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

基本信息

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
项目类别：
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

项目摘要

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) 是一种疼痛且衰弱的关节疾病，通常影响手、髋和膝老年人的关节。传统上，OA 被描述为一种退行性、磨损性疾病，但最近的研究已将其确定为一种介于健康状况和健康状况之间的免疫病理学疾病和类风湿性关节炎。临床上常规的放射线检查、磁共振成像和超声检查当前用于获得 OA 相关诊断的技术选择。然而，这些技术给解剖学信息，但不能引起功能分子和细胞水平的炎症损伤。已经发表了一些关于使用功能性核成像技术的报告，例如正电子使用 18F-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) 使用 111In-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。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 可用于靶向甲酰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。在本提案中，我们希望开发一种新型探针 cFLFLF-PEG-99mTc 用于检测和诊断通过执行以下目标，用大鼠模型进行骨关节炎炎症： 1) 验证 cFLFLF-PEG-99mTc 探针对骨关节炎 (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化诱导的 OA 模型和前交叉韧带横断 (ACLT) 模型，这是一种进展更缓慢、手术诱导的 OA 生物力学模型。探针将被合成，其将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 OA 进展的整个时期的六个时间点进行。 2) 验证 cFLFLF-PEG-99mTc 探针在先发制人和使用抗炎药美洛昔康对大鼠膝骨关节炎 ACLT 模型进行早期治疗。这该药物的抗 OA 能力将通过使用 cFLFLF-PEG-99mTc 的 SPECT 成像分析来确定探针，以及通过分析滑膜炎症、软骨退化、软骨下骨丢失和关节不适。 SPECT 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应用于临床诊断的创新方法早期 OA 并用于评估 OA 的抗炎治疗。