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Updated: Jan 6, 2026
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Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
Pioneering QSAR Modeling Study of FAP-Targeting Radiopharmaceuticals Used in Oncology
Dorrin Fatehi1, Zahra Hajimahdi1, Mona Mosayebnia1
1Department of Pharmaceutical Chemistry and Radiopharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Abstract:
Fibroblast Activation Protein (FAP) is highly expressed in the tumor microenvironment, promoting cancer growth and spread. FAP inhibitors (FAPIs) labeled with radionuclides are increasingly used for cancer diagnosis and therapy. The present study aims to explore how structural features relate to the inhibitory action of radiopharmaceuticals, representing a novel approach in the field of radiopharmacy. The 2D-QSAR using multiple linear regression analysis via the stepwise variable selection method showed promising results for both internal and external predictive ability of the model (R2 train = 0.877, Q2 LOO = 0.830, pred_R2 = 0.740). This analysis based on the genetic algorithm was also robust (R2 train = 0.846, Q2 LOO = 0.768, pred_R2 = 0.608). A 3D-QSAR model using partial least squares analysis showed better parametric results for CoMFA descriptors (R2 = 0.988, Q2 LOO = 0.518 and pred_R2 = 0.642) than the CoMSIA model as well. Our findings revealed that the steric, hydrophobic, and hydrogen-bonding properties notably impact the pIC50 values of FAPI radiopharmaceuticals. Based on virtual screening on the FDA-approved drugs, 23 potential inhibitors of the FAP enzyme were identified. To the best of our knowledge, this is the first QSAR study on radiopharmaceuticals with FAP inhibitory action, the results of which can be helpful in designing more potent ones.
Insights
This study explores structural features of Fibroblast Activation Protein inhibitors (FAPIs) for improved radiopharmaceuticals. Findings guide the design of more effective FAP-targeted cancer diagnostics and therapeutics.
Area of Science:
- Medicinal Chemistry
- Radiopharmacy
- Computational Chemistry
Background:
- Fibroblast Activation Protein (FAP) is a key target in the tumor microenvironment, driving cancer progression.
- Radiolabeled FAP inhibitors (FAPIs) are emerging as crucial tools for cancer diagnosis and therapy.
- Understanding structure-activity relationships is vital for developing potent FAPIs.
Purpose of the Study:
- To investigate the relationship between structural characteristics and inhibitory activity of FAPI radiopharmaceuticals.
- To develop predictive quantitative structure-activity relationship (QSAR) models for FAPI design.
- To identify potential FAPI candidates through virtual screening.
Main Methods:
- Employed 2D-QSAR (Multiple Linear Regression, Genetic Algorithm) and 3D-QSAR (Partial Least Squares, CoMFA, CoMSIA) analyses.
- Evaluated model performance using internal (Q2 LOO) and external (pred_R2) validation metrics.
- Conducted virtual screening of FDA-approved drugs against the FAP enzyme.
Main Results:
- Developed robust 2D-QSAR models with high predictive accuracy (e.g., R2 train=0.877, Q2 LOO=0.830).
- Achieved excellent parametric results with a 3D-QSAR CoMFA model (R2=0.988, pred_R2=0.642).
- Identified steric, hydrophobic, and hydrogen-bonding properties as critical for FAPI potency.
- Discovered 23 potential FAP inhibitors from FDA-approved drug screening.
Conclusions:
- This pioneering QSAR study provides valuable insights into FAPI radiopharmaceutical design.
- The identified structure-activity relationships and potential inhibitors can accelerate the development of novel FAP-targeted agents.
- Findings offer a foundation for designing more potent and effective radiopharmaceuticals for cancer management.
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