Automated radiosynthesis of [64Cu]Cu-FAPI-2286 for FAP-targeted PET imaging.

BACKGROUND

Fibroblast Activation Protein (FAP) is a critical target for imaging cancer-associated fibroblasts and active hepatic stellate cells in liver fibrosis. While FAPI-2286 has been widely explored with 68Ga and 177Lu, the use of copper-64 offers unique advantages for theranostics due to its amenable half-life and chemical pairing with therapeutic copper-67. This study focuses on the automated radiosynthesis of [64Cu]Cu-FAPI-2286 in a green synthetic route, detailed physicochemical characterization, quality control analysis, and initial clinical evaluation of [64Cu]Cu-FAPI-2286 in liver fibrosis.

METHODS

The [64Cu]Cu-FAPI-2286 was synthesized via manual and automated modules using aqueous solution of [64Cu]CuCl2. The reaction conditions (solvent, temperature, time) were optimized. Physicochemical evaluation included lipophilicity (logD7.4) and stability challenges against EDTA, physiological media, and human serum. A pilot PET/CT scan was performed on a patient with HCV-related decompensated cirrhosis complicated by Grade III ascites to assess biodistribution and hepatic uptake.

RESULTS

Optimized automated synthesis in aqueous medium at 40 °C yielded [64Cu]Cu-FAPI-2286 with >95% radiochemical purity and an apparent molar activity (AMA) of 258 ± 5 MBq/μmol. The radiotracer demonstrated high hydrophilicity with a logD7.4 value of -2.38 ± 0.01. The complex exhibited excellent stability (>95%) in serum and saline over 24 h and showed strong resistance to transchelation against a 500-fold excess of EDTA. Clinically, the patient with liver fibrosis demonstrated intense, diffuse hepatic uptake with a SUVmax(lbm) of 17.54, significantly higher than background, confirming active fibrogenesis.

CONCLUSION

We successfully established a robust, green, automated synthesis route for [64Cu]Cu-FAPI-2286. The tracer's favorable hydrophilicity and stability make it a promising agent. The high uptake observed in the fibrotic liver highlights its potential as a non-invasive biomarker for staging liver fibrosis and for guiding future [67Cu]Cu-FAPI-2286 therapies.