SYNTHESIS OF CATIONIC STEROID COMPOUNDS FOR DETECTION OF BACTERIAL INFECTIONS

 描述(申请人提供)：传染病仍然是世界范围内的主要健康问题和死亡原因。患者感染部位的确定和定位 是他们临床管理的关键一步，特别是在感染的局部症状不存在的情况下。及时发现感染可以通过适当的治疗治愈，而延误可能会导致死亡。如果出现局部症状，使用超声或计算机断层扫描的解剖成像可以用于识别，但它们不能区分感染和炎症。当没有局部感染症状时，核医学成像中的全身扫描将有利于成像。有多种放射性药物被用来检测感染和炎症；然而，已经表明，这些探针中的大多数不能区分感染和炎症。因此，开发一种能够检测各种临床环境中的细菌感染的显像剂具有重要的意义。在开发专门检测病毒、真菌和细菌感染的探针方面已经取得了进展。环丙沙星、卡那霉素和磺胺等放射性标记抗生素用于细菌感染的检测已被研究过，但其特异性令人担忧。本研究的目的是开发一种基于一类新型抗菌剂的PET显像剂，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，旨在模仿内源性抗菌肽的形态，已被证明对革兰氏阳性菌和革兰氏阴性菌都有效。这些化合物对真核细胞上的细菌膜表现出高度的选择性亲和力。在这些研究中，我们将用1，4，7-三氮杂环-1，4，7-三乙酸(NOTA)螯合剂对阳离子类固醇抗生素(CSA)进行修饰，使它们可以用正电子发射体64Cu进行放射性标记。将对这些结合物进行评估，以确保它们保持对细菌的活性，然后用64Cu进行放射性标记，以确定在细菌培养中的摄取和亲和力。然后，将在无菌炎症的肺部感染模型中对所产生的放射性标记结合物进行评估，以确定该制剂的特异性。该提案的具体目标是：1.)合成和评价已与NOTA和2偶联的CSA。)在肺部感染模型中评价64Cu-NOTA-CsA结合物。

 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.