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.
Experiments will be performed with two rat osteoarthritis models to validate a novel probe, which consists of the radioisotope Tc-99m and a synthetic inflammation targeting peptide cFLFLF, for imaging inflammation in osteoarthritis. This agent is expected to be advantageous over current imaging modilities because of its high specificity, and thus significantly improve the early diagnosis and treatment of osteoarthritis.
