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.
The proposed research addresses important and challenging needs in the field of rheumatoid arthritis (RA): early diagnosis, early effects of therapy, and understanding the mechanism of action of bisphosphonates in RA. In a partnership involving BioVinc, LLC and the Department of Radiology at University of North Carolina at Chapel Hill, novel bisphosphonate (BP)-based PET and PET/optical dual-modality probes will be synthesized and investigated for RA joint imaging in an animal model. The outcome of this study will be the generation of a novel class of imaging molecules for early RA detection and monitoring effects of therapy, with the goal of developing a highly specific and sensitive probe for preclinical research, and ultimately, clinical applications.
|Sun, Shuting; B?a?ewska, Katarzyna M; Kadina, Anastasia P et al. (2016) Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine. Bioconjug Chem 27:329-40|