Lappchen_2024_Molecules_29_

BACKGROUND: FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi)(2), labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs. METHODS: The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [(68)Ga]Ga-DOTA.SA.FAPi and [(68)Ga]Ga-DOTAGA.(SA.FAPi)(2). [(177)Lu]Lu-DOTA.SA.FAPi and [(177)Lu]Lu-DOTAGA.(SA.FAPi)(2), were evaluated in PC3 xenografts. Biodistribution studies of [(68)Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice. RESULTS: All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [(177)Lu]Lu-DOTAGA.(SA.FAPi)(2) was retained longer in CAFs. [(68)Ga]Ga-DOTAGA.(SA.FAPi)(2) and [(177)Lu]Lu-DOTAGA.(SA.FAPi)(2) displayed elevated lipophilicity and affinity for human serum proteins compared to [(68)Ga]Ga-DOTA.SA.FAPi and [(177)Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [(68)Ga]Ga-DOTAGA.(SA.FAPi)(2) within 3 h compared to [(68)Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [(68)Ga]Ga-DOTAGA.(SA.FAPi)(2) versus [(68)Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [(177)Lu]Lu-DOTAGA.(SA.FAPi)(2) maintained a significant tumor uptake even after 96 h p.i. compared to [(177)Lu]Lu-DOTA.SA.FAPi. CONCLUSIONS: Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.