PEG₄-Modified FAP-CAIX Heterodimeric Radioligand for Precision Imaging and Radiotherapy

Tumor heterogeneity severely limits the efficacy of single-targeted radiopharmaceuticals. FAP and CAIX are important biomarkers overexpressed in tumors and the tumor microenvironment. We designed a PEG₄-modified heterodimeric radioligand, FC, for dual targeting of FAP and CAIX. FC showed high binding affinity toward FAP (IC₅₀ = 18.2 ± 0.23 nM). [⁶⁸Ga]Ga-FC exhibited significantly higher tumor uptake than monomeric tracers in FAP- or CAIX-positive tumor models at 120 min postinjection. PEG₄ modification markedly enhanced hydrophilicity, tumor retention, and in vivo stability. Mirco-SPECT imaging showed strong tumor accumulation of [¹⁷⁷Lu]Lu-FC up to 168 h. A single dose of [¹⁷⁷Lu]Lu-FC (29.6 MBq) achieved complete tumor suppression in HEK293-FAP tumor-bearing mice with no obvious organ toxicity. [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-FC represents a promising theranostic agent for FAP-positive malignancies.