Related Experiment Video
Updated: Jan 15, 2026
![Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F68356.jpg&w=3840&q=50)
Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
Structure-Property Investigation of New "KetoFAPI" Inhibitors of Fibroblast Activation Protein (FAP): Discovery of
Pawel Brzeminski1, Emile Verhulst2, Adrian Fabisiak1
1Laboratory of Medicinal Chemistry, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Antwerp 2610, Belgium.
Abstract:
Fibroblast activation protein α (FAP) is a serine protease that has emerged as an attractive, pan-cancer radiotheranostic target. The development of effective FAP-targeting radiotheranostics critically relies on the identification of FAP inhibitors that achieve prolonged tumor retention, thereby maximizing therapeutic efficacy and ensuring sustained tumor irradiation, regardless of radionuclide half-life considerations. Here, we present the design, synthesis, and biological evaluation of potent and selective FAP inhibitors bearing an electrophilic α-ketoamide warhead (ketoFAPIs). Through structure-activity relationship studies, we identified highly potent compounds with selectivity over prolyl oligopeptidase (PREP) by up to 3 orders of magnitude. Moreover, this manuscript shows for the first time that ketoFAPIs can exhibit significantly longer target residence times than first-generation FAPIs comprising an electrophilic carbonitrile warhead, which in turn translates into extended tumor retention in a mouse cancer model. This work lays the groundwork for the use of ketoFAPIs as a versatile platform for the development of FAP-targeted radiopharmaceuticals.
Insights
New ketoFAPIs targeting fibroblast activation protein α (FAP) show prolonged tumor retention. These potent and selective FAP inhibitors offer a promising platform for developing advanced cancer radiotheranostics.
Area of Science:
- Oncology
- Radiochemistry
- Medicinal Chemistry
Background:
- Fibroblast activation protein α (FAP) is a key target for pan-cancer radiotheranostics.
- Effective FAP-targeting radiotheranostics require inhibitors with prolonged tumor retention for sustained irradiation.
Purpose of the Study:
- To design, synthesize, and evaluate novel FAP inhibitors with an α-ketoamide warhead (ketoFAPIs).
- To assess the potency, selectivity, and tumor retention capabilities of ketoFAPIs compared to existing FAP inhibitors.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted to optimize ketoFAPIs.
- In vitro assays were used to determine compound potency and selectivity against FAP and prolyl oligopeptidase (PREP).
- In vivo studies in a mouse cancer model evaluated tumor retention of ketoFAPIs.
Main Results:
- Highly potent and selective ketoFAPIs were identified, showing selectivity over PREP by up to 3 orders of magnitude.
- ketoFAPIs demonstrated significantly longer target residence times compared to first-generation FAPIs.
- Extended tumor retention was observed in vivo, correlating with improved target residence time.
Conclusions:
- ketoFAPIs represent a new class of potent and selective FAP inhibitors.
- The enhanced target residence time and tumor retention of ketoFAPIs make them a versatile platform for developing next-generation FAP-targeted radiopharmaceuticals.
![An Automated Radiosynthesis of [68Ga]Ga-FAPI-46 for Routine Clinical Use](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F66708.jpg&w=3840&q=50)
![PET/CT With [68Ga]-NOTA-FAP-2286 for Imaging of Tendon Injuries in Rat Achilles Tendon Injury Models](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F67717.jpg&w=3840&q=50)