Luna Ge1,2, Zheng Fu3, Yuchun Wei4, Dandan Shi2, Yun Geng5, Huancai Fan2, Ruojia Zhang2, Yuang Zhang1,2, Shufeng Li6, Shijie Wang4, Haojun Shi7, Guanhua Song8, Jihong Pan1,2, Kai Cheng9, Lin Wang10,11. 1. Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China. 2. Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China. 3. Department of PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China. 4. Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China. 5. Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China. 6. Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China. 7. The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, China. 8. Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China. 9. Department of PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China. kcsdut@163.com. 10. Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China. linwang@sdfmu.edu.cn. 11. Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China. linwang@sdfmu.edu.cn.
Abstract
PURPOSE: 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-[18F]-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid-conjugated FAP inhibitor 04 ([18F]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients. METHODS: 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 [18F]AlF-NOTA-FAPI-04 and 18F-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 [18F]AlF-NOTA-FAPI-04. Additionally, [18F]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients. RESULTS: The binding of [18F]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (FAP-GFP-NIH3T3 vs. GFP-NIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/105 cells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/105 cells). Compared to 18F-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, P<0.001). In addition, the binding of [18F]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [18F]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 [18F]AlF-NOTA-FAPI-04 in FAP-GFP-NIH3T3 xenografts was significantly higher than that in GFP-NIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [18F]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints. CONCLUSION: [18F]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters.
PURPOSE: 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-[18F]-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid-conjugated FAP inhibitor 04 ([18F]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients. METHODS: 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 [18F]AlF-NOTA-FAPI-04 and 18F-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 [18F]AlF-NOTA-FAPI-04. Additionally, [18F]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients. RESULTS: The binding of [18F]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (FAP-GFP-NIH3T3 vs. GFP-NIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/105 cells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/105 cells). Compared to 18F-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, P<0.001). In addition, the binding of [18F]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [18F]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 [18F]AlF-NOTA-FAPI-04 in FAP-GFP-NIH3T3 xenografts was significantly higher than that in GFP-NIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [18F]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints. CONCLUSION: [18F]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters.
Authors: Stefan Bauer; Michael C Jendro; Andreas Wadle; Sascha Kleber; Frank Stenner; Robert Dinser; Anja Reich; Erica Faccin; Stefan Gödde; Harald Dinges; Ulf Müller-Ladner; Christoph Renner Journal: Arthritis Res Ther Date: 2006 Impact factor: 5.156
Authors: Adam P Croft; Joana Campos; Kathrin Jansen; Jason D Turner; Jennifer Marshall; Moustafa Attar; Loriane Savary; Corinna Wehmeyer; Amy J Naylor; Samuel Kemble; Jenefa Begum; Kerstin Dürholz; Harris Perlman; Francesca Barone; Helen M McGettrick; Douglas T Fearon; Kevin Wei; Soumya Raychaudhuri; Ilya Korsunsky; Michael B Brenner; Mark Coles; Stephen N Sansom; Andrew Filer; Christopher D Buckley Journal: Nature Date: 2019-05-29 Impact factor: 49.962
Authors: Fan Zhang; Kevin Wei; Kamil Slowikowski; Chamith Y Fonseka; Deepak A Rao; Stephen Kelly; Susan M Goodman; Darren Tabechian; Laura B Hughes; Karen Salomon-Escoto; Gerald F M Watts; A Helena Jonsson; Javier Rangel-Moreno; Nida Meednu; Cristina Rozo; William Apruzzese; Thomas M Eisenhaure; David J Lieb; David L Boyle; Arthur M Mandelin; Brendan F Boyce; Edward DiCarlo; Ellen M Gravallese; Peter K Gregersen; Larry Moreland; Gary S Firestein; Nir Hacohen; Chad Nusbaum; James A Lederer; Harris Perlman; Costantino Pitzalis; Andrew Filer; V Michael Holers; Vivian P Bykerk; Laura T Donlin; Jennifer H Anolik; Michael B Brenner; Soumya Raychaudhuri Journal: Nat Immunol Date: 2019-05-06 Impact factor: 25.606
Authors: M Syed; P Flechsig; J Liermann; P Windisch; F Staudinger; S Akbaba; S A Koerber; C Freudlsperger; P K Plinkert; J Debus; F Giesel; U Haberkorn; S Adeberg Journal: Eur J Nucl Med Mol Imaging Date: 2020-05-23 Impact factor: 9.236
Authors: Kevin Wei; Ilya Korsunsky; Jennifer L Marshall; Anqi Gao; Gerald F M Watts; Triin Major; Adam P Croft; Jordan Watts; Philip E Blazar; Jeffrey K Lange; Thomas S Thornhill; Andrew Filer; Karim Raza; Laura T Donlin; Christian W Siebel; Christopher D Buckley; Soumya Raychaudhuri; Michael B Brenner Journal: Nature Date: 2020-04-22 Impact factor: 49.962