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（由适用提供）：类风湿关节炎（RA）是一种自身免疫性疾病，引起了慢性感染，其特征是关节吞咽，关节压痛和滑膜关节的破坏，导致严重的残疾和过早死亡。已经认识到，早期的治疗干预措施可改善临床结果，并降低关节损伤和残疾的准确性。但是，及时的干预很大程度上取决于RA的早期诊断，RA刺激了分子成像技术的研究，作为对疾病进展的敏感测量。这种技术的开发受到设计和验证具有适当高的特异性和敏感性的光学和放射性问题的要求，这受到了显着限制。此外，双膦酸盐（BPS），尤其是现代含氮BPS（N-BPS）的一代，是靶向破骨细胞活性的有效抗敏化剂，这对于RA中骨损伤的发展至关重要。许多研究发现，在动物模型和人类中，N-BP对RA治疗都是有效的，尽管作用机理尚不清楚。基于以下事实：1）BPS对骨组织高度具体，其半循环寿命短（大鼠分钟为0.5 -2 h，在人类中为0.5 -2 h），以及2）18F正电子发射断层扫描（PET）成像具有很高的特定放射性和敏感性，在此I阶段I SBIR项目中，我们建议我们创建新颖的N-BP派生的18f Pet Pet pet pet和18f-Bodipy/raip dip dip dip dip dip dip dipy/sbir。新的成像问题将在II型胶原蛋白诱导的关节炎（CIA）小鼠模型中评估，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。拟议研究的最终目标是提供一种改进的诊断方法，以帮助身体确定何时治疗疾病以及治疗的有效性。成像问题还将有助于证实基于对其分布的更好理解，并确定在受影响的关节中可达到的浓度，可以证实BPS在类风湿关节炎中的实用性。我们的计划涉及Biovinc，LLC的F. H. Ebetino博士和S. Sun博士与北卡罗来纳大学放射学系的Chapel Hill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（Biovinc），以及Radiolabieling方法论和PET学和Pet Imaging（Uncem-Ch）的专家。 B. Boyce教授，医学博士（罗切斯特大学），骨骼病理学专家和C. E. McKenna教授，博士学位。 （南加州大学），双膦酸盐探测化学的权力将作为顾问参加。