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Purpose <p>This study aims to assess DOTAGA.Glu.(FAPI)<sub>2</sub> and DO3A.Glu.(FAPI)<sub>2</sub>, specifically engineered as precursors for the development of theranostic FAPI-targeted radioligands.</p> Methods <p>DOTAGA.Glu.(FAPI)<sub>2</sub> and DO3A.Glu.(FAPI)<sub>2</sub> were radiolabeled with gallium-68 and lutetium-177, followed by in vitro (lipophilicity, protein binding, saturation, internalization and externalization) studies on FAP<sup>+</sup> CAFs. In vivo (biodistribution, metabolic stability, blood kinetics, PET/SPECT/CT imaging) and ex vivo, (autoradiography, immunohistochemistry) conducted on PC3-mice. Murine dosimetry data were extrapolated to human estimates.</p> Results <p>All radioligands achievied &gt; 98% radiochemical purity, demonstrating high FAP affinity (K<sub>d</sub>:0.7–0.9 nM) and rapid internalization in CAFs, with differences in lipophilicity and serum protein binding. In vivo studies, for [<sup>68</sup>Ga]Ga-DOTAGA.Glu.(FAPI)<sub>2</sub> and [<sup>68</sup>Ga]Ga-DO3A.Glu.(FAPI)<sub>2</sub> showed high and sustained tumor uptake up to 3&#xa0;h p.i. (18–19%I.A./g). For [<sup>177</sup>Lu]Lu-DOTAGA.Glu.(FAPI)<sub>2</sub> and [<sup>177</sup>Lu]Lu-DO3A.Glu.(FAPI)<sub>2</sub> tumor uptake was 16.2 ± 2.5 and 15 ± 1.2% IA/g at 4&#xa0;h p.i., reaching 5.1 ± 0.1 and 2.8 ± 0.4%IA/g at 48&#xa0;h, respectively. All radioligands exhibited low blood retention levels. PET/SPECT/CT imaging confirmed high tumor-to-background ratios. Uptake patterns correlate well with autoradiography images of heterogeneous FAP distribution in PC3-mice, while the detection of both murine and human FAP in PC3-tumors was demonstrated through immunohistochemistry. The extrapolated human absorbed dose estimates (Gy/GBq) for [<sup>177</sup>Lu]Lu-DOTAGA.Glu.(FAPI)<sub>2</sub> were generally higher across most organs compared to [<sup>177</sup>Lu]Lu-DO3A.Glu.(FAPI)<sub>2</sub>. Human extrapolation of the <sup>161</sup>Tb-labeled radioligands delivered on average ~ 38% higher absorbed doses in tissues as compared to their <sup>177</sup>Lu-labeled counterparts.</p> Conclusion <p>These results support the potential clinical translation of DOTAGA.Glu.(FAPI)<sub>2</sub> and DO3A.Glu.(FAPI)<sub>2</sub>, as promising candidates for precise diagnosis and treatment of FAP-expressing malignancies.</p>

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Preclinical evaluation of DOTAGA.Glu.(FAPI)2 and DO3A.Glu.(FAPI)2 as theranostics with human dosimetry extrapolation to lutetium-177 and terbium-161 analogs

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  • 出版模式：

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  • 发表日期：

    2025年10月17日

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  • Adrianna Bilinska,
  • Naveen Kumar,
  • Silvano Gnesin,
  • Tilman Läppchen,
  • Elena Menéndez,
  • Marcel Martin,
  • Frank Rösch,
  • Axel Rominger,
  • Eleni Gourni

摘要

Purpose

This study aims to assess DOTAGA.Glu.(FAPI)2 and DO3A.Glu.(FAPI)2, specifically engineered as precursors for the development of theranostic FAPI-targeted radioligands.

Methods

DOTAGA.Glu.(FAPI)2 and DO3A.Glu.(FAPI)2 were radiolabeled with gallium-68 and lutetium-177, followed by in vitro (lipophilicity, protein binding, saturation, internalization and externalization) studies on FAP+ CAFs. In vivo (biodistribution, metabolic stability, blood kinetics, PET/SPECT/CT imaging) and ex vivo, (autoradiography, immunohistochemistry) conducted on PC3-mice. Murine dosimetry data were extrapolated to human estimates.

Results

All radioligands achievied > 98% radiochemical purity, demonstrating high FAP affinity (Kd:0.7–0.9 nM) and rapid internalization in CAFs, with differences in lipophilicity and serum protein binding. In vivo studies, for [68Ga]Ga-DOTAGA.Glu.(FAPI)2 and [68Ga]Ga-DO3A.Glu.(FAPI)2 showed high and sustained tumor uptake up to 3 h p.i. (18–19%I.A./g). For [177Lu]Lu-DOTAGA.Glu.(FAPI)2 and [177Lu]Lu-DO3A.Glu.(FAPI)2 tumor uptake was 16.2 ± 2.5 and 15 ± 1.2% IA/g at 4 h p.i., reaching 5.1 ± 0.1 and 2.8 ± 0.4%IA/g at 48 h, respectively. All radioligands exhibited low blood retention levels. PET/SPECT/CT imaging confirmed high tumor-to-background ratios. Uptake patterns correlate well with autoradiography images of heterogeneous FAP distribution in PC3-mice, while the detection of both murine and human FAP in PC3-tumors was demonstrated through immunohistochemistry. The extrapolated human absorbed dose estimates (Gy/GBq) for [177Lu]Lu-DOTAGA.Glu.(FAPI)2 were generally higher across most organs compared to [177Lu]Lu-DO3A.Glu.(FAPI)2. Human extrapolation of the 161Tb-labeled radioligands delivered on average ~ 38% higher absorbed doses in tissues as compared to their 177Lu-labeled counterparts.

Conclusion

These results support the potential clinical translation of DOTAGA.Glu.(FAPI)2 and DO3A.Glu.(FAPI)2, as promising candidates for precise diagnosis and treatment of FAP-expressing malignancies.