Harnessing Insights of Hepatocyte Growth Factor Kringle 3 Domain to Develop c-Met Targeted Positron Emission...

The cellular mesenchymal-epithelial transition factor (c-Met) is overexpressed in multiple solid tumors and is normally driven by its native ligand, hepatocyte growth factor (HGF). Despite extensive structural studies, no diagnostic agents have been developed based on the individual HGF-Kringle 3 (K3) domain. Here, four HGF-K3-derived c-Met-targeted peptide radioligands were designed for positron emission tomography (PET) imaging. Among them, [⁶⁸Ga]Ga-SMIC-1014 exhibited the most favorable pharmacokinetics and achieved different tumor uptake in HCT-116, HepG2, and LNCaP xenografts. Moreover, the specific tumor targeting ability of [⁶⁸Ga]Ga-SMIC-1014 was demonstrated by coinjection with an 800-fold SMIC-1014 peptide or preinjection of an excess of 25-fold onartuzumab as blocking agents, showing significant tumor signal reduction. In conclusion, the strategy of using the interface residues has been successfully explored for the discovery of new c-Met binders. [⁶⁸Ga]Ga-SMIC-1014 shows a high tumor imaging performance and potential as a c-Met-targeted diagnostic probe.