A novel inflammation targeting Tc-99m probe for osteoarthritis imaging

一种用于骨关节炎成像的新型炎症靶向 Tc-99m 探针

• 批准号: 9387991
• 负责人: Quanjun Cui
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387991
• 关键词: 2-Fluoro-2-deoxyglucose; Acids; Adult; Affect; Aging; Anatomy; Anterior Cruciate Ligament; Anti-Inflammatory Agents; Anti-inflammatory; Area; Biochemical; Biodistribution; Blood; Cartilage; Cells; Clinic; Clinical; Clinical Trials; Data; Degenerative polyarthritis; Detection; Diagnosis; Diagnostic radiologic examination; Disease; Disease Progression; Early Diagnosis; Early treatment; Ensure; Evaluation; FPR1 gene; Folic Acid; Goals; Hand; Hip Joint; Image; Image Analysis; Imaging Techniques; Immune; Infiltration; Inflammation; Inflammatory; Injury; Joints; Knee; Knee joint; Magnetic Resonance Imaging; Measurement; Measures; Modeling; Molecular; Monitor; Operative Surgical Procedures; Orthopedics; Pain; Paper; Peptides; Pharmaceutical Preparations; Positioning Attribute; Positron-Emission Tomography; Predisposition; Principal Investigator; Process; Publishing; Radioisotopes; Rattus; Reporting; Reproducibility; Research; Research Design; Rheumatoid Arthritis; Rheumatology; Signal Transduction; Specificity; Structure; Supervision; Surgeon; Synovial Membrane; Technetium 99m; Techniques; Time; Tracer; Ultrasonography; Universities; Virginia; anatomic imaging; arthropathies; base; biomechanical model; bone loss; cartilage degradation; design; epidemiology study; experience; experimental study; folate-binding protein; glucose metabolism; imaging study; improved; innovation; macrophage; man; meloxicam; member; multidisciplinary; neoplastic cell; novel; nuclear imaging; professor; rheumatologist; single photon emission computed tomography; subchondral bone

Osteoarthritis (OA) is a painful and debilitative joint disease that commonly affects the hand, hip, and knee joints of aging adults. Classically, OA has been characterized as a degenerative, wear-and-tear disease but recent research has identified it as an immunopathological disease on a spectrum between healthy condition and rheumatoid arthritis. In clinic, conventional radiography, magnetic resonance imaging and ultrasound are the current techniques of choice to arrive at an OA related diagnosis. These techniques, however, give anatomical information but cannot elicit inflammatory injury at the functional molecular and cellular level. A few reports have been published on the use of functional nuclear imaging techniques, such as positron emission tomography (PET) with a probe of 18F-2-fluoro-2-deoxy-D-glucose and single-photon emission computed tomography (SPECT) with a probe of 111In-diethylene triamine pentaacetic acid-folates, for monitoring the inflammatory process of OA. Although these tracers have demonstrated some promise in clinical trials as well as in experimental OA models, they are not probes exactly targeting inflammation. Our recent study strongly supported that a PET probe cFLFLF-PEG-64Cu could be used for targeting formyl peptide receptor 1 of activated macrophages and for evaluating inflammation of experimental osteoarthritis in rat. In this proposal, we would like to develop a novel probe cFLFLF-PEG-99mTc for detection and diagnosis of osteoarthritis inflammation with rat models by executing the following Aims: 1) To validate the cFLFLF-PEG-99mTc probe for SPECT imaging of inflammation during osteoarthritis (OA) progression with two rat models including the monoiodoacetate (MIA) model, which is a fast-progressing biochemically induced model of OA, and the anterior cruciate ligament transection (ACLT) model, which is a more slowly progressing, surgically induced biomechanical model of OA. The probe will be synthesized and its blood clearance and biodistribution will be measured. Furthermore, the SPECT and MRI imaging will be performed at six time-points during whole period of OA progression in each model. 2) To validate the cFLFLF-PEG-99mTc probe for SPECT imaging of inflammation during pre-emptive and early treatment of an anti-inflammatory drug meloxicam using the rat knee ACLT model of osteoarthritis. The anti-OA capacity of this drug will be determined by the SPECT imaging analysis using cFLFLF-PEG-99mTc probe, as well as by analyzing synovial membrane inflammation, cartilage degradation, subchondral bone loss and joint discomfort. The relevance of the SPECT signal to each of these structural and functional changes will be evaluated. Our ultimate goal is to develop an innovative approach capable of being applied in clinic for diagnose of early stage OA and for evaluation of anti-inflammatory treatment of OA.

骨关节炎（OA）是一种疼痛和衰弱的关节疾病，通常影响手，髋关节和膝关节 老年人的关节。传统上，OA被描述为退行性、磨损性疾病， 最近的研究已经确定它是一种免疫病理学疾病， 和类风湿性关节炎。在临床上，常规X线摄影、磁共振成像和超声是 目前的技术选择，以达到OA相关的诊断。然而，这些技术使 解剖信息，但不能引起功能分子和细胞水平的炎性损伤。 已经发表了一些关于使用功能性核成像技术的报告，例如正电子成像技术。 使用18 F-2-氟-2-脱氧-D-葡萄糖探针和单光子发射的发射断层扫描（PET） 用111 In-二亚乙基三胺五乙酸-叶酸探针进行计算机断层扫描（SPECT）， 监测OA的炎症过程。虽然这些示踪剂已经证明了一些承诺， 临床试验以及实验性OA模型中，它们不是精确靶向炎症的探针。我们 最近的研究强烈支持PET探针cFLFLF-PEG-64 Cu可用于靶向甲酰基肽 受体1的表达及评价大鼠实验性骨关节炎的炎症反应。 在本研究中，我们希望开发一种新的探针cFLFLF-PEG-99 mTc，用于检测和诊断 通过执行以下目的，用大鼠模型治疗骨关节炎炎症： 1)确认cFLFLF-PEG-99 mTc探针用于骨关节炎（OA）期间炎症的SPECT成像 两种大鼠模型的进展，包括单碘乙酸（MIA）模型，这是一种快速进展的模型。 生物化学诱导的OA模型和前交叉韧带横断（ACLT）模型， 更缓慢进展的手术诱导的OA生物力学模型。探针将被合成， 测量血液清除率和生物分布。此外，SPECT和MRI成像将 在每个模型的整个OA进展期间的六个时间点进行。 2)为了验证cFLFLF-PEG-99 mTc探针在预防和治疗期间用于炎症的SPECT成像， 使用抗炎药美洛昔康早期治疗大鼠膝关节ACLT骨关节炎模型。的 将使用cFLFLF-PEG-99 mTc通过SPECT成像分析测定该药物的抗OA能力 探针，以及通过分析滑膜炎症，软骨降解，软骨下骨丢失 和关节不适。SPECT信号与这些结构和功能变化中的每一个的相关性将 被评价。 我们的最终目标是开发一种能够应用于临床诊断的创新方法， 早期OA和评价OA的抗炎治疗。