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Войти в исследования European journal of nuclear medicine and molecular imaging · 2026
Optimizing FAPI homodimers for theranostic applications: The impact of the linker design in DOTAGA.Glu2.(FAPI)2 and DOTAGA.PEG2.Glu.(FAPI)2.
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Kumar Naveen, Bilinska Adrianna, Menéndez Elena, Stephan Sarah, Rösch Frank, Rominger Axel, Gourni Eleni
Аннотация
PURPOSE: This study evaluated the imaging performance, tumor retention, and therapeutic potential of two new FAPI homodimers, DOTAGA.Glu2.(FAPI)2 and DOTAGA.PEG2.Glu.(FAPI)2, specifically designed to improve FAP-targeted tumor retention.
METHODS: DOTAGA.Glu2.(FAPI)2 and DOTAGA.PEG2.Glu.(FAPI)2 were radiolabeled with gallium-68 and lutetium-177. In vitro studies included lipophilicity, protein binding, saturation binding, internalization and externalization using FAP+ CAFs. In vivo evaluation in PC3-mice comprised biodistribution, metabolic stability, blood and organ clearance, PET/SPECT/CT imaging, and autoradiography. Therapeutic efficacy was assessed using fractionated radioligand therapy with [177Lu]Lu-DOTAGA.Glu2.(FAPI)2, as monotherapy or combined with everolimus.
RESULTS: All radioligands showed > 99% radiochemical purity, high FAP affinity (Kd: 0.9-1.5 nM), hydrophilic profiles (LogDoctanol/PBS ≤-3), and low protein binding (< 10%). They exhibited high internalization and low externalization (~ 20% for [177Lu]Lu-DOTAGA.Glu2.(FAPI)2 and ~ 35% for [177Lu]Lu-DOTAGA.PEG2.Glu.(FAPI)2). The 68Ga-labeled radiotracers displayed sustained tumor uptake up to 3 h p.i. (> 14%I.A./g) with increasing tumor-to-organ ratios. For the 177Lu-labeled analogues the initial uptake was comparable (~ 15%I.A./g at 4 h p.i.), with [177Lu]Lu-DOTAGA.Glu2.(FAPI)2, showing even improved retention compared to [177Lu]Lu-DOTAGA.PEG2.Glu.(FAPI)2 (4.2 ± 0.5 vs. 1.2 ± 0.02%I.A./g at 96 h). Blood clearance was rapid and biphasic, with faster kinetics for DOTAGA.Glu2.(FAPI)2. For the same compound, tumor half-life was significantly prolonged (44.5 vs. 19 h), resulting in 2-fold higher tumor exposure (AUC: 971 ± 74 vs. 542 ± 28%I.A.×h/g). Imaging confirmed high tumor-to-background ratios, while autoradiography revealed heterogeneous intratumoral FAP distribution. Fractionated therapy significantly inhibited tumor growth and improved survival, further enhanced by everolimus.
CONCLUSION: DOTAGA.Glu2.(FAPI)2 demonstrates superior tumor retention, favorable pharmacokinetics, and enhanced therapeutic efficacy, supporting its potential for clinical translation.
METHODS: DOTAGA.Glu2.(FAPI)2 and DOTAGA.PEG2.Glu.(FAPI)2 were radiolabeled with gallium-68 and lutetium-177. In vitro studies included lipophilicity, protein binding, saturation binding, internalization and externalization using FAP+ CAFs. In vivo evaluation in PC3-mice comprised biodistribution, metabolic stability, blood and organ clearance, PET/SPECT/CT imaging, and autoradiography. Therapeutic efficacy was assessed using fractionated radioligand therapy with [177Lu]Lu-DOTAGA.Glu2.(FAPI)2, as monotherapy or combined with everolimus.
RESULTS: All radioligands showed > 99% radiochemical purity, high FAP affinity (Kd: 0.9-1.5 nM), hydrophilic profiles (LogDoctanol/PBS ≤-3), and low protein binding (< 10%). They exhibited high internalization and low externalization (~ 20% for [177Lu]Lu-DOTAGA.Glu2.(FAPI)2 and ~ 35% for [177Lu]Lu-DOTAGA.PEG2.Glu.(FAPI)2). The 68Ga-labeled radiotracers displayed sustained tumor uptake up to 3 h p.i. (> 14%I.A./g) with increasing tumor-to-organ ratios. For the 177Lu-labeled analogues the initial uptake was comparable (~ 15%I.A./g at 4 h p.i.), with [177Lu]Lu-DOTAGA.Glu2.(FAPI)2, showing even improved retention compared to [177Lu]Lu-DOTAGA.PEG2.Glu.(FAPI)2 (4.2 ± 0.5 vs. 1.2 ± 0.02%I.A./g at 96 h). Blood clearance was rapid and biphasic, with faster kinetics for DOTAGA.Glu2.(FAPI)2. For the same compound, tumor half-life was significantly prolonged (44.5 vs. 19 h), resulting in 2-fold higher tumor exposure (AUC: 971 ± 74 vs. 542 ± 28%I.A.×h/g). Imaging confirmed high tumor-to-background ratios, while autoradiography revealed heterogeneous intratumoral FAP distribution. Fractionated therapy significantly inhibited tumor growth and improved survival, further enhanced by everolimus.
CONCLUSION: DOTAGA.Glu2.(FAPI)2 demonstrates superior tumor retention, favorable pharmacokinetics, and enhanced therapeutic efficacy, supporting its potential for clinical translation.
Предметные рубрики MeSH
AnimalsMiceHumansTissue DistributionLutetiumCell Line, TumorFibroblast Activation Protein AlphaGallium RadioisotopesRadioisotopesHeterocyclic Compounds, 1-RingDrug DesignPositron Emission Tomography Computed TomographySingle Photon Emission Computed Tomography Computed TomographyRadiopharmaceuticalsPolyethylene Glycols