Fibroblast activation
protein (FAP) is among the most popular targets in nuclear medicine imaging and
cancer theranostics. Several small-molecule moieties (FAPI-04, FAPI-46, etc.) are used for developing FAP-targeted
theranostic agents. Nonetheless, the circulation time of FAP inhibitors is relatively short, resulting in rapid clearance via kidneys, low
tumor uptake, and associated unsatisfactory treatment efficacy. To address the existing drawbacks, we engineered 3
peptides named FD1, FD2, and FD3 with different circulation times through solid-phase peptide synthesis. All the 3 reported
peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance. The diagnostic and therapeutic potential of the agents labeled with 68Ga and 177Lu was assessed in several
tumor models exhibiting different levels of FAP expression. While radiolabeled FD1 was rapidly excreted from kidneys, radiolabeled FD2/FD3 have significantly prolonged circulation, increased
tumor uptake, and decreased kidney accumulation. Our findings indicated that [68Ga]Ga-
DOTA-FD1 positron emission tomography (PET) effectively detected FAP dynamics, whereas [177Lu]Lu-
DOTA-FD2 and [177Lu]Lu-
DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing
tumor models, including
pancreatic cancer cell models characterized by abundant stroma. Moreover, a pilot translational investigation demonstrated that [68Ga]Ga-
DOTA-FD1 had the capability to identify both primary and metastatic
tumors with precision and distinction. In summary, we developed [68Ga]Ga-
DOTA-FD1 for same-day PET imaging of FAP dynamics and [177Lu]Lu-
DOTA-FD2 and [177Lu]Lu-
DOTA-FD3 for effective radioligand
therapy of FAP-overexpressing
tumors.