Peptide-Derived [68Ga]Ga-SMIC-1014 for c-Met-Targeted Tumor PET Imaging: Preclinical and Pilot Clinical Studies

Abstract As the mesenchymal–epithelial transition factor (c-Met) is a crucial therapeutic target for multiple malignancies, we previously developed a c-Met-targeted peptide-based positron emission tomography (PET) probe, [68Ga]Ga-SMIC-1014, derived from the Kringle 3 (K3) domain of hepatocyte growth factor (HGF). Given tumor heterogeneity, this study sought to further validate the preclinical performance of [68Ga]Ga-SMIC-1014 and evaluate its clinical value in cancer patients. [68Ga]Ga-SMIC-1014 was successfully synthesized with high radiochemical yield (>80%, non-decay corrected) and purity (>99%), and favorable in vitro stability in PBS and FBS. In vitro cellular uptake of the probe was positively correlated with c-Met expression levels in tumor cells, as verified by Western blot analysis. Small-animal PET and biodistribution studies demonstrated that [68Ga]Ga-SMIC-1014 exhibited significantly higher tumor accumulation in mouse models with high c-Met expression than those with low c-Met expression (1.92 ± 0.12 vs. 0.49 ± 0.07 %ID/g at 60 min post-injection). Blocking studies with unlabeled SMIC-1014 verified the specific c-Met binding of [68Ga]Ga-SMIC-1014 both in vitro and in vivo. The probe displayed good safety in human subjects, with physiological renal excretion and minimal-to-mild uptake in normal organs. Tumor uptake of [68Ga]Ga-SMIC-1014 correlated well with c-Met expression levels in lung cancer patients. Collectively, [68Ga]Ga-SMIC-1014 is safe and well tolerated in human subjects, and correlates with tumor c-Met expression, supporting its potential as a PET probe for imaging c-Met-positive tumors.