Imaging the Met Receptor Tyrosine Kinase (Met) and Assessing Tumor Responses to a Met Tyrosine Kinase Inhibitor in Human Xenograft Mouse Models with a [99mTc] (AH-113018) or Cy 5** (AH-112543) Labeled Peptide.

Abstract

Developing an imaging agent targeting the hepatocyte growth factor receptor protein (Met) status of cancerous lesions would aid in the diagnosis and monitoring of Met-targeted tyrosine kinase inhibitors (TKIs). A peptide targeting Met labeled with [(99m)Tc] had high affinity in vitro (Kd = 3.3 nM) and detected relative changes in Met in human cancer cell lines. In vivo [(99m)Tc]-Met peptide (AH-113018) was retained in Met-expressing tumors, and high-expressing Met tumors (MKN-45) were easily visualized and quantitated using single-photon emission computed tomography or optical imaging. In further studies, MKN-45 mouse xenografts treated with PHA 665752 (Met TKI) or vehicle were monitored weekly for tumor responses by [(99m)Tc]-Met peptide imaging and measurement of tumor volumes. Tumor uptake of [(99m)Tc]-Met peptide was significantly decreased as early as 1 week after PHA 665752 treatment, corresponding to decreases in tumor volumes. These results were comparable to Cy5**-Met peptide (AH-112543) fluorescence imaging using the same treatment model. [(99m)Tc] or Cy5**-Met peptide tumor uptake was further validated by histologic (necrosis, apoptosis) and immunoassay (total Met, p Met, and plasma shed Met) assessments in imaged and nonimaged cohorts. These data suggest that [(99m)Tc] or Cy5**-Met peptide imaging may have clinical diagnostic, prognostic, and therapeutic monitoring applications.

• Authors: Elaine M Jagoda, Sibaprasad Bhattacharyya, Joseph Kalen, Lisa Riffle, Avrum Leeder, Stephanie Histed, Mark Williams, Karen J Wong, Biying Xu, Lawrence P Szajek, Osama Elbuluk, Fabiola Cecchi, Kristen Raffensperger, Meghana Golla, Donald P Bottaro, Peter Choyke
• Journal: Molecular imaging (Mol Imaging) Vol. 14 Pg. 499-515 ( 2015) ISSN: 1536-0121 [Electronic] England
• PMID: 26461980 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
• AH-112543
• AH-113018
• Carbocyanines
• Indoles
• Organotechnetium Compounds
• Peptides
• Protein Kinase Inhibitors
• Sulfones
• cyanine dye 5
• Technetium
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Carbocyanines (metabolism)
• Cell Line, Tumor
• Humans
• Indoles (pharmacology)
• Mice
• Neoplasms (diagnostic imaging)
• Organotechnetium Compounds (metabolism)
• Peptides (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-met (metabolism)
• Spectrometry, Fluorescence
• Staining and Labeling
• Sulfones (pharmacology)
• Technetium
• Tissue Distribution (drug effects)
• Tomography, Emission-Computed, Single-Photon (methods)
• Tumor Burden
• Xenograft Model Antitumor Assays