Comparative study of 47Sc and 177Lu-labeled albumin binder-conjugated FAPI radiopharmaceuticals

Objective: Prolonging the systemic half-life of fibroblast-activation-protein inhibitors (FAPIs) through an albumin-binding module is an attractive strategy to amplify intratumoral dose delivery. We report a head-to-head comparison of the identical scaffold FAPI-X5 labeled with ⁶⁸Ga, ¹⁷⁷Lu and the emerging ⁴⁷Sc.

Methods: FAPI-X5 was designed by in-silico docking, synthesized, and radiolabeled with ⁶⁸Ga, ¹⁷⁷Lu or ⁴⁷Sc. Radiochemical purity, stability, lipophilicity, albumin binding, cellular uptake, biodistribution, micro-PET/SPECT imaging and single-dose radiotherapy (18.5-55.5 MBq) were evaluated in U87MG-FAP tumor-bearing mice.

Results: All conjugates showed >95% radiochemical purity and > 40% albumin binding. ⁶⁸Ga-FAPI-X5 achieved rapid tumor uptake (23.6%ID/g at 2 h) and a tumor-to-liver SUVmean ratio of 1.3, enabling high-contrast PET imaging. ¹⁷⁷Lu- and ⁴⁷Sc-FAPI-X5 exhibited prolonged tumor retention but prominent hepatic accumulation (34%ID/g for ⁴⁷Sc at 2 h), yielding tumor-to-liver SUVmean ≤0.28 and simplified hepatic absorbed doses >30 Gy. ⁴⁷Sc-FAPI-X5 additionally displayed elevated bone uptake (17%ID/g) and marrow doses 35-60% higher than the ¹⁷⁷Lu analogue. Therapy studies showed only cytostatic effects (T/C 36-43%) accompanied by dose-dependent hepatogastrointestinal toxicity.

Conclusion: While ⁶⁸Ga-FAPI-X5 is a promising PET tracer, the unfavorable tumor-to-liver and tumor-to-bone ratios of ⁴⁷Sc-FAPI-X5 preclude its clinical translation. Future ⁴⁷Sc-FAPI development must prioritize scandium-optimized chelators and nephrophilic scaffold redesign.

Albumin-binding module; Fibroblast activation protein (FAP); Lutetium-177((177)Lu); Scandium-47 ((47)Sc); Targeted radionuclide therapy.