Tailoring Fibroblast-Activation Protein Targeting for Theranostics: A Comparative Preclinical Evaluation of the Ga- and Lu-Labeled Monomeric and Dimeric Fibroblast-Activation Protein Inhibitors DOTA.SA.FAPi and DOTAGA.(SA.FAPi).

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), 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 [Ga]Ga-DOTA.SA.FAPi and [Ga]Ga-DOTAGA.(SA.FAPi). [Lu]Lu-DOTA.SA.FAPi and [Lu]Lu-DOTAGA.(SA.FAPi), were evaluated in PC3 xenografts. Biodistribution studies of [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 [Lu]Lu-DOTAGA.(SA.FAPi) was retained longer in CAFs. [Ga]Ga-DOTAGA.(SA.FAPi) and [Lu]Lu-DOTAGA.(SA.FAPi) displayed elevated lipophilicity and affinity for human serum proteins compared to [Ga]Ga-DOTA.SA.FAPi and [Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [Ga]Ga-DOTAGA.(SA.FAPi) within 3 h compared to [Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [Ga]Ga-DOTAGA.(SA.FAPi) versus [Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [Lu]Lu-DOTAGA.(SA.FAPi) maintained a significant tumor uptake even after 96 h p.i. compared to [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.