Exploring Covalent C-¹⁸F Bonding Strategies in the Design of FAP-Targeted Radiotracers

Area of Science:

• Radiochemistry
• Molecular Imaging
• Oncology

Background:

• Fibroblast activation protein inhibitors (FAPIs) are crucial for tumor diagnosis and therapy.
• Current [18F]AlF coordination chemistry for FAPIs faces challenges with stability and applicability.
• Developing novel radiotracers with enhanced properties is essential for advanced cancer imaging.

Purpose of the Study:

• To design and synthesize novel fluorinated FAPIs with stable C-18F covalent bonds.
• To evaluate the fibroblast activation protein (FAP) binding affinities and in vivo performance of these new compounds.
• To establish C-18F bond formation as a viable alternative to [18F]AlF labeling for positron emission tomography (PET) tracers.

Main Methods:

• Design and synthesis of nine novel fluorinated FAPIs based on the UAMC-1110 pharmacophore.
• Radiolabeling of compounds using stable C-18F covalent bond formation.
• Assessment of FAP binding affinities (Ki values).
• In vivo evaluation of the lead candidate ([18F]54) using PET imaging in preclinical models.

Main Results:

• All synthesized compounds demonstrated high affinity for FAP (Ki = 0.092-1.22 nM).
• [18F]54, prepared via copper-catalyzed click chemistry, exhibited excellent in vivo characteristics.
• High tumor-to-muscle ratio (TMR = 11 ± 3.1) was achieved for [18F]54 at 60 minutes postinjection.
• [18F]54 showed sustained tumor retention, with only a 19% decrease in signal from 30 to 120 minutes postinjection.

Conclusions:

• The novel C-18F labeled FAPIs, particularly [18F]54, are promising for FAP-targeted tumor imaging.
• C-18F covalent bond formation offers a robust and effective alternative to [18F]AlF labeling methods.
• [18F]54 represents a next-generation PET tracer candidate for FAP-positive tumor detection and management.