Harnessing Insights of Hepatocyte Growth Factor Kringle 3 Domain to Develop c‑Met Targeted Positron Emission Tomography Probe

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.