Anionic Phospholipid-Selective PET/SPECT Agent for Infection Imaging

用于感染成像的阴离子磷脂选择性 PET/SPECT 试剂

• 批准号: 8250164
• 负责人: Brian David Gray
• 金额: $ 22.44万
• 依托单位: MOLECULAR TARGETING TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250164
• 关键词: Abscess; Affinity; Animal Model; Animals; Antibodies; Bacteria; Bacterial Infections; Benchmarking; Binding; Binding Sites; Biodistribution; Biological; Biotin; Blood Circulation; Characteristics; Charge; Chelating Agents; Chemicals; Clinical; Colony-forming units; Communicable Diseases; Complex; Contralateral; Detection; Developing Countries; Development; Diagnosis; Diagnostic; Dose; Drug Kinetics; Early Diagnosis; Environment; Evaluation; Exclusion; Fluorescent Dyes; Goals; High Pressure Liquid Chromatography; Image; Immunocompetent; In Situ; Inbred HRS Mice; Infection; Inflammation; Inflammatory; International; Ions; Isotopes; Kinetics; Label; Lesion; Leukocytes; Life; Link; Lipopolysaccharides; Location; Massachusetts; Measurement; Measures; Mediating; Modeling; Monitor; Morbidity - disease rate; Mus; Nuclear; Optics; Patients; Phase; Phospholipids; Positron-Emission Tomography; Preparation; Process; Radiation therapy; Radioactivity; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reagent; Reproducibility; Serum; Specificity; Sterility; Streptavidin; Streptococcus pyogenes; Techniques; Testing; Thigh structure; Time; Tissues; Universities; chemical stability; clinical practice; communicable disease diagnosis; cytokine; experience; flexibility; gel electrophoresis; imaging probe; immunogenicity; improved; in vitro Assay; light scattering; medical schools; mortality; mouse model; multimodality; neutrophil; novel; novel strategies; optical imaging; radiochemical; radiotracer; research study; single photon emission computed tomography; small molecule

DESCRIPTION (provided by applicant): Although a rapid and accurate diagnosis is crucial to the management of patients suspected of bacterial infection, the currently available radiopharmaceuticals are not capable of distinguishing between sterile inflammation and bacterial infections. Our goal is to develop an infection-specific PET/SPECT radiopharmaceutical for eventual use in clinical practice. In Phase I, we will evaluate two independent approaches. In a covalent approach, we will conjugate a radionuclide chelator for PET/SPECT imaging with a Zn-DPA targeting moiety that is known to selectively target the negatively charged bacterial envelope, to provide a novel small molecule nuclear imaging agent. In an alternative, non-covalent radiolabeling approach, we will use streptavidin (SA) as a linker between the biotinylated Zn-DPA targeting motif and a biotinylated chelator to form an imaging agent which may have improved bacterial lesion accumulation over the covalent approach due to: (i) its slower pharmacokinetics because of increased size, and (ii) its potential to bind up to three DPA groups for affinity enhancement. Our Specific Aims include: 1) Synthesize and characterize DOTA- DPA-(1 Zn) for the covalent conjugation approach, DOTA/SA/DPA-(1 Zn) for the non-covalent approach and radiolabel the DOTA containing agents with the PET isotope 68Ga, as well as the SPECT isotope 111In. 2) Serum stability assays and in vitro evaluation of the covalent [68Ga /111In-DOTA-DPA-(1 Zn)] and non- covalent [68Ga/111In-DOTA/SA/DPA-(1 Zn)] agents to S. pyogenes. Specific binding to bacteria will be evaluated by measuring binding to bacteria with increasing concentrations of unlabeled DOTA-DPA-Zn. Thereafter, labeled bacteria will be evaluated in 37o C serum environments to determine the stability of both radionuclide within the chelate and the stability of both agents to the bacteria. 3) Evaluate the covalent and non-covalent approaches in infection and inflammation mouse models for evidence of specific accumulations. SKH1 hairless mice will be injected in the thigh with live S. pyogenes to provide the bacterial infection model or lipopolysaccharide to provide the inflammation model. We will evaluate the agents radiolabeled with 68Ga as well as 111In in the mouse models using small animal PET and SPECT/CT cameras respectively. In all cases, the location and extent of infection will be monitored by co-injecting PSVue(R) 794 (a fluorescent bacteria targeting probe) and imaging on a small animal optical camera. Agents will be evaluated for their pharmacokinetics, their accumulation in the target, their target thigh/contralateral normal thigh accumulation, evidence of specific infection imaging and sensitivity of detection. At sacrifice, full biodistributions of each radiolabel will be done to supplement the imaging results. Key benchmarks for Phase I will be to obtain using either 68Ga/ 111In-DOTA- DPA-Zn or 68Ga/111In-DOTA/SA/DPA-Zn an infected thigh/normal thigh ratio of greater than 5 within a 10 h (68Ga) or 24 h (111In) period, obtain a statistically higher accumulation in the infected thighs compared to the inflammation thighs, and obtain an estimate of the lower limits of detection in the infection model. PUBLIC HEALTH RELEVANCE: Bacterial infection is one of the major causes of morbidity and mortality not only in developing countries but globally. Early diagnosis of infection and an ability to distinguish between bacterial infection and sterile inflammation is critical to the effective management of these patients. However, despite the efforts of many international imaging groups, there is currently no validated bacterial imaging agent that can distinguish infection from sterile inflammation. Obviously, the development of such an agent would greatly advance our ability to detect, localize, and quantify infections, to prescribe the appropriate treatment and to follow the patient throughout the treatment. In this project we propose to evaluate two novel approaches aimed at developing a new radiopharmaceutical which would allow noninvasive imaging of bacterial infections with the sensitivity that nuclear imaging approaches promise and would also allow infectious and inflammatory abscesses to be distinguished.

描述（由申请人提供）：尽管快速准确的诊断对于疑似细菌感染患者的管理至关重要，但目前可用的放射性药物无法区分无菌炎症和细菌感染。我们的目标是开发一种感染特异性PET/SPECT放射性药物，最终用于临床实践。在第一阶段，我们将评估两种独立的方法。在共价方法中，我们将用于PET/SPECT成像的放射性核素螯合剂与已知选择性靶向带负电荷的细菌包膜的Zn-DPA靶向部分缀合，以提供新型小分子核成像剂。在替代的非共价放射性标记方法中，我们将使用链霉亲和素（SA）作为生物素化的Zn-DPA靶向基序和生物素化的螯合剂之间的接头，以形成成像剂，其可能具有优于共价方法的改善的细菌病变积累，这是由于：（i）由于尺寸增加，其较慢的药代动力学，和（ii）其结合多达三个DPA基团以增强亲和力的潜力。我们的具体目标包括：1）合成和表征用于共价缀合方法的DOTA-DPA-（1 Zn）、用于非共价方法的DOTA/SA/DPA-（1 Zn），并用PET同位素68 Ga以及SPECT同位素111 In放射性标记含DOTA的试剂。2)共价[68 Ga/111 In-DOTA-DPA-（1 Zn）]和非共价[68 Ga/111 In-DOTA/SA/DPA-（1 Zn）]试剂对S.化脓将通过用增加浓度的未标记DOTA-DPA-Zn测量与细菌的结合来评价与细菌的特异性结合。此后，将在37 ° C血清环境中评价标记的细菌，以确定螯合物中两种放射性核素的稳定性以及两种试剂对细菌的稳定性。3)评价感染和炎症小鼠模型中共价和非共价方法的特异性蓄积证据。SKH 1无毛小鼠将在大腿中注射活S.化脓性链球菌以提供细菌感染模型或脂多糖以提供炎症模型。我们将分别使用小动物PET和SPECT/CT相机在小鼠模型中评估用68 Ga和111 In放射性标记的试剂。在所有情况下，将通过共同注射PSVue（R）794（荧光细菌靶向探针）并在小动物光学相机上成像来监测感染的位置和程度。将评价药物的药代动力学、在靶部位的蓄积、靶大腿/对侧正常大腿蓄积、特异性感染成像证据和检测灵敏度。处死时，将完成每种放射性标记的完整生物分布，以补充成像结果。阶段I的关键基准将是使用68 Ga/111 In-DOTA- DPA-Zn或68 Ga/111 In-DOTA/SA/DPA-Zn在10小时（68 Ga）或24小时（111 In）时间段内获得大于5的感染大腿/正常大腿比率，与炎症大腿相比在感染大腿中获得统计学上更高的积累，并获得感染模型中检测下限的估计。 公共卫生相关性：细菌感染不仅是发展中国家而且是全球发病和死亡的主要原因之一。感染的早期诊断以及区分细菌感染和无菌性炎症的能力对于这些患者的有效管理至关重要。然而，尽管许多国际成像小组做出了努力，但目前还没有经过验证的细菌成像剂可以区分感染和无菌性炎症。显然，这种药物的开发将大大提高我们检测、定位和量化感染的能力，从而制定适当的治疗方案，并在整个治疗过程中跟踪患者。在这个项目中，我们建议评估两种新的方法，旨在开发一种新的放射性药物，这将允许无创成像的敏感性，核成像方法承诺的细菌感染，也将允许区分感染性和炎症性疾病。