| Autor: |
Luna, Ge, Zheng, Fu, Yuchun, Wei, Dandan, Shi, Yun, Geng, Huancai, Fan, Ruojia, Zhang, Yuang, Zhang, Shufeng, Li, Shijie, Wang, Haojun, Shi, Guanhua, Song, Jihong, Pan, Kai, Cheng, Lin, Wang |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
European journal of nuclear medicine and molecular imaging. 49(12) |
| ISSN: |
1619-7089 |
| Popis: |
Fibroblast-like synoviocytes (FLSs) are key effector cells in the inflamed joints of patients with rheumatoid arthritis (RA). Previous studies have suggested that fibroblast activation protein (FAP) is highly expressed in RA-derived FLSs and is a specific marker of activated RA FLSs. In this study, we developed aluminum-[sup18/supF]-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid-conjugated FAP inhibitor 04 ([sup18/supF]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients.RA FLSs and NIH3T3 cells transfected with FAP were used to perform in vitro-binding studies. Biodistribution was conducted in normal DBA1 mice. Collagen-induced arthritis (CIA) models with different arthritis scores were subjected to [sup18/supF]AlF-NOTA-FAPI-04 andsup18/supF-FDG PET imaging. Histological examinations were performed to evaluate FAP expression and Cy3 dye-labeled FAPI-04(Cy3-FAPI-04) uptake. Blocking studies with excess unlabeled FAPI-04 in CIA mice and NIH3T3 xenografts in immunocompromised mice were used to evaluate the binding specificity of [sup18/supF]AlF-NOTA-FAPI-04. Additionally, [sup18/supF]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients.The binding of [sup18/supF]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (supFAP-GFP-/supNIH3T3 vs.supGFP-/supNIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/10sup5/supcells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/10sup5/supcells). Compared tosup18/supF-FDG imaging, [18F]AlF-NOTA-FAPI-04 showed high uptake in inflamed joints in the early stage of arthritis, which was positively correlated with the arthritic scores (Pearson r=0.834, Plt;0.001). In addition, the binding of [sup18/supF]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [sup18/supF]AlF-NOTA-FAPI-04 in arthritic joints both could be blocked by excessive unlabeled FAPI-04. Fluorescent staining showed that the intensity of Cy3-FAPI-04 binding to FAP increased accordingly as the expression of FAP protein increased in cells and tissue sections. Furthermore, the uptake of [sup18/supF]AlF-NOTA-FAPI-04 insupFAP-GFP-/supNIH3T3 xenografts was significantly higher than that insupGFP-/supNIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [sup18/supF]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints.[sup18/supF]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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