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）是一种痛苦且具有典白的关节疾病，通常会影响手，臀部和膝盖 衰老成年人的关节。从经典上讲，OA被认为是一种退化性的磨损疾病，但 最近的研究已将其确定为健康状况之间的一种免疫病理学疾病 和类风湿关节炎。在诊所中，传统的X射线照相，磁共振成像和超声是 当前选择的技术可以进行与OA相关的诊断。但是，这些技术给出了 解剖信息，但不能在功能分子和细胞水平上引起炎症性损伤。 已经发表了一些有关使用功能性核成像技术的报告，例如正电子 发射断层扫描（PET），其探针为18f-2-fluoro-2-脱氧-D-葡萄糖和单光子发射 计算机断层扫描（SPECT）的探针为111in-二乙烯三亚胺五乙酸 - 乙酸酸酯，用于 监测OA的炎症过程。尽管这些示踪剂在 临床试验以及实验性OA模型中，它们并不是完全针对炎症的探针。我们的 最近的研究强烈支持PET探针CFLFLF-PEG-64CU可用于靶向甲基肽 活化巨噬细胞的受体1，用于评估大鼠实验性骨关节炎的炎症。 在此提案中，我们想开发一种新型的探针CFLFLF-PEG-99MTC，以检测和诊断 通过执行以下目的，骨关节炎炎症与大鼠模型炎症： 1）验证CFLFLF-PEG-99MTC探针在骨关节炎（OA）期间的炎症成像（OA） 具有两个大鼠模型的进展，包括单二乙酸（MIA）模型，这是一个快速发展的 OA的生化诱导模型和前交叉韧带横向（ACLT）模型，这是一个 OA的进展缓慢，手术诱导的生物力学模型。该探测器将被合成，并 将测量血液清除和生物分布。此外，SPECT和MRI成像将是 在每个模型的OA进展过程中以六个时间点进行。 2）验证CFLFLF-PEG-99MTC探针在预先避免和 使用大鼠膝关节骨关节炎的大鼠ACLT模型早期治疗抗炎药物素毒素。这 该药物的抗OA能力将通过使用CFLFLF-PEG-99MTC进行SPECT成像分析确定 探针以及分析滑膜炎症，软骨降解，软骨下骨损失 和关节不适。 Specs信号与这些结构和功能变化的相关性将 进行评估。 我们的最终目标是开发一种能够在诊所应用于诊断的创新方法 早期OA和用于评估OA的抗炎治疗。