Development of a SPECT Tracer to Image c-Met Expression in a Xenograft Model of Non–Small Cell Lung Cancer

Abstract

Elevated expression of the c-Met receptor plays a crucial role in cancers. In non-small cell lung cancer (NSCLC), aberrant activation of the c-Met signaling pathway contributes to tumorigenesis and cancer progression and may mediate acquired resistance to epidermal growth factor receptor-targeted therapy. c-Met is therefore emerging as a promising therapeutic target for NSCLC, and methods for noninvasive in vivo assessment of c-Met expression would improve NSCLC treatment and diagnosis. We developed a new c-Met-binding peptide (cMBP) radiotracer,Tc-hydrazine nicotinamide (HYNIC)-cMBP, for SPECT imaging. Cell uptake assays were performed on 2 NSCLC cell lines with different c-Met expressions: H1993 (high expression) and H1299 (no expression). In vivo tumor specificity was assessed by SPECT imaging in tumor-bearing mice at 0.5, 1, 2, and 4 h after injection of the probe. Blocking assays, biodistribution, and autoradiography were also conducted to determine probe specificity. Tc-HYNIC-cMBP was prepared with high efficiency and showed higher uptake in H1993 cells than in H1299 cells. Biodistribution and autoradiography also showed significantly higher percentages of the injected dose forTc-HYNIC-cMBP in H1993 tumors than in H1299 tumors at 0.5 h (4.74 ± 1.43%/g and 1.00 ± 0.37%/g, respectively; < 0.05). H1993 tumors were clearly visualized at 0.5 h in SPECT images, whereas H1299 tumors were not observed at any time. The specificity of Tc-HYNIC-cMBP for c-Met was demonstrated by a competitive block with an excess of nonradiolabeled peptide. For c-Met-targeted SPECT imaging of NSCLC, we developed Tc-HYNIC-cMBP, a tracer that specifically binds to c-Met with favorable pharmacokinetics in vitro and in vivo.

Photoradiosynthesis of 68Ga-Labeled HBED-CC-Azepin-MetMAb for Immuno-PET of c-MET Receptors

“…17 Molecular imaging of c-MET expression has the potential to support the clinical evaluation of MET-targeted therapies by assisting in patient selection and in monitoring drug efficacy. [18][19][20] MetMAb (onartuzumab, Genentech Inc., South San Francisco, CA) contains a humanized one-armed monovalent anti-MET antibody designed to bind the extracellular domain of c-MET and thereby block activation by HGF. 21,22 MetMAb has been investigated in phase III trials as a treatment for non-small-cell lung cancer (NSCLC).…”

Preliminary application of micro‐SPECT/CT imaging by 99mTc‐tricine‐EDDA‐HYNIC‐c‐Met for non‐small‐cell lung cancer

“…Antibodies have inherent limitations including large size, weak tissue penetration, prolonged clearance, and potential immunogenicity. Compared with antibodies, low molecular weight peptides’ molecular imaging agents present some advantages such as favorable pharmacokinetic and tissue distribution patterns, higher permeability, lower toxicity, less immunogenicity, and easy accessibility for chemical modification (Han et al, ).…”

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

“…In recent years, many studies have shown that the expression level and activation status of MET are closely correlated to MET-targeted therapy response and clinical prognosis, thus highlighting the importance of evaluating the MET status during and prior to targeted therapy [ 27 , 281 ]. Due to a limited number of validated MET mAbs that work in formalin-fixed and paraffin embedded biopsy samples, immunohistochemical evaluation of MET expression is a challenge [ 282 ].…”