Comparative Study of Dimeric Fibroblast Activation Protein-Targeting Radioligands Labeled with Fluorine-18,...

Area of Science:

• Nuclear Medicine
• Radiochemistry
• Oncology

Background:

• Fibroblast activation protein inhibitors (FAPIs) are crucial for cancer diagnosis and therapy.
• Current radiolabeled FAPIs, like those with gallium-68 and lutetium-177, face limitations such as short tumor retention times, hindering therapeutic efficacy.

Purpose of the Study:

• To synthesize and evaluate novel dimeric FAPIs labeled with fluorine-18, copper-64, and gallium-68.
• To enhance tumor retention and therapeutic potential of FAP-targeting radioligands.

Main Methods:

• Three dimeric FAPIs ([18F]1, [64Cu]2, [68Ga]3) were synthesized using NOTA-E-(FAPI)2 and DOTA-E-(FAPI)2 chelators.
• Radioligands were characterized for binding affinity, stability, and in vitro/in vivo performance using cell-based assays and PET imaging in tumor-bearing mice.

Main Results:

• Dimeric FAPIs showed higher binding affinity for FAP than monomeric FAPI-04.
• All radioligands were synthesized with high radiochemical yields and demonstrated stability.
• [68Ga]3 exhibited FAP-specific cellular uptake, favorable pharmacokinetics, and superior tumor retention compared to monomeric [68Ga]Ga-FAPI-04.
• PET imaging confirmed high tumor uptake and significant blocking effect with FAPI-04 preadministration.

Conclusions:

• Novel dimeric FAPIs, particularly [68Ga]3, offer improved tumor targeting and retention for FAP-expressing cancers.
• These dimeric FAPIs show significant potential as theranostic agents for enhanced cancer management.