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Life sciences · Journal article
Acs Omega · August 11, 2026
Early or partial results. Treat as a signal, not a conclusion.
This work describes the synthesis and preclinical characterization of a series of novel homodimeric FAP inhibitor radiopharmaceuticals with engineered linkers and chelators. In vitro studies show subnanomolar FAP binding affinity, high cellular internalization, and favorable labeling chemistry with 68Ga and 177Lu, but no in vivo efficacy, animal models, or clinical data are presented. The authors conclude these are promising candidates for 177Lu-based targeted radioligand therapy, pending further in vivo evaluation.
Preclinical in vitro chemical and radiochemical characterization study. Cancer-associated fibroblasts (CAFs) in vitro; no human subjects or animal models studied.. Intervention: Novel homodimeric FAP inhibitor compounds: NPyr-, Glu2-, and PEG2.Glu-linked dimers, each coupled to DOTAGA or DO3A chelator, radiolabeled with 68Ga or 177Lu.. Compared with: Implicit comparison to prior DOTAGA.Glu.(FAPi)2 results; no explicit control arm or head-to-head trial structure reported..
All FAPi homodimers exhibited subnanomolar FAP affinity with high selectivity over PREP and DPP4 Saturation binding studies of 68Ga-labeled Glu2- and PEG2.Glu-linked DOTAGA derivatives showed high FAP affinity (Kd: 1.1–1.2 nM) Internalization was rapid, with up to 95% of total cell-bound activity internalized within 30 min in CAFs
Authors acknowledge further in vivo studies are warranted; pharmacological properties for therapeutic application not yet assessed. 68Ga-labeled radioligands remained stable in plasma with favorable pharmacokinetics by PET quantification
This is early-stage radiochemistry work not yet ready to guide clinical practice. Clinicians and researchers should view these compounds as development-stage candidates requiring comprehensive in vivo pharmacology and safety studies before any therapeutic application can be considered.
This is preclinical chemical and radiochemical characterization of novel compounds with in vitro binding and cell studies, lacking in vivo efficacy data or clinical translation to support therapeutic claims.
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This is early-stage radiochemistry work not yet ready to guide clinical practice. Clinicians and researchers should view these compounds as development-stage candidates requiring comprehensive in vivo pharmacology and safety studies before any therapeutic application can be considered.
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Abstract Monomeric fibroblast activation protein inhibitors (FAPi) based PET tracers have demonstrated very suitable imaging characteristics preclinically in various cancer models. More recently, homodimeric FAP inhibitors (FAPi dimers), that consist of two identical FAPi targeting vectors, have been developed, offering prolonged tumor retention and thus enhancing the potential of targeted radioligand therapy (TRT) with long-lived therapeutic radionuclides such as 177Lu. Building on the promising results of DOTAGA.Glu.(FAPi)2 in preclinical and patient studies, we synthesized a series of novel homodimeric compounds incorporating different linker and spacer units (NPyr-, Glu2-, and PEG2.Glu-linked dimers), each coupled to either DOTAGA or DO3A as the chelator. Radiolabeling with 68Ga and 177Lu resulted in high to quantitative radiochemical conversion and purity. All FAPi homodimers exhibited high hydrophilicity, excellent stability in both human serum and PBS and showed subnanomolar FAP affinity with high selectivity over PREP (prolyl endopeptidase) and DPP4 (dipeptidyl peptidase 4). In parallel, saturation binding studies were performed to determine the affinity of the corresponding 68Ga-labeled Glu2- and PEG2.Glu-linked DOTAGA derivatives and exhibited high FAP affinity (Kd: 1.1–1.2 nM). Internalization was rapid, with up to 95% of total cell-bound activity internalized within 30 min in CAFs (cancer-associated fibroblasts). Metabolic studies confirmed that 68Ga-labeled radioligands remained stable in plasma, and PET quantification demonstrated favorable pharmacokinetics. Overall, these findings highlight the new FAPi homodimers as promising candidates for efficient 177Lu-based TRT. Further in vivo studies are warranted to comprehensively assess their pharmacological properties for therapeutic application.
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