Development of [Ga]Ga/[Lu]Lu-DOTA-NI-FAPI-04 Containing a Nitroimidazole Moiety as New FAPI Radiotracers with Improved Tumor Uptake and Retention.

Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs), represents a promising target for cancer diagnosis and therapy. Hypoxia is a common feature of solid tumors. A bivalent agent, DOTA-NI-FAPI-04 (), was developed by incorporating hypoxia-sensitive nitroimidazole (NI) into the FAP-targeting agent FAPI-04. Compound exhibited a strong FAP binding affinity with an IC of 7.44 nM. Radiolabeled [Ga]Ga- and [Lu]Lu- demonstrated enhanced cell uptake. positron emission tomography/computed tomography (PET/CT) imaging showed that [Ga]Ga- displayed significantly higher specific uptake and retention in U87MG tumor-bearing mice compared to [Ga]Ga-FAPI-04 (SUV: 7.87 vs 1.99% ID/mL at 120 min). Biodistribution studies confirmed superior tumor uptake of [Ga]Ga- (48.15 vs 5.72% ID/g at 120 min). Similarly, [Lu]Lu- exhibited higher tumor uptake than [Lu]Lu-FAPI-04 (50.75 vs 20.48% ID/g at 120 min). These preliminary results suggest that a nitroimidazole-containing bivalent-targeting agent, [Ga]Ga/[Lu]Lu-, is a promising candidate for tumor theranostics.