Preliminary study of FAP-targeted radiopharmaceuticals based on covalent targeting strategy and pharmacokinetic characteristics

In tumor imaging and therapy, fibroblast activation protein (FAP)-targeted radiotracers remains a research hotspot. The recently reported [68Ga]Ga/[177Lu]Lu-DOTA-mFS-FAPI-04 has been demonstrated to address limitations in conventional FAP-targeted agents, such as low tumor uptake, short retention time, and suboptimal therapeutic efficacy. However, [68Ga]Ga-DOTA-mFS-FAPI-04 positron emission tomography (PET) clinical imaging revealed high uptake in salivary glands, thyroid, and pancreas, necessitating further structural optimization. To address this limitation, we developed two novel radiopharmaceuticals. [68Ga]Ga-DOTA-mFS-FAP-2286 and [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 demonstrated favorable targeting specificity and diagnostic efficacy. [68Ga]Ga-DOTA-mFS-FAP-2286 exhibited dual excretion pathways (hepatobiliary and urinary systems), whereas [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 showed exclusive urinary excretion, demonstrating superior pharmacokinetic properties. [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 exhibited significantly enhanced tracer uptake compared to [68Ga]Ga-DOTA-FAP-2286 in primary tumors (SUVmax: 11.03 ± 1.45 vs. 5.47 ± 1.66), lymph node metastases (SUVmax: 12.13 ± 2.22 vs. 5.70 ± 1.08), and distant metastases (SUVmax: 12.03 ± 6.56 vs. 6.83 ± 0.36) (all p < 0.05). Both [68Ga]Ga-DOTA-mFS-FAP-2286 and [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 effectively overcame the drawback of high uptake in salivary glands, thyroid, and pancreas observed with [68Ga]Ga-DOTA-mFS-FAPI-04. [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 demonstrated superior pharmacokinetic characteristics with urinary excretion and showed the potential for superior diagnostic efficacy compared with [68Ga]Ga-DOTA-FAP-2286.