们提出了一种PET成像 一种利用细菌特有的代谢途径，针对革兰氏阳性和革兰氏阳性菌的技术 阴性生物体。我们相信，一种检测所有或至少大多数致病菌的技术将 在临床实践中最有用。一旦影像异常被确定为感染，组织 可能仍需要采样、染色和培养。一种可以区分活动性感染的成像方法 从频繁的模仿，立即成为各种住院和门诊患者的护理标准 设置。 在这项建议中，我们开发了18F和11C示踪剂，用于正电子发射断层扫描(PET)，使用D-Met衍生 示踪剂，并首次在人类脊椎感染患者中进行研究。我们已经确定了11C-D-MET 作为放射性示踪剂，具有(1)简单、高产额的放射性合成(2)良好的体内稳定性(3)适当的模拟 内源底物(4)高掺入细菌肽聚糖和(5)低摄取率 背景纸巾。我们将从精制对映体11C-D-MET的合成开始，并进行深入的调查 促进细菌摄取的11C-D-MET的结构亲缘关系(特定目标1)。然后我们将研究我们的领先优势 D-MET示踪剂在引人注目的临床前感染模型中的应用，包括椎体骨髓炎-腰椎炎模型 (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表现。

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.