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）是一种自身免疫性疾病，引起慢性炎症，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。人们已经认识到，早期治疗干预可以改善临床结局，减少关节损伤和残疾的发生。然而，及时干预强烈依赖于RA的早期诊断，这刺激了分子影像学技术作为疾病进展的敏感措施的研究。这种技术的发展受到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的要求的极大限制。此外，二膦酸盐（BP），特别是现代一代的含氮BP（N-BP），是有效的抗吸收剂，靶向破骨细胞活性，这是RA骨损伤发展的核心。许多研究发现，N-BP在动物模型和人类中对RA治疗有效，尽管作用机制仍不清楚。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（在大鼠中为几分钟，在人类中为0.5 - 2小时），和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，在该I期SBIR项目中，我们提出创建用于RA成像的新型N-BP衍生的18F PET探针和18F-BODIPY PET/光学双模态探针。新的成像探针将在II型胶原诱导的关节炎（CIA）小鼠模型中进行评估，以检测软骨或骨的早期结构变化及其与关节炎病变发展的关系。拟议研究的最终目标是提供一种改进的诊断方法，以帮助医生确定何时治疗疾病以及治疗的有效性。成像探针还将有助于证实BP在类风湿性关节炎中的效用，这是基于对其分布的更好理解，以及确定受影响关节中可达到的浓度。我们的项目涉及F博士之间的伙伴关系。H. Ebetino和S. BioVinc，LLC的Sun和查佩尔山的北卡罗来纳州大学放射学系的Zibo Li教授，结合了双膦酸盐化学和生物学（BioVinc）的互补优势以及放射性标记方法学和PET成像（UNC-CH）的专业知识。B教授。博伊斯，医学博士（罗切斯特大学），骨骼病理学专家和C。E. McKenna博士（南加州大学），双膦酸盐探针化学的权威，将作为顾问参加。