Monovalent and Divalent Designs of Copper Radiotheranostics Targeting Fibroblast Activation Protein in Cancer

Area of Science:

• Nuclear medicine
• Radiopharmaceutical chemistry
• Oncology

Background:

• Fibroblast activation protein (FAP) is a target for cancer theranostics due to its presence in the tumor microenvironment.
• Existing FAP-targeted agents suffer from poor tumor retention and rapid clearance, limiting therapeutic efficacy.
• Copper radionuclides (64Cu and 67Cu) offer an ideal theranostic pair for developing advanced radiopharmaceuticals.

Purpose of the Study:

• To design, synthesize, and evaluate monovalent and divalent FAP-targeted theranostic conjugates.
• To compare the efficacy of monovalent versus divalent conjugates for FAP-targeting.
• To assess the potential of a bifunctional chelator scaffold (BFS) for developing improved radiotheranostic agents.

Main Methods:

• Synthesis and characterization of monovalent and divalent conjugates using a bifunctional chelator scaffold (BFS) based on CB-TE2A.
• Radiolabeling of conjugates with Copper-64 (64Cu) for in vitro and in vivo studies.
• In vitro cell assays for stability and FAP-mediated binding/internalization.
• In vivo positron emission tomography (PET) imaging in mouse models.

Main Results:

• Both 64Cu-labeled conjugates exhibited high in vitro stability and specific binding to FAP-expressing cells.
• The divalent conjugate demonstrated significantly higher FAP-specific tumor uptake compared to the monovalent version.
• PET imaging confirmed enhanced tumor targeting and retention with the divalent construct.

Conclusions:

• The BFS-based multivalent approach effectively enhances FAP-targeted radiopharmaceutical tumor uptake.
• Divalent FAP-targeted conjugates show superior performance over monovalent counterparts.
• This strategy offers a promising platform for developing advanced radiotheranostic agents for cancer diagnosis and therapy.