Native Ligand-Inspired peptides for c-MET targeted PET probes development

Area of Science:

• Radiopharmaceutical chemistry
• Molecular imaging
• Oncology

Background:

• Native ligand-derived peptides are crucial for developing targeted radiopharmaceuticals.
• Mesenchymal-epithelial transition factor (c-MET) is a key target in cancer therapy.
• Hepatocyte growth factor (HGF) is an endogenous biomolecule that binds to c-MET.

Purpose of the Study:

• To develop novel c-MET targeted peptide positron emission tomography (PET) probes.
• To utilize the endogenous biomolecule hepatocyte growth factor (HGF) as a basis for probe design.
• To evaluate the efficacy of these novel probes in vitro and in vivo.

Main Methods:

• Designed three c-MET targeted peptides from the N-terminal and kringle 1 domain of HGF.
• Conjugated peptides with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with Gallium-68 ([68Ga]).
• Evaluated the resulting [68Ga]Ga-DOTA-labeled probes ([68Ga]Ga-DOTA-K1, [68Ga]Ga-DOTA-A-C5, and [68Ga]Ga-DOTA-A-M8) in vitro and in vivo using cell lines and small animal PET/CT imaging.

Main Results:

• [68Ga]Ga-DOTA-A-M8 showed high affinity for c-MET (IC50 = 5.43 nM) and specific uptake in c-MET-expressing HCT-116 cells.
• Small animal PET/CT imaging visualized tumors with good contrast using [68Ga]Ga-DOTA-A-M8.
• Biodistribution studies indicated high tumor uptake (2.91 ± 0.20%ID/g at 30 min) and favorable tumor-to-background ratios, with primary clearance via the kidney-bladder pathway.

Conclusions:

• A novel c-MET-targeting PET probe, [68Ga]Ga-DOTA-A-M8, was successfully developed.
• The probe demonstrated high tumor-targeting capability and specificity.
• Developing PET probes based on native ligands is a powerful and generalizable strategy for radiopharmaceutical discovery.