Medical Radiology and Radiation Safety. 2026. Vol. 71. № 3

DOI:10.33266/1024-6177-2026-71-3-110-121

A.A. Medvedeva, L.A. Tashireva, R.V. Zelchan, V.I. Chernov

The Use of Radioconjugates Targeting the Fibroblast Activation Protein: Current State of the Art

Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia

Contact person: A.A. Medvedeva, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

CONTENTS 

To review the current state and prospects of targeting fibroblast activation protein (FAP) in the tumor microenvironment for the diagnostic imaging and therapy of malignant neoplasms. Includes the following sections:

∙Structure of BAF.

∙Function of BAF in norm and in malignant tumors.

∙Radiotracers for visualization.

∙Radiopharmaceuticals for theranostics.

∙Conclusion.

An analysis of literature data was conducted, focusing on the structure and function of FAP under normal conditions and in malignancies, the role of cancer-associated fibroblasts (CAFs), as well as the main trends in the development of FAP inhibitor (FAPI)-based radiopharmaceuticals and clinical trials of FAPIs.

Keywords:  fibroblast activation protein, cancer, radionuclide diagnostics, theranostics

For citation:  Medvedeva AA, Tashireva LA, Zelchan RV, Chernov VI. The Use of Radioconjugates Targeting the Fibroblast Activation Protein: Current State of the Art. Medical Radiology and Radiation Safety. 2026;71(3):110–121. DOI:10.33266/1024-6177-2026-71-3-110-121

 

References

1.Kratochwil C., Flechsig P., Lindner T., Abderrahim L., Altmann A., Mier W., et al. 68Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer. J Nucl Med. 2019;60;6:801-5. Doi: 10.2967/jnumed.119.227967.

2.Hirmas N., Hamacher R., Sraieb M., Ingenwerth M., Kessler L., Pabst K.M., et al. Fibroblast-Activation Protein PET and Histopathology in a Single-Center Database of 324 Patients and 21 Tumor Entities. J Nucl Med. 2023;64;5:711-6. Doi: 10.2967/jnumed.122.264689.

3.Mori Y., Dendl K., Cardinale J., Kratochwil C., Giesel F.L., Haberkorn U. FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease. Radiology. 2023;306;2:e220749. Doi: 10.1148/radiol.220749.

4.Giammarile F., Knoll P., Paez D., Estrada Lobato E., Calapaquí Terán A.K., Delgado Bolton R.C. Fibroblast Activation Protein Inhibitor (FAPI) PET Imaging in Sarcomas: a New Frontier in Nuclear Medicine. Semin Nucl Med. 2024;54;3:340-4. Doi: 10.1053/j.semnuclmed.2024.01.001.

5.Delgado Bolton R.C., Calapaquí Terán A.K., Herrmann K., Fanti S., Giammarile F. Are we Approaching a Change in Paradigm in PET/CT Imaging of Solid Gastrointestinal (or Digestive) Tract Tumors with the Clinical Application of FAPI Imaging? Clin Nucl Med. 2023;48;4:318-9. Doi: 10.1097/RLU.0000000000004602.

6.Fouillet J., Torchio J., Rubira L., Fersing C. Unveiling the Tumor Microenvironment through Fibroblast Activation Protein Targeting in Diagnostic Nuclear Medicine: a Didactic Review on Biological Rationales and Key Imaging Agents. Biology (Basel). 2024;13;12:967. Doi: 10.3390/biology13120967.

7.Lee K.N., Jackson K.W., Christiansen V.J., Lee C.S., Chun J.G., McKee P.A. Antiplasmin-Cleaving Enzyme is a Soluble Form of Fibroblast Activation Protein. Blood. 2006;107;4:1397-404. Doi: 10.1182/blood-2005-08-3452.

8.Goldstein L.A., Ghersi G., Pineiro-Sanchez M.L., Salamone M., Yeh Y., Flessate D., et al. Molecular Cloning of Seprase: a Serine Integral Membrane Protease from Human Melanoma. Biochim Biophys Acta. 1997;1361;1:11-9. Doi: 10.1016/s0925-4439(97)00032-x.

9.Collins P.J., McMahon G., O’Brien P., O’Connor B. Purification, Identification and Characterisation of Seprase from Bovine Serum. Int J Biochem Cell Biol. 2004;36;12:2320-33. Doi: 10.1016/j.biocel.2004.05.006.

10.Keane F.M., Nadvi N.A., Yao T.W., Gorrell M.D. Neuropeptide Y. B-type Natriuretic Peptide, Substance P and Septide YY are Novel Substrates of Fibroblast Activation Protein-α. FEBS J. 2011;278;8:1316-32. Doi: 10.1111/j.1742-4658.2011.08051.x.

11.Christiansen V.J., Jackson K.W., Lee K.N., McKee P.A. Effect of Fibroblast Activation Protein and Alpha2-Antiplasmin Cleaving Enzyme on Collagen Types I, III, and IV. Arch Biochem Biophys. 2007;457;2:177-86. Doi: 10.1016/j.abb.2006.11.006.

12.Lee K.N., Jackson K.W., Christiansen V.J., Chung K.H., McKee P.A. A Novel Plasma Proteinase Potentiates Alpha2-Antiplasmin Inhibition of Fibrin Digestion. Blood. 2004;103;10:3783-8. Doi: 10.1182/blood-2003-12-4240.

13.Dunshee D.R., Bainbridge T.W., Kljavin N.M., Zavala-Solorio J., Schroeder A.C., Chan R., et al. Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21. J Biol Chem. 2016;291;11:5986-96. Doi: 10.1074/jbc.M115.710582.

14.Ramirez-Montagut T., Blachere N.E., Sviderskaya E.V., Bennett D.C., Rettig W.J., Garin-Chesa P., et al. FAPα, a Surface Peptidase Expressed during Wound Healing, is a Tumor Suppressor. Oncogene. 2004;23;32:5435-46. Doi: 10.1038/sj.onc.1207730.

 15.Huang Y., Simms A.E., Mazur A., Wang S., Leon N.R., Jones B., et al. Fibroblast Activation Protein-α Promotes Tumor Growth and Invasion of Breast Cancer Cells through Non-Enzymatic Functions. Clin Exp Metastasis. 2011;28;6:567-79. Doi: 10.1007/s10585-011-9392-x.

16.Lv B., Xie F., Zhao P., Ma X., Jiang W.G., Yu J., et al. Promotion of Cellular Growth and Motility is Independent of Enzymatic Activity of Fibroblast Activation Protein-α. Cancer Genomics Proteomics. 2016;13;3:201-8.

17.Sun S., Albright C.F., Fish B.H., George H.J., Selling B.H., Kingsley D., et al. Expression, Purification, and Kinetic Characterization of Full-Length Human Fibroblast Activation Protein. Protein Expr Purif. 2002;24;2:274-81. Doi: 10.1006/prep.2001.1572.

18.Ghersi G., Zhao Q., Salamone M., Yeh Y., Zucker S., Chen W.T. The Protease Complex Consisting of Dipeptidyl Peptidase IV and Seprase Plays a Role in the Migration and Invasion of Human Endothelial Cells in Collagenous Matrices. Cancer Res. 2006;66;9:4652-61. Doi: 10.1158/0008-5472.CAN-05-1245.

19.Mueller S.C., Ghersi G., Akiyama S.K., Cao X., Chen W.T. A Novel Protease-Docking Function of Integrin at Invadopodia. J Biol Chem. 1999;274;35:24947-52. Doi: 10.1074/jbc.274.35.24947.

20.Artym V.V., Kindzelskii A.L., Chen W.T., Petty H.R. Molecular Proximity of Seprase and the Urokinase-Type Plasminogen Activator Receptor on Malignant Melanoma Cell Membranes: Dependence on Beta1 Integrins and the Cytoskeleton. Carcinogenesis. 2002;23;10:1593-601. Doi: 10.1093/carcin/23.10.1593.

21.Kanamori A., Brown D.D. The Analysis of Complex Developmental Programmes: Amphibian Metamorphosis. Genes Cells. 1996;1;5:429-35. Doi: 10.1046/j.1365-2443.1996.d01-251.x.

22.Niedermeyer J., Garin-Chesa P., Kriz M., Hilberg F., Mueller M.M., Ahmad A., et al. Expression of the Fibroblast Activation Protein During Mouse Embryo Development. Int J Dev Biol. 2001;45;2:445-7. Doi: 10.1387/ijdb.11330865.

23.Roberts E.W., Deonarine A., Jones J.O., Denton A.E., Feig C., Lyons S.K., et al. Depletion of Stromal Cells Expressing Fibroblast Activation Protein-α From Skeletal Muscle and Bone Marrow Results in Cachexia and Anemia. J Exp Med. 2013;210;6:1137-51. Doi: 10.1084/jem.20122344.

24.Fitzgerald A.A., Weiner L.M. The Role of Fibroblast Activation Protein in Health and Malignancy. Cancer Metastasis Rev. 2020;39;3:783-803. Doi: 10.1007/s10555-020-09909-3.

25.Lo A., Li C.P., Buza E.L., Blomberg R., Govindaraju P., Avery D., et al. Fibroblast Activation Protein Augments Progression and Metastasis of Pancreatic Ductal Adenocarcinoma. JCI Insight. 2017;2;19:e92232. Doi: 10.1172/jci.insight.92232.

26.Ariga N., Sato E., Ohuchi N., Nagura H., Ohtani H. Stromal Expression of Fibroblast Activation Protein/Seprase, a Cell Membrane Serine Proteinase and Gelatinase, is Associated with Longer Survival in Patients with Invasive Ductal Carcinoma of Breast. Int J Cancer. 2001;95;1:67-72. Doi: 10.1002/1097-0215(20010120)95:1<67::aid-ijc1012>3.0.co;2-u.

27.Pedersen R.S., Thorlacius-Ussing J., Raimondo M.G., Langholm L.L., Schett G., Ramming A., et al. Fibroblast Activation Protein (FAP)-Mediated Cleavage of Type III Collagen Reveals Serum Biomarker Potential in Non-Small Cell Lung Cancer and Spondyloarthritis. Biomedicines. 2024;12;3:545. Doi: 10.3390/biomedicines12030545.

28.Деев С.М., Лебеденко Е.Н. Современные технологии создания неприродных антител для клинического применения // Acta Naturae. 2009. Т.1. №1. С. 32-50 [Deyev S.M., Lebedenko Ye.N. Modern Technologies for Creating Non-Natural Antibodies for Clinical Use. Acta Naturae. 2009;1;1:32-50 (In Russ.)]. Doi: 10.32607/20758251-2009-1-1-32-50.

29.Welt S., Divgi C.R., Scott A.M., Garin-Chesa P., Finn R.D., Graham M., et al. Antibody Targeting in Metastatic Colon Cancer: a Phase I Study of Monoclonal Antibody F19 against a Cell-Surface Protein of Reactive Tumor Stromal Fibroblasts. J Clin Oncol. 1994;12;6:1193-203. Doi: 10.1200/JCO.1994.12.6.1193.

30.Чернов В.И., Брагина О.Д., Синилкин И.Г., Медведева А.А., Зельчан Р.В. Радиоиммунотерапия: современное состояние проблемы // Вопросы онкологии. 2016. Т. 62. №1. С. 24–30 [Chernov V.I., Bragina O.D., Sinilkin I.G., Medvedeva A.A., Zel’chan R.V. Radioimmunotherapy: Current State of the Problem. Voprosy Onkologii = Problems in Oncology. 2016;62;1:24–30 (In Russ.)]. Doi: 10.37469/0507-3758-2016-62-1-24-30.

31.Nicholes N., Date A., Beaujean P., Hauk P., Kanwar M., Ostermeier M. Modular Protein Switches Derived from Antibody Mimetic Proteins. Protein Eng Des Sel. 2016;29;2:77-85. Doi: 10.1093/protein/gzv062.

32.Чернов В.И., Медведева А.А., Синилкин И.Г., Зельчан Р.В., Брагина О.Д. Разработка радиофармпрепаратов для радионуклидной диагностики в онкологии // Медицинская визуализация. 2016. №2. С. 63-66 [Chernov V.I., Medvedeva A.A., Sinilkin I.G., Zel’chan R.V., Bragina O.D. Development of Radiopharmaceuticals for Radionuclide Diagnostics in Oncology. Meditsinskaya Vizualizatsiya = Medical Visualization. 2016;2:63-66 (In Russ.)].

33.Chernov V., Rybina A., Zelchan R., Medvedeva A., Bragina O., Lushnikova N., et al. Phase I Trial of [99mTc]Tc-MASSS-PEG2-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors. Cancers. 2023;15;6:1631. doi: 10.3390/cancers

15061631.

34.Medvedeva A., Chernov V., Larkina M., Rybina A., Zelchan R., Bragina O., et al. Single-Photon Emission Computer Tomography Imaging of Prostate-Specific Membrane Antigen (PSMA) Expression in Prostate Cancer Patients Using a Novel Peptide-Based Probe [99mTc]Tc-BQ0413 with Picomolar Affinity to PSMA: a Phase I/II Clinical Study. ACS Pharmacol Transl Sci. 2025;8;3:736-47. Doi: 10.1021/acsptsci.4c00637.

35.Edosada C.Y., Quan C., Tran T., Pham V., Wiesmann C., Fairbrother W., Wolf B.B. Peptide Substrate Profiling Defines Fibroblast Activation Protein as an Endopeptidase of Strict Gly(2)-Pro(1)-Cleaving Specificity. FEBS Lett. 2006;580;6:1581-6. Doi: 10.1016/j.febslet.2006.01.087.

36.Jansen K., Heirbaut L., Verkerk R., Cheng J.D., Joossens J., Cos P., et al. Extended Structure-Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)Glycyl-2-Cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP). J Med Chem. 2014;57;7:3053-74. Doi: 10.1021/jm500031w.

37.De Decker A., Vliegen G., Van Rompaey D., Peeraer A., Bracke A., Verckist L., et al. Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP). ACS Med Chem Lett. 2019;10;8:1173-9. Doi: 10.1021/acsmedchemlett.9b00191.

38.Van Rymenant Y., Tanc M., Van Elzen R., Bracke A., De Wever O., Augustyns K., et al. In Vitro and In Situ Activity-Based Labeling of Fibroblast Activation Protein with UAMC1110-Derived Probes. Front Chem. 2021;9:640566. Doi: 10.3389/fchem.2021.640566.

39.Jansen K., Heirbaut L., Cheng J.D., Joossens J., Ryabtsova O., Cos P., et al. Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-Glycyl-2-Cyanopyrrolidine Scaffold. ACS Med Chem Lett. 2013;4;5:491-6. Doi: 10.1021/ml300410d.

40.Loktev A., Lindner T., Mier W., Debus J., Altmann A., Jäger D., et al. A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts. J Nucl Med. 2018;59;9:1423-9. Doi: 10.2967/jnumed.118.210435.

41.Millul J., Bassi G., Mock J., Elsayed A., Pellegrino C., Zana A., et al. An Ultra-High-Affinity Small Organic Ligand of Fibroblast Activation Protein for Tumor-Targeting Applications. Proc Natl Acad Sci U S A. 2021;118;16:e2101852118. Doi: 10.1073/pnas.2101852118.

42.Lindner T., Loktev A., Altmann A., Giesel F., Kratochwil C., Debus J., et al. Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein. J Nucl Med. 2018;59;9:1415-22. Doi: 10.2967/jnumed.118.210443.

43.Loktev A, Lindner T, Burger EM, Altmann A, Giesel F, Kratochwil C, et al. Development of Fibroblast Activation Protein–Targeted Radiotracers with Improved Tumor Retention. J Nucl Med. 2019;60(10):1421-9. doi: 10.2967/jnumed.118.224469.

44.Zhao L, Niu B, Fang J, Zhu Z, Chen H, Zhang J. Synthesis, Preclinical Evaluation, and a Pilot Clinical PET Imaging Study of 68Ga-Labeled FAPI Dimer. J Nucl Med. 2021;63(6):862-8. doi: 10.2967/jnumed.121.263016.

45.Chen X, Xia D, Zeng X, Li Z, Wang Y, Li Y, et al. Rational Design and Pharmacomodulation of 18F-Labeled Biotin/FAPI-Conjugated Heterodimers. J Med Chem. 2024;67(10):8361-71. doi: 10.1021/acs.jmedchem.4c00544.

46.Backhaus P, Gierse F, Burg MC, Büther F, Asmus I, Dorten P, et al. Translational Imaging of the Fibroblast Activation Protein (FAP) Using the New Ligand [68Ga]Ga-OncoFAP-DOTAGA. Eur J Nucl Med Mol Imaging. 2022;49(6):1822-32. doi: 10.1007/s00259-021-05653-0.

47.Moses WW. Fundamental Limits of Spatial Resolution in PET. Nucl Instrum Methods Phys Res A. 2011;648(Suppl 1):S236-S240. doi: 10.1016/j.nima.2010.11.092.

48.Lindner T, Altmann A, Giesel F, Kratochwil C, Kleist C, Krämer S, et al. 18F-Labeled Tracers Targeting Fibroblast Activation Protein. EJNMMI Radiopharm Chem. 2021;6(1):26. doi: 10.1186/s41181-021-00144-x.

49.Huang R, Pu Y, Huang S, Yang C, Yang F, Pu Y, et al. FAPI-PET/CT in Cancer Imaging: A Potential Novel Molecule of the Century. Front Oncol. 2022;12:854658. doi: 10.3389/fonc.2022.854658.

50.Fersing C, Bouhlel A, Cantelli C, Garrigue P, Lisowski V, Guillet B. A Comprehensive Review of Non-Covalent Radiofluorination Approaches Using Aluminum [18F]Fluoride: Will [18F]AlF Replace 68Ga for Metal Chelate Labeling? Molecules. 2019;24(16):2866. doi: 10.3390/molecules24162866.

51.Dahl K, Jussing E, Bylund L, Moein MM, Samén E, Tran T. Fully Automated Production of the Fibroblast Activation Protein Radiotracer [18F]FAPI-74. J Labelled Comp Radiopharm. 2021;64(8):346-52. doi: 10.1002/jlcr.3926.

52.Naka S, Watabe T, Lindner T, Cardinale J, Kurimoto K, Moore M, et al. One-Pot and One-Step Automated Radio-Synthesis of [18F]AlF-FAPI-74 Using a Multi Purpose Synthesizer: A Proof-of-Concept Experiment. EJNMMI Radiopharm Chem. 2021;6(1):28. doi: 10.1186/s41181-021-00142-z.

53.Wang S, Zhou X, Xu X, Ding J, Liu S, Hou X, et al. Clinical Translational Evaluation of Al18F-NOTA-FAPI for Fibroblast Activation Protein-Targeted Tumour Imaging. Eur J Nucl Med Mol Imaging. 2021;48(13):4259-71. doi: 10.1007/s00259-021-05470-5.

54.Wei Y, Zheng J, Ma L, Liu X, Xu S, Wang S, et al. [18F]AlF-NOTA-FAPI-04: FAP-Targeting Specificity, Biodistribution, and PET/CT Imaging of Various Cancers. Eur J Nucl Med Mol Imaging. 2022;49(8):2761-73. doi: 10.1007/s00259-022-05758-0.

55.Hu K, Wang L, Wu H, Huang S, Tian Y, Wang Q, et al. [18F]FAPI-42 PET Imaging in Cancer Patients: Optimal Acquisition Time, Biodistribution, and Comparison with [68Ga]Ga-FAPI-04. Eur J Nucl Med Mol Imaging. 2022;49(8):2833-43. doi: 10.1007/s00259-021-05646-z.

56.Mu X, Mo B, Qin J, Li Z, Chong W, Zeng Y, et al. Comparative Analysis of Two Timepoints on [18F]FAPI-42 PET/CT in Various Cancers. Eur J Hybrid Imaging. 2023;7(1):27. doi: 10.1186/s41824-023-00186-1.

57.Yang L, Xu S, Cheng L, Gao C, Cao S, Chang Z, et al. [18F]AlF-NOTA-FAPI-04 PET/CT as a Promising Tool for Imaging Fibroblast Activation Protein in Gastrointestinal System Cancers: A Prospective Investigation of Comparative Analysis with 18F-FDG. Eur J Nucl Med Mol Imaging. 2023;50(13):4051-63. doi: 10.1007/s00259-023-06351-9.

58.Dong Y, Huang S, Wu H, Cao M, Huang Y, Tang G, et al. Superiority of 18F-FAPI-42 PET/CT in the Detection of Primary Tumor and Management of Appendiceal Neoplasm to 18F-FDG PET/CT and CE-CT. Cancer Imaging. 2024;24(1):58. doi: 10.1186/s40644-024-00706-7.

59.Giesel FL, Adeberg S, Syed M, Lindner T, Jiménez-Franco LD, Mavriopoulou E, et al. FAPI-74 PET/CT Using Either 18F-AlF or Cold-Kit 68Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients. J Nucl Med. 2021;62(2):201-7. doi: 10.2967/jnumed.120.245084.

60.Novruzov E, Giesel FL, Mori Y, Choyke PL, Dabir M, Mamlins E, et al. Head-to-Head Intra-Individual Comparison of Biodistribution and Tumor Uptake of [18F]FAPI-74 with [18F]FDG in Patients With PDAC: A Prospective Exploratory Study. Cancers. 2023;15(10):2798. doi: 10.3390/cancers15102798.

61.Van den Hoven AF, Keijsers RGM, Lam MGEH, Ververs TFT, De Geus-Oei LF. Current Research Topics in FAPI Theranostics: A Bibliometric Analysis. Eur J Nucl Med Mol Imaging. 2023;50(4):1014-27. doi: 10.1007/s00259-022-06052-9.

62.Van den Wyngaert T, Elvas F, De Schepper S, Kennedy JA, Israel O. SPECT/CT: Standing on the Shoulders of Giants, it is Time to Reach for the Sky. J Nucl Med. 2020;61(9):1284-91. doi: 10.2967/jnumed.119.236943.

63.Boschi A, Urso L, Uccelli L, Martini P, Filippi L. 99mTc-Labeled FAPI Compounds for Cancer and Inflammation: from Radiochemistry to the First Clinical Applications. EJNMMI Radiopharm Chem. 2024;9(1):36. doi: 10.1186/s41181-024-00264-0.

64.Roy J, Hettiarachchi SU, Kaake M, Mukkamala R, Low PS. Design and Validation of Fibroblast Activation Protein Alpha Targeted Imaging and Therapeutic Agents. Theranostics. 2020;10(13):5778-89. doi: 10.7150/thno.41409.

65.Lindner T, Altmann A, Krämer S, Kleist C, Loktev A, Kratochwil C, et al. Design and Development of 99mTc-Labeled FAPI Tracers for SPECT Imaging and 188Re Therapy. J Nucl Med. 2020;61(10):1507-13. doi: 10.2967/jnumed.119.239731.

66.Yang X, Li G, Ruan C, Hu K, Tang G. Formulation and Preclinical Testing of 99m Tc-Labeled HYNIC-Glc-FAPT as a FAP-Targeting Tumor Radiotracer. Bioconjug Chem. 2023;34(11):2133-43. doi: 10.1021/acs.bioconjchem.3c00442.

67.Ruan Q, Wang Q, Jiang Y, Feng J, Yin G, Zhang J. Synthesis and Evaluation of 99mTc-Labeled FAP Inhibitors with Different Linkers for Imaging of Fibroblast Activation Proteins in Tumors. J Med Chem. 2023;66(7):4952-60. doi: 10.1021/acs.jmedchem.2c02062.

68.Luo X, Zhang Z, Cheng C, Wang T, Fang D, Zuo C, et al. SPECT Imaging with 99mTc-Labeled HYNIC-FAPI-04 to Extend the Differential Time Window in Evaluating Tumor Fibrosis. Pharmaceuticals. 2023;16(3):423. doi: 10.3390/ph16030423.

69.Jia X, Li X, Jia B, Yang Y, Wang Y, Liu Y, et al. The Role of [99mTc]Tc-HFAPi SPECT/CT in Patients with Malignancies of Digestive System: First Clinical Experience. Eur J Nucl Med Mol Imaging. 2023;50(4):1228-39. doi: 10.1007/s00259-022-06068-1.

70.Pang Y, Zhao L, Luo Z, Hao B, Wu H, Lin Q, et al. Comparison of 68Ga-FAPI and 18F-FDG Uptake in Gastric, Duodenal, and Colorectal Cancers. Radiology. 2021;298(2):393-402. doi: 10.1148/radiol.2020203275.

71.Ma M, Yang G, Zhao M, Liu Y, Ge X, Jia B, et al. Synthesis and Preliminary Study of 99mTc-Labeled HYNIC-FAPi for Imaging of Fibroblast Activation Proteins in Tumors. Mol Pharm. 2024;21(2):735-44. doi: 10.1021/acs.molpharmaceut.3c00886.

72.Ruan Q, Feng J, Jiang Y, Zhang X, Duan X, Wang Q, et al. Preparation and Bioevaluation of 99mTc-Labeled FAP Inhibitors as Tumor Radiotracers to Target the Fibroblast Activation Protein. Mol Pharm. 2022;19(1):160-71. doi: 10.1021/acs.molpharmaceut.1c00712.

73.Ruan Q, Ding D, Diao L, Jiang Y, Feng J, Yin G, et al. Synthesis and Preclinical Evaluation of Novel 99mTc-Labeled FAPI-46 Derivatives with Significant Tumor Uptake and Improved Tumor-to-Nontarget Ratios. J Med Chem. 2024;67(4):3190-202. doi: 10.1021/acs.jmedchem.4c00031.

74.Ruan Q, Zhou C, Wang Q, Jiang Y, Feng J, Yin G, et al. A Simple Kit Formulation for Preparation and Exploratory Human Studies of a Novel 99mTc-Labeled Fibroblast Activation Protein Inhibitor Tracer for Imaging of the Fibroblast Activation Protein in Cancers. Mol Pharm. 2023;20(6):2942-50. doi: 10.1021/acs.molpharmaceut.2c01094.

75.Trujillo-Benítez D, Luna-Gutiérrez M, Ferro-Flores G, Ocampo-García B, Santos-Cuevas C, Bravo-Villegas G, et al. Design, Synthesis and Preclinical Assessment of 99mTc-iFAP for In Vivo Fibroblast Activation Protein (FAP) Imaging. Molecules. 2022;27(1):264. doi: 10.3390/molecules27010264.

76.Vallejo-Armenta P, Ferro-Flores G, Santos-Cuevas C, García-Pérez FO, Casanova-Triviño P, Sandoval-Bonilla B, et al. [99mTc]Tc-iFAP/SPECT Tumor Stroma Imaging: Acquisition and Analysis of Clinical Images in Six Different Cancer Entities. Pharmaceuticals. 2022;15(6):729. doi: 10.3390/ph15060729.

77.Coria-Domínguez L, Vallejo-Armenta P, Luna-Gutiérrez M, Ocampo-García B, Gibbens-Bandala B, García-Pérez F, et al. [99mTc]Tc-iFAP Radioligand for SPECT/CT Imaging of the Tumor Microenvironment: Kinetics, Radiation Dosimetry, and Imaging in Patients. Pharmaceuticals. 2022;15(5):590. doi: 10.3390/ph15050590.

78.Meng L, Fang J, Zhang J, Zhu Z, Chen H, Zhao L. Rational Design and Comparison of Novel 99mTc-Labeled FAPI Dimers for Visualization of Multiple Tumor Types. J Med Chem. 2024;67(10):8460-72. doi: 10.1021/acs.jmedchem.4c00772.

79.Bartoli F, Elsinga P, Nazario LR, Zana A, Galbiati A, Millul J, et al. Automated Radiosynthesis, Preliminary in Vitro/in Vivo Characterization of OncoFAP-Based Radiopharmaceuticals for Cancer Imaging and Therapy. Pharmaceuticals. 2022;15(8):958. doi: 10.3390/ph15080958.

80.Bodei L, Kavan P, Liberman M, Taunk N, Metser U, Juneau D, et al. FRONTIER: FAPi Radioligand Open-Label, Phase 1 Study to Evaluate Safety, Tolerability and Dosimetry of [Lu-177]-PNT6555 – a Dose Escalation Study for Treatment of Patients with Select Solid Tumors. J Clin Oncol. 2023;41(16_suppl):TPS3161. doi: 10.1200/JCO.2023.41.16_suppl.TPS3161.

81.ClinicalTrials.gov. FAPi Radioligand Open-Label, Phase 1 Study to Evaluate Safety, Tolerability and Dosimetry of [Lu-177]-PNT6555 – a Dose Escalation Study for Treatment of Patients with Select Solid Tumors (FRONTIER). NCT05432193. https://clinicaltrials.gov/study/NCT05432193. Published 2024. Accessed July 16, 2024.

82.Zorzi A, Deyle K, Heinis C. Cyclic Peptide Therapeutics: Past, Present and Future. Curr Opin Chem Biol. 2017;38:24-9. doi: 10.1016/j.cbpa.2017.02.006.

83.Namjoshi S, Benson HAE. Cyclic Peptides as Potential Therapeutic Agents for Skin Disorders. Biopolymers. 2010;94(5):673-80. doi: 10.1002/bip.21476.

84.Zboralski D, Hoehne A, Bredenbeck A, Schumann A, Nguyen M, Schneider E, et al. Preclinical Evaluation of FAP-2286 for Fibroblast Activation Protein Targeted Radionuclide Imaging and Therapy. Eur J Nucl Med Mol Imaging. 2022;49(11):3651-67. doi: 10.1007/s00259-022-05842-5.

85.Pang Y, Zhao L, Meng T, Xu W, Lin Q, Wu H, et al. PET Imaging of Fibroblast Activation Protein in Various Types of Cancer Using 68Ga-FAP-2286: Comparison With 18F-FDG and 68Ga-FAPI-46 in a Single-Center, Prospective Study. J Nucl Med. 2023;64(3):386-94. doi: 10.2967/jnumed.122.264544.

86.Kline B, Yadav S, Seo Y, Ippisch RC, Castillo J, Aggarwal RR, et al. 68Ga-FAP-2286 PET of Solid Tumors: Biodistribution, Dosimetry, and Comparison with 18F-FDG. J Nucl Med. 2024;65(6):938-43. doi: 10.2967/jnumed.123.267281.

87.Liu L, Zhong J, Zhang Z, Ye X, Wang X, Liu S, et al. Preclinical Study and First-in-Human Imaging of [18F]FAP-2286, and Comparison with 2-[18F]FDG PET/CT in Various Cancer Patients. Eur J Nucl Med Mol Imaging. 2024;51(7):2012-22. doi: 10.1007/s00259-024-06626-9.

88.Baum RP, Schuchardt C, Singh A, Chantadisai M, Robiller FC, Zhang J, et al. Feasibility, Biodistribution, and Preliminary Dosimetry in Peptide-Targeted Radionuclide Therapy of Diverse Adenocarcinomas Using 177Lu-FAP-2286: First-in-Humans Results. J Nucl Med. 2022;63(3):415-23. doi: 10.2967/jnumed.120.259192.

89.ClinicalTrials.gov. A Study of 177Lu-FAP-2286 in Advanced Solid Tumors (LuMIERE). NCT04939610. https://clinicaltrials.gov/study/NCT04939610. Published 2024. Accessed July 17, 2024.

90.Greifenstein L, Gunkel A, Hoehne A, Osterkamp F, Smerling C, Landvogt C, et al. 3BP-3940, a Highly Potent FAP-Targeting Peptide for Theranostics – Production, Validation and First in Human Experience with Ga-68 and Lu-177. IScience. 2023;26(12):108541. doi: 10.1016/j.isci.2023.108541.

91.Baum RP, Greifenstein L, Kramer C, Klega A, Landvogt C, Mueller C, et al. Peptide Targeted Radiotherapy Using Cancer-Associated Fibroblasts as Target in Solid Tumors: First Clinical Experience with the 177Lu-, 225Ac- and 90Y-Labeled Peptide 3BP-3940 (Single Isotope and TANDEM) Targeting the Fibroblast Activating Protein. J Nucl Med. 2022;63(suppl 2):2269.

92.Baum RP, Jakobsson V, Eismant A, Kramer C, Greifenstein L, Mishra A, et al. FAP-Targeted Radiopeptide Therapy Using 177Lu-, 225Ac- and 90Y-Labeled 3BP-3940 in Diverse Advanced Solid Tumors: First-in-Humans Results [abstract P1612]. J Nucl Med. 2023;64(suppl 1):P1612.

93.Luo Y, Xu Y, Li W, Hua Y, Shen Q, Wang J, et al. Rational Design and Preliminary Evaluation of a Radiopharmaceutical Targeting Fibroblast Activation Proteins [68Ga]Ga/[177Lu]Lu-FAPI-JNU for Tumor Imaging and Therapy. J Med Chem. 2025;68(12):12745-55. doi: 10.1021/acs.jmedchem.5c00637.

94.Xu M, Song H, Cai J, Chen J, Wang C, Wang R, et al. Design, Structure Optimization, and Preclinical Evaluation of 188Re-Labeled FAPI for Targeted Radionuclide Therapy. J Med Chem. 2025;68(12):12940-9. doi: 10.1021/acs.jmedchem.5c00837.

95.García Megías I, Almeida LS, Calapaquí Terán AK, Pabst KM, Herrmann K, Giammarile F, et al. FAPI Radiopharmaceuticals in Nuclear Oncology and Theranostics of Solid Tumours: are we Nearer to Surrounding the Hallmarks of Cancer? Ann Nucl Med. 2025;39(5):407-23. doi: 10.1007/s12149-025-02022-x.

 

 

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Conflict of interest. The authors declare no conflict of interest.

Financing. The study had no sponsorship.

Contribution. The article was prepared by one author.

Article received: 20.02.2026. Accepted for publication: 25.03.2026.