Molecular Imaging for Pulmonary Infections and Inflammation

 描述（由申请人提供）：非侵入性成像是用于早期诊断和监测各种疾病过程的强大临床工具。下一代分子成像有望为肺部感染和炎症的可视化提供无与伦比的机会，因为分子和细胞的改变在病理过程中比结构变化更早发生。这种快速发展的技术已成为肿瘤学领域的重要工具，对肺部感染和炎症具有类似的潜力。 在第一阶段资助期间，我们开发并验证了三种新的分子成像示踪剂，用于用正电子发射断层扫描（PET）评估肺部疾病：1）124 I-碘-DPA-713，转运蛋白（TSPO）的合成配体，作为巨噬细胞相关肺部炎症的特异性成像生物标志物，预测结核分枝杆菌小鼠感染模型中的治疗疗效和复发; 2）18F-氟脱氧山梨醇（18F-FDS），山梨醇的类似物，食品和药物管理局（FDA）批准的“无糖”甜味剂，由革兰氏阴性细菌选择性代谢（肠杆菌科），而不是哺乳动物细胞，用于快速、特异性检测革兰氏阴性医院内肺炎; 3）11 C-利福平，FDA批准的一线TB药物，用于快速、非侵入性多室药代动力学（PK）评估。本申请中提出的所有成像示踪剂均已在临床前模型中得到充分验证，并具有几个有希望的特征：a）具有特定细胞靶点的机制基础; B）低分子量，具有适合肺部成像的PK; c）静脉注射后方便时间的高靶组织与非靶组织比。我们的中心假设是，基于机制的靶向病理过程的特定PET成像示踪剂将提供实时，早期和具体的信息，肺部感染和炎症性疾病的患者。 我们提出了一个多学科的合作，特别是响应这个RFA（第2阶段），使用FDA研究新药（IND）或RDRC机制在人类受试者中进行初步的安全性和有效性测试。我们的最终目标是将新型成像示踪剂从实验室翻译到床边，用于肺部疾病过程的快速和非侵入性评估，并作为药物开发工具。通过这一提议开发的成像示踪剂可能成为肺部医学的有价值的临床工具，也将广泛适用于感染性疾病和其他炎症性疾病。(End摘要）

 DESCRIPTION (provided by applicant):Non-invasive imaging is a powerful clinical tool for the early diagnosis, and monitoring of various disease processes. Next generation molecular imaging promises unparalleled opportunities for visualizing pulmonary infection and inflammation since molecular and cellular alterations occur earlier in a pathologic process, than structural changes. This rapidly developing technology has become an essential tool in the field of oncology, with similar potential for pulmonary infectious and inflammatory conditions. During phase 1 funding, we developed and validated three novel molecular imaging tracers for evaluating pulmonary diseases with positron emission tomography (PET): 1) 124I-iodo-DPA-713, a synthetic ligand for the translocator protein (TSPO), as a specific imaging biomarker for macrophage-associated pulmonary inflammation, predictive of treatment efficacy and relapse in a Mycobacterium tuberculosis murine infection model; 2) 18F-fluorodeoxysorbitol (18F-FDS), an analog of sorbitol, a Food and Drug Administration (FDA) approved "sugar free" sweetener, metabolized selectively by Gram-negative bacteria (Enterobacteriaceae), but not mammalian cells, for rapid, specific detection of Gram-negative nosocomial pneumonias and; 3) 11C- Rifampin, a FDA approved first-line TB drug, for rapid, noninvasive multi-compartment pharmacokinetic (PK) assessments. All imaging tracers proposed in this application have been fully validated in preclinical models and have several promising features: a) basis in mechanism with specific cellular targets; b) low molecular weight with suitable PK for lung imaging and; c) high target-to-non-target tissue ratios at convenient times after intravenous injection. Our centra hypothesis is that mechanism-based targeting of pathologic processes by specific PET imaging tracers would provide real-time, early and specific information about pulmonary infections and inflammatory diseases in patients. We propose a multi-disciplinary collaboration, specifically responsive to this RFA (phase 2) to perform initial safety and efficacy testing in human subjects using the FDA Investigational New Drug (IND) or RDRC mechanisms. Our ultimate goal is the bench-to-bedside translation of novel imaging tracers for rapid and noninvasive assessment of pulmonary disease processes and as drug development tools. Imaging tracers developed through this proposal could become valuable clinical tools for pulmonary medicine, and will also be broadly applicable to infectious diseases and other inflammatory conditions. (End of Abstract)