Objective <p>Fibroblast activation protein (FAP) is a promising biomarker for the development of tumor-targeting agents. To date, various FAP-targeting radioligands have been developed. In particular, [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-FAPI-46 are recognized as prospective FAP-targeting radioligands. However, the therapeutic efficacy of [¹⁷⁷Lu]Lu-FAPI-46 for radioligand therapy (RLT) is limited due to its insufficient tumor accumulation. To address this issue, we previously reported an albumin binder (ALB)-conjugated FAP-targeting radioligand, [¹¹¹In]In-FAPI-46-I. [¹¹¹In]In-FAPI-46-I demonstrated higher tumor accumulation than [¹¹¹In]In-FAPI-46, suggesting its potential utility for FAP-targeted RLT. In this study, we radiolabeled FAPI-46-I with ¹⁷⁷Lu, a widely used therapeutic radionuclide, and evaluated its utility as a FAP-targeted RLT agent.</p> Methods <p>[¹⁷⁷Lu]Lu-FAPI-46-I was synthesized by incubating the precursor with [¹⁷⁷Lu]LuCl₃ in acetate buffer. <i>In vitro</i> stability of [¹⁷⁷Lu]Lu-FAPI-46-I was evaluated in murine plasma for 24&#xa0;h. An <i>in vitro</i> cell competition binding assay was performed using U87MG cells with high FAP expression. The pharmacokinetics of [¹⁷⁷Lu]Lu-FAPI-46-I was evaluated using U87MG tumor-bearing mice. A SPECT/CT study was conducted using U87MG (high FAP expression) and HT-1080 (low FAP expression) tumor-bearing mice. An RLT study was also carried out using U87MG tumor-bearing mice, comparing the therapeutic effects of [¹⁷⁷Lu]Lu-FAPI-46-I, [¹⁷⁷Lu]Lu-FAPI-46, and vehicle control.</p> Results <p>[¹⁷⁷Lu]Lu-FAPI-46-I was synthesized with high radiochemical purity and exhibited marked stability in murine plasma for 24&#xa0;h. The FAP-binding affinity of [^natLu]Lu-FAPI-46-I (IC₅₀ = 1.5 ± 0.3 nM) was comparable with that of [^natIn]In-FAPI-46-I and [^natIn]In-FAPI-46. [¹⁷⁷Lu]Lu-FAPI-46-I exhibited prolonged blood retention and enhanced tumor accumulation due to the interaction between its ALB moiety and albumin in blood, resulting in selective accumulation in FAP-expressing tumors. Furthermore, administration of [¹⁷⁷Lu]Lu-FAPI-46-I led to tumor growth suppression and shrinkage, demonstrating superior therapeutic efficacy compared with [¹⁷⁷Lu]Lu-FAPI-46.</p> Conclusion <p>[¹⁷⁷Lu]Lu-FAPI-46-I achieved prolonged tumor accumulation and marked tumor growth inhibition. Therefore, [¹⁷⁷Lu]Lu-FAPI-46-I is a promising candidate for FAP-targeted RLT.</p>