Synthesis, Preclinical Investigations, and Pilot Clinical Imaging Studies of ⁶⁸Ga-Labeled Peptide-Derived...

The mesenchymal epithelial transition factor (c-Met) has emerged as a key therapeutic target in diverse malignancies, driving the development of c-Met-targeted PET probes. We report a series of peptide-derived probes, [⁶⁸Ga]Ga-NOTA-PEG_n-Glc-MetP (n = 2, 4, 6), synthesized with high radiochemical yield (>80%), purity (>95%), and in vitro and in vivo stability (>90%). All radiotracers exhibited satisfactory affinity and specificity for c-Met in preclinical studies. Among them, [⁶⁸Ga]Ga-NOTA-PEG₂-Glc-MetP demonstrated superior in vivo performance and was advanced to clinical evaluation, where its safety was confirmed in human participants. It was excreted via the urinary system and exhibited mild uptake in other organs. Additionally, at 60 min postinjection, it showed satisfactory radioactive uptake in lung cancer (tumor-to-lung ratio [TLR]: 4.87 [range, 3.12-7.55]), which positively correlated with c-Met expression (R = 0.71, P = 0.034). Overall, [⁶⁸Ga]Ga-NOTA-PEG₂-Glc-MetP shows favorable pharmacokinetics and a strong correlation with c-Met expression, supporting its potential as a promising PET imaging agent.