title: Synthesis and comparative evaluation of novel (64)Cu-labeled high affinity cell-specific peptides for positron emission tomography imaging of tumor vasculature.
abstract: Tumor angiogenesis, the formation of new tumor blood supply, has been recognized as a hallmark of cancer and represents an important target for clinical management of various angiogenesis-dependent solid tumors. Previously, by screening a bacteriophage peptide library we have discovered the FHT-peptide sequence that binds specifically to bone marrow-derived tumor vasculature with high affinity. Here in an effort to determine the potential of the FHT-peptide for in vivo positron emission tomography (PET) imaging of aggressive tumor vasculature we studied four FHT-derivatives: NOTA-FHT, NOTA-(FHT)2, NOTA-PEG-FHT, and NOTA-PEG-(FHT)2. These peptide analogs were synthesized, labeled with the PET radionuclide (64)Cu, and characterized side-by-side with small animal PET and computed tomography imaging (microPET/CT) at 1 h, 4 h, and 24 h post injection in a subcutaneous Lewis lung carcinoma (LLC) tumor model. Because of its excellent in vivo kinetic properties and high tumor-to-background ratio, the (64)Cu-NOTA-FHT radiopeptide was selected for more detailed evaluation. Blocking studies with excess of unlabeled peptide showed specific and peptide mediated (64)Cu-NOTA-FHT tumor uptake. Biodistribution experiments in the same tumor model confirmed microPET/CT imaging results. Human radiation absorbed dose extrapolated from rodent biodistribution of (64)Cu-NOTA-FHT revealed favorable dosimetry profile. The findings from this investigation warrant further development of (64)Cu-NOTA-FHT as a potential targeted diagnostic radiopharmaceutical for PET imaging of aggressive tumor vasculature.
authors.affiliation: Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: joseph_merrill@med.unc.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Merrill
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: krzysztof_krajewski@med.unc.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Krajewski
authors.affiliation: Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: hong_yuan@med.unc.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: jonathan_frank@med.unc.edu.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Frank
authors.affiliation: Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biomedical Engineering, North Carolina State University, Raleigh, NC 27695, USA. Electronic address: dslalush@ncsu.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Lalush
authors.affiliation: NewYork Presbyterian Hospital, Weill Cornell Medical Center, New York, NY 10065, USA. Electronic address: cpatters@nyp.org.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Department of Biomedical Engineering, North Carolina State University, Raleigh, NC 27695, USA; Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA. Electronic address: anveleva@ncsu.edu.
authors.forename: Anka N
authors.initials: AN
authors.lastname: Veleva
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000737:chemistry*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D011829:Radiation Dosage; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D003301:Copper Radioisotopes; D010455:Peptides
keywords: (64)Cu-labeled cell-specific peptides; Diagnostic PET radiopharmaceuticals; Molecular imaging; Radiation absorbed dose; Tumor angiogenesis