title: 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.forename: Elaine M
authors.initials: EM
authors.lastname: Jagoda
authors.forename: Sibaprasad
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Joseph
authors.initials: J
authors.lastname: Kalen
authors.forename: Lisa
authors.initials: L
authors.lastname: Riffle
authors.forename: Avrum
authors.initials: A
authors.lastname: Leeder
authors.forename: Stephanie
authors.initials: S
authors.lastname: Histed
authors.forename: Mark
authors.initials: M
authors.lastname: Williams
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Wong
authors.forename: Biying
authors.initials: B
authors.lastname: Xu
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Szajek
authors.forename: Osama
authors.initials: O
authors.lastname: Elbuluk
authors.forename: Fabiola
authors.initials: F
authors.lastname: Cecchi
authors.forename: Kristen
authors.initials: K
authors.lastname: Raffensperger
authors.forename: Meghana
authors.initials: M
authors.lastname: Golla
authors.forename: Donald P
authors.initials: DP
authors.lastname: Bottaro
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
mesh_terms: D000818:Animals; D002232:Carbocyanines / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging*; D015609:Organotechnetium Compounds / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013194:Staining and Labeling; D013450:Sulfones / Q000494:pharmacology; D013667:Technetium; D014018:Tissue Distribution / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C480541:5-((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; C000605547:AH-112543; C000605546:AH-113018; D002232:Carbocyanines; D007211:Indoles; D015609:Organotechnetium Compounds; D010455:Peptides; D047428:Protein Kinase Inhibitors; D013450:Sulfones; C085321:cyanine dye 5; D013667:Technetium; D019859:Proto-Oncogene Proteins c-met