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

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 (t_1/2 = 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.