{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T06:22:16Z","timestamp":1782886936785,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T00:00:00Z","timestamp":1683849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["19H03602"],"award-info":[{"award-number":["19H03602"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["16H06278"],"award-info":[{"award-number":["16H06278"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Drug Discovery Science Division, Open and Transdisciplinary Research Initiative of Osaka University","award":["19H03602"],"award-info":[{"award-number":["19H03602"]}]},{"name":"Drug Discovery Science Division, Open and Transdisciplinary Research Initiative of Osaka University","award":["16H06278"],"award-info":[{"award-number":["16H06278"]}]},{"name":"JSPS Grant-in-Aid for Scientific Research on Innovative Areas","award":["19H03602"],"award-info":[{"award-number":["19H03602"]}]},{"name":"JSPS Grant-in-Aid for Scientific Research on Innovative Areas","award":["16H06278"],"award-info":[{"award-number":["16H06278"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor (FAPI) is used as a probe to deliver nuclides to cancer tissues. In this study, we designed and synthesized four novel 211At-FAPI(s) possessing polyethylene glycol (PEG) linkers between the FAP-targeting and 211At-attaching moieties. 211At-FAPI(s) and piperazine (PIP) linker FAPI exhibited distinct FAP selectivity and uptake in FAPII-overexpressing HEK293 cells and the lung cancer cell line A549. The complexity of the PEG linker did not significantly affect selectivity. The efficiencies of both linkers were almost the same. Comparing the two nuclides, 211At was superior to 131I in tumor accumulation. In the mouse model, the antitumor effects of the PEG and PIP linkers were almost the same. Most of the currently synthesized FAPI(s) contain PIP linkers; however, in our study, we found that PEG linkers exhibit equivalent performance. If the PIP linker is inconvenient, a PEG linker is expected to be an alternative.<\/jats:p>","DOI":"10.3390\/ijms24108701","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T10:49:51Z","timestamp":1683888591000},"page":"8701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Evaluation of Astatine-211-Labeled Fibroblast Activation Protein Inhibitor (FAPI): Comparison of Different Linkers with Polyethylene Glycol and Piperazine"],"prefix":"10.3390","volume":"24","author":[{"given":"Ayaka","family":"Aso","sequence":"first","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hinako","family":"Nabetani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshifumi","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Kadonaga","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2352-9057","authenticated-orcid":false,"given":"Yoshifumi","family":"Shirakami","sequence":"additional","affiliation":[{"name":"Division of Science, Institute for Radiation Sciences, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8658-2395","authenticated-orcid":false,"given":"Tadashi","family":"Watabe","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7276-5614","authenticated-orcid":false,"given":"Taku","family":"Yoshiya","sequence":"additional","affiliation":[{"name":"Peptide Institute, Inc., 7-2-9 Saito-asagi, Ibaraki 567-0085, Osaka, Japan"},{"name":"Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayoshi","family":"Mochizuki","sequence":"additional","affiliation":[{"name":"Peptide Institute, Inc., 7-2-9 Saito-asagi, Ibaraki 567-0085, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Ooe","sequence":"additional","affiliation":[{"name":"Radioisotope Research Center, Institute for Radiation Sciences, Osaka University, 2-4 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, 7-1 Mihogaoka, Ibaraki 567-0047, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Jinno","sequence":"additional","affiliation":[{"name":"R&D Division, Alpha Fusion Inc., 10-1 Mihogaoka, Ibaraki 567-0047, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Toyoshima","sequence":"additional","affiliation":[{"name":"Division of Science, Institute for Radiation Sciences, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromitsu","family":"Haba","sequence":"additional","affiliation":[{"name":"RIKEN Nishina Center for Accelerator-Based Science, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"RIKEN Nishina Center for Accelerator-Based Science, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6558-966X","authenticated-orcid":false,"given":"Jens","family":"Cardinale","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University Hospital D\u00fcsseldorf, Moorenstr. 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik Lars","family":"Giesel","sequence":"additional","affiliation":[{"name":"Division of Science, Institute for Radiation Sciences, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"},{"name":"Department of Nuclear Medicine, University Hospital D\u00fcsseldorf, Moorenstr. 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1910-0450","authenticated-orcid":false,"given":"Atsushi","family":"Shimoyama","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6657-5059","authenticated-orcid":false,"given":"Kazuko","family":"Kaneda-Nakashima","sequence":"additional","affiliation":[{"name":"Division of Science, Institute for Radiation Sciences, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"},{"name":"Core for Medicine and Science Collaborative Research and Education, Forefront Research Center, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8844-0710","authenticated-orcid":false,"given":"Koichi","family":"Fukase","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"},{"name":"Division of Science, Institute for Radiation Sciences, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"},{"name":"Core for Medicine and Science Collaborative Research and Education, Forefront Research Center, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3412","DOI":"10.1016\/j.bmcl.2012.03.107","article-title":"Acylated Gly-(2-cyano)pyrrolidines as inhibitors of fibroblast activation protein (FAP) and the issue of FAP\/prolyl oligopeptidase (PREP)-selectivity","volume":"22","author":"Ryabtsova","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6573","DOI":"10.1021\/jm1002556","article-title":"Substituted 4- carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein","volume":"53","author":"Tsai","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1021\/ml300410d","article-title":"Selective inhibitors of fibroblast activation protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine scaffold","volume":"4","author":"Jansen","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.2967\/jnumed.118.210443","article-title":"Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein","volume":"59","author":"Lindner","year":"2018","journal-title":"J. Nucl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"854658","DOI":"10.3389\/fonc.2022.854658","article-title":"FAPI-PET\/CT in cancer imaging: A potential novel molecule of the century","volume":"12","author":"Huang","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.7150\/thno.69475","article-title":"Fibroblast activation protein-based theranostics in cancer research: A state-of-the-art review","volume":"12","author":"Zhao","year":"2022","journal-title":"Theranostics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.2967\/jnumed.118.210435","article-title":"A tumor-imaging method targeting cancer-associated fibroblasts","volume":"59","author":"Loktev","year":"2018","journal-title":"J. Nucl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s41181-019-0069-0","article-title":"Targeting of activated fibroblasts for imaging and therapy","volume":"4","author":"Lindner","year":"2019","journal-title":"EJNMMI Radiopharm. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"201","DOI":"10.2967\/jnumed.120.245084","article-title":"FAPI-74 PET\/CT using either 18F-AlF or cold-kit 68Ga-labeling: Biodistribution, radiation dosimetry and tumor delineation in lung cancer patients","volume":"62","author":"Giesel","year":"2021","journal-title":"J. Nucl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.2967\/jnumed.118.224469","article-title":"Development of fibroblast activation protein\u2013targeted radiotracers with improved tumor retention","volume":"60","author":"Loktev","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.2967\/jnumed.119.239731","article-title":"Design and development of 99mTc-labeled FAPI tracers for SPECT imaging and 188Re therapy","volume":"61","author":"Lindner","year":"2020","journal-title":"J. Nucl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.2967\/jnumed.122.264069","article-title":"Repetitive early FAPI-PET acquisition comparing FAPI-02, FAPI-46 and FAPI-74: Methodological and diagnostic implications for malignant, inflammatory and degenerative lesions","volume":"63","author":"Glatting","year":"2022","journal-title":"J. Nucl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1007\/s00259-021-05307-1","article-title":"Head-to-head intra-individual comparison of biodistribution and tumor uptake of 68Ga-FAPI and 18F-FDG PET\/CT in cancer patients","volume":"48","author":"Giesel","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.radonc.2021.04.016","article-title":"68Ga-FAPI-PET\/CT improves diagnostic staging and radiotherapy planning of adenoid cystic carcinomas\u2014Imaging analysis and histological validation","volume":"160","author":"Syed","year":"2021","journal-title":"Radiother. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"862","DOI":"10.2967\/jnumed.121.263016","article-title":"Synthesis, preclinical evaluation, and a pilot clinical PET imaging study of 68Ga-labeled FAPI Dimer","volume":"63","author":"Zhao","year":"2022","journal-title":"J. Nucl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.apsb.2021.09.032","article-title":"Preclinical evaluation and pilot clinical study of [18F]AlF-labeled FAPI-tracer for PET imaging of cancer associated fibroblasts","volume":"12","author":"Hu","year":"2022","journal-title":"Acta Pharm. Sin. B."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4259","DOI":"10.1007\/s00259-021-05470-5","article-title":"Clinical translational evaluation of Al18F-NOTA-FAPI for fibroblast activation protein-targeted tumour imaging","volume":"48","author":"Wang","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1007\/s00259-020-05132-y","article-title":"Biodistribution, pharmacokinetics, dosimetry of [68Ga]Ga-DOTA.SA.FAPi, and the head-to-head comparison with [18F]F-FDG PET\/CT in patients with various cancers","volume":"48","author":"Ballal","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Greifenstein, L., Kramer, C.S., Moon, E.S., R\u00f6sch, F., Klega, A., Landvogt, C., M\u00fcller, C., and Baum, R.P. (2022). From Automated Synthesis to In Vivo Application in Multiple Types of Cancer-Clinical Results with [68Ga]Ga-DATA5m.SA.FAPi. Pharmaceuticals, 15.","DOI":"10.3390\/ph15081000"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s41181-021-00142-z","article-title":"One-pot and one-step automated radio-synFthesis of [18F]AlF-FAPI-74 using a multi purpose synthesizer: A proof-of-concept experiment","volume":"6","author":"Naka","year":"2021","journal-title":"EJNMMI Radiopharm. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s00259-021-05554-2","article-title":"Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac]FAPI-46 in a pancreatic cancer model","volume":"49","author":"Liu","year":"2022","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"563","DOI":"10.2967\/jnumed.119.233122","article-title":"Theranostics targeting fibroblast activation protein in the tumor stroma: 64Cu- and 225Ac-labeled FAPI-04 in pancreatic cancer xenograft mouse models","volume":"61","author":"Watabe","year":"2020","journal-title":"J. Nucl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"116600","DOI":"10.1016\/j.bmc.2021.116600","article-title":"In vitro and in vivo evaluation of 211At-labeled fibroblast activation protein inhibitor for glioma treatment","volume":"55","author":"Ma","year":"2022","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1246\/cl.220391","article-title":"Substrate study for dihydroxyboryl astatine substitution reaction with Fibroblast Activation Protein Inhibitor (FAPI)","volume":"51","author":"Aso","year":"2022","journal-title":"Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"12982","DOI":"10.1038\/s41598-021-92476-6","article-title":"Synthesis of [211At]4-astato-L-phenylalanine by dihydroxyboryl-astatine substitution reaction in aqueous solution","volume":"11","author":"Shirakami","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.2967\/jnumed.118.222638","article-title":"Enhancement of astatine-211 uptake via the sodium iodide symporter by the addition of ascorbic acid in targeted alpha therapy of thyroid cancer","volume":"60","author":"Watabe","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00259-021-05431-y","article-title":"Why bother with alpha particles?","volume":"49","author":"King","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sathekge, M., Bruchertseifer, F., Vorster, M., Lawal, O.I., Mokoala, K., Reed, J., Maseremule, L., Ndlovu, H., Hlongwa, K., and Maes, A. (Eur. J. Nucl. Med. Mol. Imaging, 2023). 225Ac-PSMA-617 radioligand therapy of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC): Preliminary clinical findings, Eur. J. Nucl. Med. Mol. Imaging, in press.","DOI":"10.1007\/s00259-023-06165-9"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1080\/14737140.2020.1814151","article-title":"The potential of PSMA-targeted alpha therapy in the management of prostate cancer","volume":"20","author":"Filippi","year":"2020","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1111\/cas.14761","article-title":"\u03b1-Emitting cancer therapy using 211At-AAMT targeting LAT1","volume":"112","author":"Zhang","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1002\/anie.201510868","article-title":"Spin-Selective Generation of Triplet Nitrenes: Olefin Aziridination through Visible-Light Photosensitization of Azidoformates","volume":"55","author":"Scholz","year":"2016","journal-title":"Angew. Chem. Int. Ed."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8701\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:34:05Z","timestamp":1760124845000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8701"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,12]]},"references-count":31,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108701"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108701","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,12]]}}}