[⁶⁸Ga]Ga-PG2-2FAPI: A DPro-Gly-Modified Dimeric FAPI Probe with Enhanced Tumor Uptake and Retention

Area of Science:

• Biomedical Imaging
• Radiochemistry
• Molecular Imaging

Background:

• Fibroblast Activation Protein (FAP) is a key biomarker in tumor microenvironments.
• Developing targeted imaging agents for FAP is crucial for cancer diagnosis and therapy.

Purpose of the Study:

• To design and synthesize a novel FAP-targeting ligand, DOTA-PG2-2FAPI.
• To evaluate the binding affinity, stability, and in vitro/in vivo performance of the FAP-targeting probe.

Main Methods:

• Molecular docking was used to assess binding affinity.
• Synthesis and radiolabeling of DOTA-PG2-2FAPI with ⁶⁸Ga.
• In vitro cellular uptake studies in FAP-expressing cells.
• In vivo positron emission tomography (PET) imaging in tumor-bearing mice models.

Main Results:

• DOTA-PG2-2FAPI exhibited significantly higher binding affinity to FAP compared to monomeric FAPI-46 (IC₅₀ = 6.65 nM).
• The ⁶⁸Ga-labeled probe ([⁶⁸Ga]Ga-PG2-2FAPI) showed excellent radiochemical purity (>95%), stability, and hydrophilicity.
• High cellular uptake and tumor accumulation were observed in FAP-positive tumors, with rapid accumulation and sustained retention.
• Specific PET imaging was achieved across multiple tumor models, demonstrating broad-spectrum potential.

Conclusions:

• DOTA-PG2-2FAPI is a highly effective FAP-targeting agent with superior binding affinity.
• The ⁶⁸Ga-labeled probe is suitable for sensitive and specific tumor imaging.
• This FAP-targeting probe shows significant promise as a broad-spectrum diagnostic agent for clinical applications.