^99mTc-NTP 15-5 Imaging for Cartilage Involvement in Experimental Rheumatoid Arthritis: Comparison with Routinely Used Molecular Imaging Methods and Sensitivity to Chronic Nonsteroidal Antiinflammatory Drug Treatment

Abstract

This study determined, using the intraarticular complete Freund adjuvant arthritis mice model, whether the radiotracer 99m Tc-N-(triethylammonium)-3-propyl- [15]ane-N5 ( 99m Tc-NTP 15-5) targeting proteoglycans has a pathophysiologic validity for in vivo imaging of rheumatoid arthritis (RA) and its response to chronic nonsteroidal antiinflammatory drugs. Methods: We investigated the time course of cartilage remodeling by 99m Tc-NTP 15-5 scintigraphy, bone damages by 99m Tc-hydroxymethylene diphosphonate imaging, inflammation by 18 F-FDG PET, and joint proteoglycan content and pain behavior in animals, without and with meloxicam treatment. Paw circumference, thermal pain behavior, and histology as well as proteoglycan content of the whole joint were determined. Results: 99m Tc-NTP 15-5 showed specific tracer accumulation within RA joints, with a significant increase in scintigraphic ratio observed in RA versus shams from day 3 to day 28. 18 F-FDG evidenced uptake in RA joints from day 15 to day 29. Animals treated with meloxicam (5 mg/kg) exhibited a dose-dependent decrease in both 99m Tc-NTP 15-5 and 18 F-FDG uptake ratios versus saline-treated animals. 99m Tc-hydroxymethylene diphosphonate bone scans were only positive at day 14 in RA versus shams, with a significant effect of meloxicam. An increase in proteoglycans of RA joint and thermal pain behavior were observed and were dose-dependently reduced by meloxicam. Conclusion: These experimental results bring data in favor of the 99m Tc-NTP 15-5 radiotracer for assessing, in vivo, cartilage remodeling in RA that could be used to monitor therapy.

99mTc-NTP 15-5 is a companion radiotracer for assessing joint functional response to sprifermin (rhFGF-18) in a murine osteoarthritis model

“…For these animals, increase in scintigraphic ratios in response to sprifermin was concomitant with proteoglycan ratio increase. Such relation between 99m Tc-NTP 15-5 scintigraphic ratio and proteoglycan content was previously demonstrated in an experimental model of rheumatoid arthritis, under meloxicam treatment thus reinforcing the specificity of 99m Tc-NTP 15-5 to monitor the effect of treatments as well as monitoring disease progression 21 .…”

“…99m Tc-NTP 15-5 was previously demonstrated to be a candidate for the in vivo functional nuclear imaging of proteoglycan remodeling in degenerative pathologies of cartilage 16 – 21 . In the present study, we evaluated in the surgically induced DMM model the relevance of 99m Tc-NTP 15-5 nuclear imaging for monitoring in vivo cartilage remodelling in response to sprifermin (rhFGF-18), an anabolic agent which previously demonstrated cartilage repair properties 9 – 14 .…”

“…Because cartilage contains up to 10% PG consisting of mainly chondroitin sulphate aggrecan which chains are negatively charged 15 , our strategy is based on the use of a bi-functional agent, the radiotracer 99m Tc-N-(triethylammonium)-3-propyl-[15]ane-N5 ( 99m Tc-NTP 15-5), that contains in its structure a positively charged quaternary ammonium function for binding to PG and a polyazamacrocycle to complex 99m Tc. Based on many preclinical studies, we believe that 99m Tc-NTP 15-5 and in vivo functional imaging of PG could provide a suitable set of criteria for quantifying cartilage functionality, and the efficacy of new emerging therapeutic strategies 16 – 21 .…”

Screening for peptides targeted to IL-7Rα for molecular imaging of rheumatoid arthritis synovium

“…Among them, only 18 F-FDG, TSPO-targeted radiotracers (e.g., 11 CPBR28, 18 F-GE-180), the α v β 3 -specific imaging probe 68 Ga-BNOTA-PRGD2 and the PET probe 18 F-FHBG employed for the imaging of reporter genes, are currently undergoing clinical trials according to the US National Institutes of Health [ 32 ]. Examples of new imaging tracers include 99m Tc-labeled derivative of octreotide peptide employed to image somatostatin receptor expressed by T lymphocytes [ 33 ], and several radiotracers used to monitor therapy response in human or experimental arthritis, such as 99m Tc-NTP 15–5 targeted to proteoglycans in the RA joints [ 34 ], 111 In-RGD2 (α v β 3 -targeted), 111 In-anti-fibroblast activation protein antibody and 111 In-antimurine macrophage antibody [ 35 ]. Therefore, there is active research to meet the increasing demand of imaging methods and probes able to provide precocious and reliable information on the clinical outcome, pathophysiological process, the disease severity and location, and the disease response to novel molecular therapies.…”

Frequent, quantitative bone planar scintigraphy for determination of bone anabolism in growing mice

“…Despite widespread use of bone planar scintigraphy in patients, its application in mice remains anecdotal ( Khairnar et al, 2015 ; Tin Ong et al, 2008 ), even though data on bone turnover can be obtained, which otherwise require bone biopsies. We now demonstrate that frequent quantitative planar scintigraphy with subcutaneous tracer injection is feasible in mice and allows for frequent longitudinal assessment of bone turnover during the growing period.…”