Development of a Long-Acting FAPI Dimer Albb-2FAPI for Diagnosis and Therapy of FAP-Positive Tumors.

Abstract

Fibroblast activation protein (FAP)-targeted radiotheranostics show strong promise for cancer imaging and therapy, yet their clinical translation is limited by the trade-off between rapid tumor targeting and insufficient systemic residence time. To address this challenge, we report the design and evaluation of 177Lu-Albb-2FAPI, a long-acting dimeric FAPI derivative that integrates FAPI-02 dimerization with an Evans Blue-based reversible albumin-binding motif to achieve improved tumor targeting while preserving a favorable pharmacokinetic profile. Molecular docking revealed enhanced FAP binding via avidity-driven stabilization without compromising albumin interaction. In vitro studies confirmed rapid, FAP-specific cellular uptake, while in vivo SPECT/CT imaging and biodistribution analyses demonstrated higher and more sustained tumor accumulation, together with improved early tumor-to-background contrast, compared with the monomeric analogue Albb-1FAPI. In the Panc02 tumor model, characterized by moderate FAP expression, 177Lu-Albb-2FAPI exhibited durable tumor retention and induced rapid tumor regression while preserving hematological safety. By coupling dimerization-enhanced target engagement with controlled albumin binding, 177Lu-Albb-2FAPI overcomes key diagnostic and therapeutic limitations of existing long-acting FAP radioligands, establishing a refined molecular design strategy for next-generation FAP-targeted radiotheranostics with strong translational potential.