2. Academic Validation
  3. Harnessing Insights of Hepatocyte Growth Factor Kringle 3 Domain to Develop c-Met Targeted Positron Emission Tomography Probe

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

  • J Med Chem. 2026 Jan 8;69(1):488-500. doi: 10.1021/acs.jmedchem.5c02886.
Renli Luo 1 2,  Luming Sun 3 2,  Xuanyan Zhao 4 2,  Yonghao Li 2,  Boyu Tan 2 5,  Tao Wang 2,  Qi Guo 4 2,  Ying Zhang 2,  Rui Cao 6,  Chunrong Qu 2 7,  Zhen Cheng 2 7 8
Affiliations

Affiliations

  • 1 Institute of Molecular Medicine, College of Life and Health Sciences, Northeastern University, Shenyang 110167, China.
  • 2 State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Pharmacy, Henan University, Kaifeng 475004, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 201203, China.
  • 5 School of Biomedical Engineering, ShanghaiTech University, Shanghai 201210. China.
  • 6 Department of Nuclear Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200235, China.
  • 7 School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road. Beijing 100049, China.
  • 8 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 41452847 DOI: 10.1021/acs.jmedchem.5c02886
Abstract

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.

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