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, FSND, which is modified with three Asp-peptide adapters to enable both Ga ([Ga]Ga-FSND) and F ([F]AlF-FSND) PET imaging. Compared to [Ga]Ga-FAPI-04, [Ga]Ga-FAPI-42, and [F]AlF-FAPI-42, [F]AlF-FSND and [Ga]Ga-FSND 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 [F]AlF- and [Ga]Ga-FSND exhibited comparable uptake in the primary lesion, higher-contrast images, and higher uptake in some metastases like in bone and brain, to 2-[F] FDG PET/CT imaging. As a proof of concept, these results offer a significant enhancement to the diversity of the FAP-targeted tracer arsenal.