A PET Diagnostic for Imaging Bacterial Infection

细菌感染成像 PET 诊断

• 批准号: 10006663
• 负责人: PETER J TONGE
• 金额: $ 22.13万
• 依托单位: CHRONUS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-21 至 2023-07-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006663
• 关键词: Adverse effects; Animal Model; Antibiotic Therapy; Bacteria; Bacterial Infections; Blood; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Crystalline Lens; Cyclic GMP; Data; Detection; Diagnosis; Diagnostic; Diagnostic Imaging; Diagnostic Procedure; Disease model; Dose; Drug Kinetics; Glucose; Goals; Gonadal structure; Health Care Costs; Heart; Heart Valves; Hospital Charges; Hospital Mortality; Hour; Human; Human body; Image; Incidence; Infection; Infective endocarditis; Inflammation; Investigational Drugs; Joint Prosthesis; Knowledge; Lead; Location; Medical; Modeling; Monitor; Morbidity - disease rate; Morphology; Mus; Noise; Organ; Osteomyelitis; Outcome; Participant; Pathology; Patient Monitoring; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Phase; Physiological; Positron-Emission Tomography; Pre-Clinical Model; Preparation; Prodrugs; Property; Radiation; Radiation exposure; Rattus; Research; Rodent Model; Safety; Signal Transduction; Site; Small Business Technology Transfer Research; Soft Tissue Infections; Staphylococcus aureus; Staphylococcus aureus infection; Surface; Time; Tissue Model; Tissues; Toxic effect; Toxicology; Tracer; Treatment outcome; United States Food and Drug Administration; Visual; base; bone; chemotherapy; clinically relevant; commercial application; dosimetry; fluorodeoxyglucose; improved; mortality; noninvasive diagnosis; novel; pathogenic bacteria; pre-clinical; programs; radiochemical; radiotracer; response; soft tissue; technological innovation; tool; uptake

PROJECT SUMMARY Bacterial infections such as those of prosthetic joints, bones (osteomyelitis) and heart valves (infective endocarditis) are 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 to develop a positron emission tomography (PET) radiotracer that can be used for non-invasive PET imaging to detect and localize bacterial pathogens in humans. This radiotracer will serve as a non-invasive diagnostic to accurately identify bacterial infections and inform on bacterial load during chemotherapy, thereby identifying and improving treatment outcomes of patients with infectious diseases. We have synthesized a novel radiotracer, CC-001, that is selectively taken up by bacteria including clinically relevant strains of Staphylococcus aureus. We have shown that CC-001 accumulates at the site of S. aureus infection in a soft tissue infection model of disease. Significantly, CC-001 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 CC-001 in a preclinical model of infection and perform studies in preparation for an investigational new drug submission. In Aim 1 we will demonstrate that CC-001 can detect and image S. aureus in a preclinical model of infective endocarditis 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 projected radiation exposure at a clinically relevant human dose. We will also demonstrate that CC-001 does not display any adverse effects at 100 and 1000 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 U.S Food and Drug Administration. This Phase I STTR will pave the way for a Phase II STTR in which we will gather additional preclinical data and subsequently transition into clinical trials.

项目摘要 细菌感染，例如假体关节，骨骼（骨髓炎）和心脏瓣膜（感染性） 心内膜炎）很难诊断和治疗，并且是死亡率，发病率和医疗保健的主要原因 费用。我们计划的长期目标是开发正电子排放层析成像（PET）radiotracer 可用于非侵入性PET成像，以检测和定位人类中的细菌病原体。这个放射性示例 将用作非侵入性诊断，以准确识别细菌感染并告知细菌负荷 在化学疗法期间，从而鉴定并改善了传染病患者的治疗结果。 我们已经合成了一种新型的放射性示踪剂CC-001，该细菌在包括临床上有选择性地吸收了 金黄色葡萄球菌的相关菌株。我们已经表明，CC-001在金黄色葡萄球菌的位置积聚 软组织感染模型中的感染。值得注意的是，CC-001可以区分细菌感染与 与广泛使用的临床宠物示踪剂2-脱氧-2- [18F]氟-D-葡萄糖（[18F] FDG）不同，炎症不同。对象 该阶段I的STTR是在感染的临床前模型中验证CC-001并进行制备研究 用于调查新药提交。在AIM 1中，我们将证明CC-001可以检测和图像S。 在感染性心内膜炎的临床前模型中金黄色 抗生素治疗的功能。在AIM 2中，我们将进行剂量测定研究，以评估预计 临床相关的人剂量下的辐射暴露。我们还将证明CC-001不显示 在小鼠中预计人剂量的100和1000倍的任何不良影响。因此，我们将证明辐射 提出的用于临床研究的放射性示意剂剂量引起的负担和毒性在可接受之内 范围基于美国食品和药物管理局的数据。这个阶段我的sttr将为A铺平道路 第二阶段的STTR将收集其他临床前数据，然后转变为临床试验。

项目成果

Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton's Tyrosine Kinase.

• DOI: 10.1021/acsptsci.2c00215
• 发表时间: 2023-02
• 期刊: ACS pharmacology & translational science
• 影响因子: 6
• 作者: Kaixuan Li;Mingqian Wang;Melike Akoglu;Alyssa C. Pollard;J. Klecker;P. Alfonso;Ana Corrionero;Niall Prendiville;Wenchao Qu;Matthew F. L. Parker;N. Turkman;Jules A. Cohen;P. Tonge