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.