Design, Synthesis, Molecular Docking, and Preclinical Evaluation of a New Radiolabeled PEG3-Linked FAPI Derivative for Fibroblast Activation Protein Targeting
| Author | Mahshid Kiani | en |
| Author | Mehdi Akhlaghi | en |
| Author | Safura Jokar | en |
| Author | Omid Bavi | en |
| Author | Hooman Hafezi | en |
| Author | Khosrou Abdi | en |
| Author | Omid Sabzevari | en |
| Author | Saeed Balalaie | en |
| Author | Farhad Golmohammadi | en |
| Author | Zahra Ghiamaty | en |
| Author | Sara Roustaei | en |
| Author | Alireza Foroumadi | en |
| Author | Davood Beiki | en |
| Orcid | Saeed Balalaie [0000-0002-5764-0442] | en |
| Orcid | Davood Beiki [0000-0002-2862-0581] | en |
| Issued Date | 2026-12-31 | en |
| Abstract | Background: Fibroblast activation protein (FAP) is a promising molecular target for cancer theranostic applications. However, current fibroblast activation protein inhibitors (FAPIs) have limitations, including rapid clearance and limited tumor retention. Objectives: This study aimed to develop a novel PEG3-linked FAPI derivative, [68Ga]Ga-FAPI-MKG, with enhanced tumor accumulation and retention. FAPI-MKG was prepared by incorporating a PEG3 linker into the FAPI-04 structure to optimize its pharmacokinetic profile. Methods: The compound was synthesized via an 11-step route starting from quinine sulfate and radiolabeled with gallium-68. In vitro studies included determination of lipophilicity (Log P) and stability assays in saline and human serum albumin. Preclinical evaluation in BALB/c mice bearing CT-26 tumors included biodistribution, blocking studies, and PET/CT imaging. Molecular docking and molecular dynamics simulations were performed to provide mechanistic insights into binding interactions. Results: [68Ga]Ga-FAPI-MKG was successfully synthesized with high radiochemical purity (> 98%) and a molar activity of 414.79 mCi/μmol. It demonstrated moderate hydrophilicity (Log P = -3.26 ± 0.18) compared with the reference radiotracer, [68Ga]Ga-FAPI-46 (-3.58 ± 0.29), and high stability (RCP > 90% after 120 minutes). In vivo studies showed significantly higher tumor uptake (7.18 ± 0.56% ID/g at 60 minutes; 3.20 ± 0.11% ID/g at 120 minutes) and prolonged retention compared with the reference radiotracer, along with dual hepatobiliary and renal excretion pathways. Blocking studies confirmed FAP-specific uptake. Computational analyses indicated strong binding energy (-9.8 kcal/mol) and optimized electrostatic interactions with FAP. The strategic incorporation of a PEG3 linker into [68Ga]Ga-FAPI-MKG significantly improved tumor accumulation, extended tumor retention, and increased the tumor-to-background ratio. Conclusions: These findings suggest that [68Ga]Ga-FAPI-MKG may be a promising candidate for clinical translation for imaging and theranostics of FAP-expressing cancers. | en |
| DOI | https://doi.org/10.5812/ijpr-170734 | en |
| URI | https://brieflands.com/journals/ijpr/articles/170734 | en |
| Keyword | Cancer-associated Fibroblasts | en |
| Keyword | Gallium-68 | en |
| Keyword | Molecular Imaging | en |
| Keyword | Molecular Dynamics | en |
| Keyword | PET Imaging | en |
| Keyword | Radiolabeling | en |
| Publisher | Brieflands | en |
| Title | Design, Synthesis, Molecular Docking, and Preclinical Evaluation of a New Radiolabeled PEG3-Linked FAPI Derivative for Fibroblast Activation Protein Targeting | en |
| Type | Research Article | en |