Related Experiment Video
Updated: Oct 7, 2025
![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
Fibroblast Activation Protein (FAP) targeting homodimeric FAP inhibitor radiotheranostics: a step to improve tumor
Euy Sung Moon1, Sanjana Ballal2, Madhav Prasad Yadav2
1Department of Chemistry-TRIGA Site, Johannes Gutenberg University Mainz 55128 Mainz, Germany.
Abstract:
Several radiopharmaceuticals targeting fibroblast activation protein (FAP) based on the highly potent FAP inhibitor UAMC1110 are currently under investigation. Pre-clinical as well as clinical research exhibited the potential of these imaging agents. However, the monomeric small molecules seemed to have a short retention time in the tumor in combination with fast renal clearance. Therefore, our strategy was to develop homodimeric systems having two FAP inhibitors to improve residence time and tumor accumulation. The homodimers with two squaramide coupled FAP inhibitor conjugates DOTA.(SA.FAPi)2 and DOTAGA.(SA.FAPi)2 were synthesized and radiochemically evaluated with gallium-68. [68Ga]Ga-DOTAGA.(SA.FAPi)2 was tested for its in vitro stability, lipophilicity and affinity properties. In addition, human PET/CT scans were performed for [68Ga]Ga-DOTAGA.(SA.FAPi)2 with a head-to-head comparison with [68Ga]Ga-DOTA.SA.FAPi and [18F]FDG. Labeling with gallium-68 demonstrated high radiochemical yields. Inhibition measurements revealed excellent affinity and selectivity with low nanomolar IC50 values for FAP. In PET/CT human studies, significantly higher tumor uptake as well as longer tumor retention could be observed for [68Ga]Ga-DOTAGA.(SA.FAPi)2 compared to [68Ga]Ga-DOTA.SA.FAPi. Therefore, the introduction of the dimer led to an advance in human PET imaging indicated by increased tumor accumulation and prolonged retention times in vivo and thus, the use of dimeric structures could be the next step towards prolonged uptake of FAP inhibitors resulting in radiotherapeutic analogs of FAP inhibitors.
Insights
Developing dimeric fibroblast activation protein (FAP) inhibitors improved tumor targeting in PET imaging. These new FAP inhibitors show enhanced retention and accumulation in tumors compared to earlier versions.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Oncology Imaging
Background:
- Fibroblast activation protein (FAP) is a target for cancer imaging and therapy.
- Current FAP-targeting radiopharmaceuticals have limitations, including short tumor retention and rapid renal clearance.
- Monomeric FAP inhibitors based on UAMC1110 show potential but require optimization for improved in vivo performance.
Purpose of the Study:
- To develop novel dimeric FAP inhibitors to enhance tumor residence time and accumulation.
- To evaluate the radiochemical properties and in vitro characteristics of dimeric FAP inhibitors.
- To compare the in vivo performance of dimeric FAP inhibitors against monomeric counterparts and a standard PET tracer in human subjects.
Main Methods:
- Synthesis of homodimeric FAP inhibitor conjugates: DOTA.(SA.FAPi)2 and DOTAGA.(SA.FAPi)2.
- Radiochemical evaluation using Gallium-68 (Ga-68) labeling, assessing radiochemical yields.
- In vitro characterization of [68Ga]Ga-DOTAGA.(SA.FAPi)2, including stability, lipophilicity, and FAP binding affinity (IC50).
- Human PET/CT scans comparing [68Ga]Ga-DOTAGA.(SA.FAPi)2 with [68Ga]Ga-DOTA.SA.FAPi and [18F]FDG.
Main Results:
- Successful radiolabeling of dimeric conjugates with Ga-68 achieved high radiochemical yields.
- In vitro studies demonstrated excellent affinity and selectivity of [68Ga]Ga-DOTAGA.(SA.FAPi)2 for FAP, with low nanomolar IC50 values.
- Human PET/CT imaging revealed significantly higher tumor uptake and prolonged tumor retention for [68Ga]Ga-DOTAGA.(SA.FAPi)2 compared to the monomeric [68Ga]Ga-DOTA.SA.FAPi.
Conclusions:
- Dimeric FAP inhibitors demonstrate improved in vivo performance in human PET imaging.
- The enhanced tumor accumulation and retention of dimeric FAP inhibitors represent an advancement over monomeric agents.
- Dimeric structures hold promise for developing next-generation FAP inhibitors with prolonged uptake for potential radiotherapeutic applications.
![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)
