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Background <p>Fibroblast activation protein (FAP)-targeting radioligands have gained attention for the ability to image multiple tumor types. Current FAP-targeting radioligands are labeled with <sup>68</sup>Ga and <sup>18</sup>F, but their short half-lives limit distribution range after production and later time-point imaging. This study describes the development Kalios, a novel class of NODAGA-conjugated FAP-targeting radioligands labeled with the cyclotron-produced Copper-61 (t<sub>1/2</sub> = 3.33&#xa0;h), for greater temporal range for FAP-targeted imaging.</p> Results <p>Four Kalios ligands were synthesized and radiolabeled with [<sup>61</sup>Cu]CuCl<sub>2</sub> in high yield and radiochemical purity within 5&#xa0;min at room temperature. All radioligands demonstrated high hydrophilicity and strong affinity for FAP, and were primarily internalized after incubation with FAP-positive cells. PET/CT images obtained at 0–1&#xa0;h and 4&#xa0;h post-injection (p.i.) illustrated accumulation of all radioligands in FAP-positive tumors. Biodistribution studies of [<sup>61</sup>Cu]Cu-Kalios-02 demonstrated stable tumor uptake between 1 and 4&#xa0;h p.i., with washout from normal tissues at 4&#xa0;h, resulting in improved tumor-to-background ratios.</p> Conclusions <p>Kalios ligands represent a new class of FAP-targeting <sup>61</sup>Cu-labeled radioligands. The half-life of <sup>61</sup>Cu allowed delayed 4-h imaging with improved tumor-to-background ratios. The improved delayed imaging and greater distribution range of these <sup>61</sup>Cu-labeled FAP-targeting radioligands demonstrates their clear potential for clinical translation, while combination with the therapeutic twin <sup>67</sup>Cu allows for truly paired Kalios theranostics.</p>

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Enhanced contrast in FAP-targeting PET imaging with 61Cu-labeled FAP inhibitors: development and preclinical evaluation of novel [61Cu]Cu-Kalios PET radioligands

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月21日

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  • Jacopo Millul,
  • Tais Basaco Bernabeu,
  • Raghuvir H. Gaonkar,
  • Francesco De Rose,
  • Leila Jaafar-Thiel,
  • Gary A. Ulaner,
  • Rosalba Mansi,
  • Melpomeni Fani

摘要

Background

Fibroblast activation protein (FAP)-targeting radioligands have gained attention for the ability to image multiple tumor types. Current FAP-targeting radioligands are labeled with 68Ga and 18F, but their short half-lives limit distribution range after production and later time-point imaging. This study describes the development Kalios, a novel class of NODAGA-conjugated FAP-targeting radioligands labeled with the cyclotron-produced Copper-61 (t1/2 = 3.33 h), for greater temporal range for FAP-targeted imaging.

Results

Four Kalios ligands were synthesized and radiolabeled with [61Cu]CuCl2 in high yield and radiochemical purity within 5 min at room temperature. All radioligands demonstrated high hydrophilicity and strong affinity for FAP, and were primarily internalized after incubation with FAP-positive cells. PET/CT images obtained at 0–1 h and 4 h post-injection (p.i.) illustrated accumulation of all radioligands in FAP-positive tumors. Biodistribution studies of [61Cu]Cu-Kalios-02 demonstrated stable tumor uptake between 1 and 4 h p.i., with washout from normal tissues at 4 h, resulting in improved tumor-to-background ratios.

Conclusions

Kalios ligands represent a new class of FAP-targeting 61Cu-labeled radioligands. The half-life of 61Cu allowed delayed 4-h imaging with improved tumor-to-background ratios. The improved delayed imaging and greater distribution range of these 61Cu-labeled FAP-targeting radioligands demonstrates their clear potential for clinical translation, while combination with the therapeutic twin 67Cu allows for truly paired Kalios theranostics.