Novel Bisphosphonate 18F-PET and PET/optical Dual Modality Probes for Rheumatoid Arthritis Imaging

用于类风湿关节炎成像的新型双膦酸盐 18F-PET 和 PET/光学双模态探针

• 批准号: 8904990
• 负责人: Frank H. Ebetino
• 金额: $ 22.5万
• 依托单位: BIOVINC, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904990
• 关键词: Address; Adjuvant Arthritis; Adsorption; Affect; Affinity; Age; Animal Model; Apoptosis; Arthritis; Autoimmune Diseases; BODIPY; Binding; Binding Sites; Biological; Biological Assay; Biology; Bone Development; California; Cartilage; Chemistry; Chronic; Clinical; Collagen-Induced Arthritis; Detection; Development; Diagnostic; Diagnostic Procedure; Disease; Disease Progression; Doctor of Medicine; Doctor of Philosophy; Early Diagnosis; Equilibrium; Evaluation; Fluorescence; Gender; Generations; Goals; Human; Hydroxyapatites; Image; Imaging Techniques; Immune response; In Vitro; Inflammation; Inflammatory Arthritis; Intervention; Investigation; Joints; Label; Lesion; Mass Spectrum Analysis; Measures; Methodology; Methods; Minerals; Modality; Modeling; Monitor; Mus; Nitrogen; North Carolina; Optics; Organ; Osteoclasts; Outcome; Outcome Study; Pathology; Patients; Pharmaceutical Preparations; Phase; Physicians; Positron-Emission Tomography; Premature Mortality; Preparation; Race; Radioactivity; Radioisotopes; Radiolabeled; Radiology Specialty; Rattus; Research; Resolution; Rheumatoid Arthritis; Risedronate; Sensitivity and Specificity; Small Business Innovation Research Grant; Staging; Swelling; Symptoms; TNF gene; Techniques; Technology; Therapeutic Intervention; Time; Tissues; Treatment Effectiveness; Universities; Work; Zoledronate; analog; authority; base; bisphosphonate; bone; bone erosion; bone loss; clinical application; design; disability; fluorescence imaging; imaging probe; improved; in vitro testing; joint destruction; joint injury; microPET; molecular imaging; mouse model; novel; optical imaging; pre-clinical research; prenylation; prevent; professor; programs; public health relevance; radiotracer

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an autoimmune disease causing chronic inflammation, which is characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to severe disability and premature mortality. It has been recognized that early therapeutic intervention improves clinical outcomes and reduces the accrual of joint damage and disability. However, timely intervention strongly depends on the early diagnosis of RA, which has stimulated the investigation of molecular imaging techniques as a sensitive measure of disease progression. The development of such techniques has been significantly limited by the requirement to design and validate optical and radionuclide probes with suitably high specificity and sensitivity. In addition, bisphosphonates (BPs), especially the modern generation of nitrogen-containing BPs (N-BPs), are effective anti-resorptive agents targeting osteoclast activity, which is central to the development of bone damage in RA. A number of studies have found that N-BPs are effective for RA treatment in both animal models and humans although the mechanism of action remains unclear. Based on the facts that 1) BPs are highly specific for osseous tissue, with short circulating half lives (minutes in rat and 0.5 -2 h in humans), and 2) 18F positron emission tomography (PET) imaging has high specific radioactivity and sensitivity, in this Phase I SBIR project we propose to create novel N-BP derived 18F PET probes and 18F-BODIPY PET/optical dual modality probes for RA imaging. The new imaging probes will be evaluated in a type II collagen-induced arthritis (CIA) mouse model for detection of early structural changes in cartilage or bone and their relation to development of arthritis lesions. The ultimate goal of the proposed research is to provide an improved diagnostic method to aid the physician in determining when to treat the disease, and the effectiveness of treatment. The imaging probes will also help substantiate the utility of BPs in rheumatoid arthritis based on a better understanding of their distribution, and on identifying the concentrations that are achievable in affected joints. Our program involves a partnership between Dr. F. H. Ebetino and S. Sun at BioVinc, LLC and Professor Zibo Li at the Department of Radiology of University of North Carolina at Chapel Hill, combining complementary strengths in bisphosphonate chemistry and biology (BioVinc) and expertise in radiolabeling methodology and PET imaging (UNC-CH). Prof. B. Boyce, M.D. (University of Rochester), an expert on bone pathology and Prof. C. E. McKenna, Ph.D. (University of Southern California), an authority on bisphosphonate probe chemistry, will participate as consultants.

 描述（申请人提供）：类风湿性关节炎（RA）是一种引起慢性炎症的自身免疫性疾病，其特征是关节肿胀、关节压痛和滑膜关节破坏，导致严重残疾和过早死亡。干预可以改善临床结果并减少关节损伤和残疾的发生，然而，及时干预很大程度上取决于 RA 的早期诊断，这刺激了分子成像技术作为疾病进展的敏感测量方法的发展。由于需要设计和验证具有适当高特异性和灵敏度的光学和放射性核素探针，此类技术的应用受到了极大限制。此外，双磷酸盐（BP），尤其是现代一代的含氮BP（N-BP）是有效的。针对破骨细胞活性的抗再吸收药物，破骨细胞活性是 RA 骨损伤发展的核心。许多研究发现，N-BP 对动物模型和人类的 RA 治疗均有效。作用机制尚不清楚。基于以下事实：1) BP 对骨组织具有高度特异性，循环半衰期短（大鼠为几分钟，人类为 0.5 -2 小时），2) 18F 正电子发射断层扫描 (PET) 成像。具有高比放射性和灵敏度，在这个第一期SBIR项目中，我们建议创建新型N-BP衍生的18F PET探针和18F-BODIPY PET/光学双模态RA 成像探针将在 II 型胶原诱导关节炎 (CIA) 小鼠模型中进行评估，以检测软骨或骨骼的早期结构变化及其与关节炎病变发展的关系。研究的目的是提供一种改进的诊断方法，帮助医生确定何时治疗该疾病，并且成像探针还将有助于在更好地了解 BP 的分布的基础上证实其在类风湿性关节炎中的效用。确定浓度我们的项目涉及 BioVinc, LLC 的 F. H. Ebetino 博士和 S. Sun 以及北卡罗来纳大学教堂山分校放射学系的 Zibo Li 教授的合作，结合了双膦酸盐化学和B. Boyce 教授，医学博士（罗切斯特大学），骨病理学专家和教授。双膦酸盐探针化学领域的权威 C. E. McKenna 博士（南加州大学）将作为顾问参与其中。