Optimizing FAPI homodimers for theranostic applications: The impact of the linker design in DOTAGA.Glu<sub>2</sub>.(FAPI)<sub>2</sub> and DOTAGA.PEG<sub>2</sub>.Glu.(FAPI)<sub>2</sub>.
basic_science · Level V
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- Also identified by DOI 10.1007/s00259-026-08078-9.
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Abstract
This study evaluated the imaging performance, tumor retention, and therapeutic potential of two new FAPI homodimers, DOTAGA.Glu<sub>2</sub>.(FAPI)<sub>2</sub> and DOTAGA.PEG<sub>2</sub>.Glu.(FAPI)<sub>2</sub>, specifically designed to improve FAP-targeted tumor retention. DOTAGA.Glu<sub>2</sub>.(FAPI)<sub>2</sub> and DOTAGA.PEG<sub>2</sub>.Glu.(FAPI)<sub>2</sub> were radiolabeled with gallium-68 and lutetium-177. In vitro studies included lipophilicity, protein binding, saturation binding, internalization and externalization using FAP<sup>+</sup> 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 [<sup>177</sup>Lu]Lu-DOTAGA.Glu<sub>2</sub>.(FAPI)<sub>2</sub>, as monotherapy or combined with everolimus. All radioligands showed > 99% radiochemical purity, high FAP affinity (K<sub>d</sub>: 0.9-1.5 nM), hydrophilic profiles (LogD<sub>octanol/PBS</sub> ≤-3), and low protein binding (< 10%). They exhibited high internalization and low externalization (~ 20% for [<sup>177</sup>Lu]Lu-DOTAGA.Glu<sub>2</sub>.(FAPI)<sub>2</sub> and ~ 35% for [<sup>177</sup>Lu]Lu-DOTAGA.PEG<sub>2</sub>.Glu.(FAPI)<sub>2</sub>). The <sup>68</sup>Ga-labeled radiotracers displayed sustained tumor uptake up to 3 h p.i. (> 14%I.A./g) with increasing tumor-to-organ ratios. For the <sup>177</sup>Lu-labeled analogues the initial uptake was comparable (~ 15%I.A./g at 4 h p.i.), with [<sup>177</sup>Lu]Lu-DOTAGA.Glu<sub>2</sub>.(FAPI)<sub>2</sub>, showing even improved retention compared to [<sup>177</sup>Lu]Lu-DOTAGA.PEG<sub>2</sub>.Glu.(FAPI)<sub>2</sub> (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.Glu<sub>2</sub>.(FAPI)<sub>2</sub>. 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. DOTAGA.Glu<sub>2</sub>.(FAPI)<sub>2</sub> demonstrates superior tumor retention, favorable pharmacokinetics, and enhanced therapeutic efficacy, supporting its potential for clinical translation.