Journal Article

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

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

2025

Overview

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 68 Ga and 18 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 1/2  = 3.33 h), for greater temporal range for FAP-targeted imaging. Results Four Kalios ligands were synthesized and radiolabeled with [ 61 Cu]CuCl 2 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 [ 61 Cu]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 61 Cu-labeled radioligands. The half-life of 61 Cu allowed delayed 4-h imaging with improved tumor-to-background ratios. The improved delayed imaging and greater distribution range of these 61 Cu-labeled FAP-targeting radioligands demonstrates their clear potential for clinical translation, while combination with the therapeutic twin 67 Cu allows for truly paired Kalios theranostics.

• Publisher: Springer International Publishing,Springer Nature B.V,SpringerOpen
• Subject: 61/67Cu theranostics / 61Cu / Computed tomography / Copper / Copper chloride / Cyclotrons / FAPI / Fibroblast activation protein / Fibroblast Activation Protein Inhibitor (FAPI): novel tracers and approaches for optimized imaging and therapy / Fibroblast activation protein-α (FAP) / Half-life / Imaging / Late time-point imaging / Ligands / Medical imaging / Medicine / Medicine & Public Health / Molecular Medicine / Nuclear Chemistry / Nuclear Medicine / PET / Pharmacotherapy / Positron emission / Precision medicine / Radiochemistry / Radioisotopes / Radiology / Research Article / Retention / Room temperature / Tumors