Imaging c-Met expression using 18F-labeled binding peptide in human cancer xenografts.

Weihua Li,Jiankai Xu,Shaodong Cao,Hongqun Zheng,Peng Xiao,Xiuan Xu,Waldemar Debinski

doi:10.1371/journal.pone.0199024

Abstract

Objectivesc-Met is a receptor tyrosine kinase shown inappropriate expression and actively involved in progression and metastasis in most types of human cancer. Development of c-Met-targeted imaging and therapeutic agents would be extremely useful. Previous studies reported that c-Met-binding peptide (Met-pep1, YLFSVHWPPLKA) specifically targets c-Met receptor. Here, we evaluated 18F-labeled Met-pep1 for PET imaging of c-Met positive tumor in human head and neck squamous cell carcinoma (HNSCC) xenografted mice.Methodsc-Met-binding peptide, Met-pep1, was synthesized and labeled with 4-nitrophenyl [18F]-2-fluoropropionate ([18F]-NPFP) ([18F]FP-Met-pep1). The cell uptake, internalization and efflux of [18F]FP-Met-pep1 were assessed in UM-SCC-22B cells. In vivo pharmacokinetics, blocking and biodistribution of the radiotracers were investigated in tumor-bearing nude mice by microPET imaging.ResultsThe radiolabeling yield for [18F]FP-Met-pep1 was over 55% with 97% purity. [18F]FP-Met-pep1 showed high tumor uptake in UM-SCC-22B tumor-bearing mice with clear visualization. The specificity of the imaging tracer was confirmed by significantly decreased tumor uptake after co-administration of unlabeled Met-pep1 peptides. Prominent uptake and rapid excretion of [18F]FP-Met-pep1 was also observed in the kidney, suggesting this tracer is mainly excreted through the renal-urinary routes. Ex vivo biodistribution showed similar results that were consistent with microPET imaging data.ConclusionsThese results suggest that 18F-labeled c-Met peptide may potentially be used for imaging c-Met positive HNSCC cancer in vivo and for c-Met-targeted cancer therapy.

Highlights

The specificity of the imaging tracer was confirmed by significantly decreased tumor uptake after co-administration of unlabeled Met-pep1 peptides
Prominent uptake and rapid excretion of [18F]FP-Met-pep1 was observed in the kidney, suggesting this tracer is mainly excreted through the renal-urinary routes
These results suggest that 18F-labeled c-Met peptide may potentially be used for imaging cMet positive head and neck squamous cell carcinoma (HNSCC) cancer in vivo and for c-Met-targeted cancer therapy

Summary

Introduction

Mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase for hepatocyte growth factor (HGF), and activation of c-Met can lead to tumor progression, metastasis and angiogenesis [1,2,3]. Anti-c-Met monoclonal antibodies (mAb) were rapidly developed as nuclear imaging agents for treating various human cancers [19,20,21], but poor tumor penetration due to the big size of molecules, as well as liver or bone marrow toxicity, has limited applications [22]. Zhao et al identified a c-Met binding peptide (Met-pep, YLFSVHWPPLKA) targets explicitly c-Met receptor from a phage display of a combinatorial peptide library [24]. This peptide labeled with Iodine-125 reacted with c-Met on the cell surface and competed with the binding of HGF to c-Met. the image quality was not optimal using this tracer. When the iodine is labeled on the tyrosine residue, deiodination can occur thyroid accumulation of radioactivity especially when the tracer is internalized inside the cells

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