Modification of Asp-Peptide Adapters: Giving the FAP-Targeted Radioligand a "Squirrel Tail"

Fibroblast activation protein (FAP) is a promising target for cancer theranostics, but most FAP-targeted radioprobes showed relatively insufficient tumor uptake and retention, which seriously hampered their further application. Inspired by the squirrel tail, this study developed a novel FAP-targeted molecule, FSND₃, which is modified with three Asp-peptide adapters to enable both ⁶⁸Ga ([⁶⁸Ga]Ga-FSND₃) and ¹⁸F ([¹⁸F]AlF-FSND₃) PET imaging. Compared to [⁶⁸Ga]Ga-FAPI-04, [⁶⁸Ga]Ga-FAPI-42, and [¹⁸F]AlF-FAPI-42, [¹⁸F]AlF-FSND₃ and [⁶⁸Ga]Ga-FSND₃ showed enhanced tumor uptake and prolonged residence in HT-1080-FAP and pancreatic tumor models, demonstrating the effectiveness of Asp-peptide adapters in pharmacomodulating FAP-targeted radioligands. The first-in-human pilot study revealed that [¹⁸F]AlF- and [⁶⁸Ga]Ga-FSND₃ exhibited comparable uptake in the primary lesion, higher-contrast images, and higher uptake in some metastases like in bone and brain, to 2-[¹⁸F] FDG PET/CT imaging. As a proof of concept, these results offer a significant enhancement to the diversity of the FAP-targeted tracer arsenal.