title: Novel (64)Cu- and (68)Ga-labeled RGD conjugates show improved PET imaging of α(ν)β(3) integrin expression and facile radiosynthesis.
abstract: PET with (18)F-labeled arginine-glycine-aspartic acid (RGD) peptides can visualize and quantify α(ν)β(3) integrin expression in patients, but radiolabeling is complex and image contrast is limited in some tumor types. The development of (68)Ga-RGD peptides would be of great utility given the convenience of (68)Ga production and radiolabeling, and (64)Cu-RGD peptides allow for delayed imaging with potentially improved tumor-to-background ratios.
  
  
  METHODS
  We used the chelators DOTA,1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), and 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) to radiolabel the cyclic pentapeptide c(RGDfK) with (68)Ga or (64)Cu. NODAGA-c(RGDfK) was labeled at room temperature with both radionuclides within 10 min. Incubation at 95°C for up to 30 min was used for the other conjugates. The affinity profile of the metallopeptides was evaluated by a cell-based receptor-binding assay. Small-animal PET studies and biodistribution studies were performed in nude mice bearing subcutaneous U87MG glioblastoma xenografts.
  
  
  RESULTS
  The conjugates were labeled with a radiochemical purity greater than 97% and specific activities of 15-20 GBq/μmol. The affinity profile was similar for all metallopeptides and comparable to the reference standard c(RGDfV). In the biodistribution studies, all compounds demonstrated a relatively similar tumor and normal organ uptake at 1 h after injection that was comparable to published data on (18)F-labeled RGD peptides. At 18 h after injection, however, (64)Cu-NODAGA-c(RGDfK) and (64)Cu-CB-TE2A-c(RGDfK) showed up to a 20-fold increase in tumor-to-organ ratios. PET studies demonstrated high-contrast images of the U87MG tumors at 18 h, confirming the biodistribution data.
  
  
  CONCLUSIONS
  The ease of radiolabeling makes (68)Ga-NODAGA-c(RGDfK) an attractive alternative to (18)F-labeled RGD peptides. The high tumor-to-background ratios of (64)Cu-NODAGA-c(RGDfK) and (64)Cu-CB-TE2A-c(RGDfK) at 18 h warrant testing of (64)Cu-labeled RGD peptides in patients.
authors.affiliation: Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Dumont
authors.forename: Friederike
authors.initials: F
authors.lastname: Deininger
authors.forename: Roland
authors.initials: R
authors.lastname: Haubner
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Weber
authors.forename: Melpomeni
authors.initials: M
authors.lastname: Fani
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D003287:Contrast Media / Q000494:pharmacology; D003301:Copper Radioisotopes / Q000494:pharmacology*; D005260:Female; D005710:Gallium Radioisotopes / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D013696:Temperature; D013997:Time Factors
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D003301:Copper Radioisotopes; D005710:Gallium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010455:Peptides; C047981:arginyl-glycyl-aspartic acid