A highly Sensitive 99mTc-NTP 15-5 SPECT imaging targeting proteoglycans for assessing ostearthritis response to innovative therapeutic approaches. – A-SPECT

Osteoarthritis (OA), in the context of an aging population, has a major impact on the quality of life of patients and is a very significant health problem in western countries. OA is a slowly, progressive, ultimately degenerative disorder of movable joints, mainly characterized by pain and functional limitation and affecting all joint structures such as cartilage, subchondral bone, ligaments, capsule, synovium, and menisci.
Progress in understanding OA pathophysiology has identifyed promising therapeutic targets, with the emergence of Disease Modifying OsteoArthritis Drugs (DMOAD), aiming at preventing or slowing disease progression. Despite extensive research in DMOAD, there are currently no pharmacological interventions approved by the FDA, available for patients that has demonstrated efficacy. Regulatory agencies postulated that time to total joint replacement surgery is finally the most relevant clinical end-point available at present for the evaluation of efficacy of a new DMOAD.
Authors consider that research and development towards DMOAD is hampered by the lack of specific and sensitive imaging tools to reliably quantify OA progression, and monitore response to therapy. Higher sensitive imaging approaches appear of real need to evaluate OA progression and to follow response to innovative therapies.
A-SPECT project proposes the validation of a molecular imaging targeting cartilage proteoglycans in vivo, which has the opportunity to provide an in vivo and functional access to joint in nuclear medicine.
The “proteoglycan targeting strategy” developed and validated by our lab for many years, and covered by the patent WO 01/00621 A1, aims at validating an innovative imaging management of patients with OA.
This strategy dedicated to cartilage imaging, is based on the use of a bi-functional agent (named as 99mTc-NTP 15-5), that contains in its structure a quaternary ammonium function for cartilage proteoglycans (PG) targeting and an oxotechnetium complex, 99mTc being the ideal isotope for nuclear medicine examination. On the basis of many preclinical studies, we believe that 99mTc-NTP 15-5 could be the strong candidate for a relevant and specific functional molecular imaging of cartilage at the PG level: Its sensitivity for PG imaging can provide a suitable set of criteria for quantifying cartilage functionality, which is of major interest for assessing both the early signs of OA disease and the efficacy of new emerging therapeutic strategies.
This project has the potential to provide data susceptible to open the way at shorter terms to further first into human phase imaging aiming at evaluating joint functional level in nuclear medicine using the 99mTc-NTP 15-5 radiotracer. Objectives of A-SPECT are:
(i) determining the dosimetry profile associated to 99mTc-NTP 15-5 imaging of cartilage
(ii) assessing the relevance of 99mTc-NTP 15-5 imaging for monitoring innovative DMOAD approaches, with the opportunity to bridge the gap between preclinical and clinical testing, such as:
- supplementation therapeutic approach using lubricin
- symptomatic approach for pain management, exploiting antibodies to NGF (tanezumab)
- subchondral bone targeting using strontium ranelate.
(iii) establishing the non clinical regulatory toxicology studies necessary for the submission of Innovative Medicinal Product Dossier (IMPD) for the first phase into human phase
By combining the high sensitivity of 99mTc-NTP 15-5 radiotracer to PG content changes with the high sensitivity of SPECT imaging, (which is considered to be the most sensitive medical imaging technique), we strongly believe that this project has the potential to initiate the development of a new radiopharmaceutical designed at joint function evaluation in nuclear medicine.
We should not forget that OA affects 30–50% of adults over 65 years, with costs estimated in 2002 in France to exceed 1.6 billion Euros,