SYNTHESIS OF CATIONIC STEROID COMPOUNDS FOR DETECTION OF BACTERIAL INFECTIONS

用于检测细菌感染的阳离子类固醇化合物的合成

基本信息

批准号：
9090097
负责人：
Buck E. Rogers
金额：
$ 22.81万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9090097
关键词：
Abscess Acids Acute Affinity Amines Anatomy Antibiotic Therapy Antibiotics Bacteria Bacterial Infections Bacterial Proteins Binding Blood Vessels Cause of Death Chelating Agents Chronic Ciprofloxacin Citrates Clinical Clinical Management Communicable Diseases Detection Development Discipline of Nuclear Medicine Ensure Eukaryotic Cell Evaluation Fever of Unknown Origin Goals Gram-Negative Bacteria Health Image Immunocompromised Host Implant Infection Inflammation Kanamycin Label Leukocytes Lung Lung Inflammation Membrane Modeling Monitor Morphology Mycoses Osteomyelitis Oximes Oxyquinoline Parents Patients Peptide Fragments Peptides Photons Positron Positron-Emission Tomography Postoperative Period Radioactive Radioimmunoconjugate Radiolabeled Radiopharmaceuticals Site Specificity Sterility Steroids Symptoms Thymidine Kinase Ultrasonography Virus Diseases X-Ray Computed Tomography antimicrobial antimicrobial drug antimicrobial peptide base cancer imaging chemokine design fluorodeoxyglucose imaging agent mortality mouse model novel nucleoside analog radiotracer response single photon emission computed tomography triazacyclononane uptake whole body imaging

项目摘要

DESCRIPTION (provided by applicant): Infectious diseases remain a major health problem and cause of death worldwide. The identification and localization of sites of infection in patients is a critical step in their clinical management, particularly when localized symptoms of the infection are not present. The prompt identification of infections can be cured with proper treatment, while delays can result in mortality. Anatomic imaging using ultrasound or computed tomography can be used for identification if local symptoms are present, however, they cannot differentiate between an infection and inflammation. Whole body scans in nuclear medicine imaging would be advantageous for imaging when there are no local symptoms of infection. There are a variety of radiopharmaceuticals that are used to detect infection and inflammation; however, it has been shown that the majority of these probes cannot distinguish between infection and inflammation. Therefore, the development of an imaging agent that is specific for detection of bacterial infections in a variety of clinical contexts would be highly significant. Soe progress has been made on the development of probes for the specific detection of viral, fungal, and bacterial infections. The use of radiolabeled antibiotics such as ciprofloxacin, kanamycin, and sulphanilamide for the detection of bacterial infections has been investigated, but there is concern about their specificity. The goal of this study is to develop a PET imaging agent based on a novel class of antimicrobial agents for the specific detection of bacterial infections. These novel antimicrobial agents are cationic steroid compounds, designed to mimic the morphology of endogenous antimicrobial peptides and have been shown to be effective against both Gram-positive and Gram-negative bacteria. These compounds display high and selective affinity for bacterial membranes over eukaryotic cells. In these studies, we will modify the cationic steroid antibiotics (CSAs) with the 1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA) chelator such that they can be radiolabeled with the positron-emitter, 64Cu. These conjugates will be evaluated to ensure that they maintain their activity against bacteria and then radiolabeled with 64Cu to determine uptake and affinity in bacterial cultures. The resulting radiolabeled conjugates will then be evaluated in a lung infection model in sterile inflammation to determine the specificity of the agent. The specific aims of the proposal are: 1.) Synthesize and evaluate CSAs that have been conjugated to NOTA and 2.) Evaluate 64Cu-NOTA-CSA conjugates in a lung infection model.

描述（由申请人提供）：传染病仍然是世界范围内的一个主要健康问题和死亡原因。患者感染部位的识别和定位。是临床管理中的关键一步，特别是当不存在感染的局部症状时，可以通过适当的治疗来治愈感染，而使用超声或计算机断层扫描进行的解剖成像可用于治疗延误。如果存在局部症状，则无法区分感染和炎症。当没有局部感染症状时，核成像中的全身扫描将有利于成像。有多种放射性药物可用于检测感染。和炎症；然而，已经表明大多数这些探针无法区分感染和炎症，因此，开发一种特异性检测各种临床环境中细菌感染的成像剂将是非常重要的。开发用于特异性检测病毒、真菌和细菌感染的探针已经研究了使用环丙沙星、卡那霉素和磺胺等放射性标记抗生素来检测细菌感染，但仍存在担忧。本研究的目的是开发一种基于新型抗菌剂的 PET 成像剂，用于特异性检测细菌感染。这些新型抗菌剂是阳离子类固醇化合物，旨在模拟内源性抗菌肽的形态。并已被证明对革兰氏阳性和革兰氏阴性细菌均有效。在这些研究中，我们将修饰阳离子类固醇抗生素。 (CSA) 与 1, 4, 7-三氮杂环壬烷-1, 4, 7-三乙酸 (NOTA) 螯合剂，以便它们可以用正电子发射体 64Cu 进行放射性标记。将对这些缀合物进行评估，以确保它们保持其功能。其对细菌的活性，然后用 64Cu 进行放射性标记，以确定细菌培养物中的吸收和亲和力，然后在肺部感染模型中评估所得的放射性标记缀合物。该提案的具体目标是：1.) 合成并评估已与 NOTA 缀合的 CSA；2.) 在肺部感染模型中评估 64Cu-NOTA-CSA 缀合物。