title: Comparison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and (64)Cu-NODAGA-E[c(RGDyK)]2; in vivo imaging studies in human xenograft tumors.
abstract: BACKGROUND
  The aim of this study was to synthesize and perform a side-by-side comparison of two new tumor-angiogenesis PET tracers (68)Ga-NODAGA-E[c(RGDyK)](2) and (64)Cu-NODAGA-E[c(RGDyK)](2) in vivo using human xenograft tumors in mice. Human radiation burden was estimated to evaluate potential for future use as clinical PET tracers for imaging of neo-angiogenesis.
  
  
  METHODS
  A (68)Ge/(68)Ga generator was used for the synthesis of (68)Ga-NODAGA-E[c(RGDyK)](2). (68)Ga and (64)Cu labeled NODAGA-E[c(RGDyK)](2) tracers were administrated in nude mice bearing either human glioblastoma (U87MG) or human neuroendocrine (H727) xenograft tumors. PET/CT scans at 3 time points were used for calculating the tracer uptake in tumors (%ID/g), integrin αVβ3 target specificity was shown by blocking with cold NODAGA-E[c(RGDyK)](2), and biodistribution in normal organs were also examined. From biodistribution data in mice human radiation-absorbed doses were estimated using OLINDA/EXM software.
  
  
  RESULTS
  (68)Ga-NODAGA-E[c(RGDyK)](2) was synthesized with a radiochemical purity of 89%-99% and a specific activity (SA) of 16-153 MBq/nmol. (64)Cu-NODAGA-E[c(RGDyK)](2) had a purity of 92%-99% and an SA of 64-78 MBq/nmol. Both tracers showed similar uptake in xenograft tumors 1h after injection (U87MG: 2.23 vs. 2.31%ID/g; H727: 1.53 vs. 1.48%ID/g). Both RGD dimers showed similar tracer uptake in non-tumoral tissues and a human radiation burden of less than 10 mSv with an administered dose of 200 MBq was estimated.
  
  
  CONCLUSIONS
  (68)Ga-NODAGA-E[c(RGDyK)](2) and (64)Cu-NODAGA-E[c(RGDyK)](2) can be easily synthesized and are both promising candidates for PET imaging of integrin αVβ3 positive tumor cells. (68)Ga-NODAGA-E[c(RGDyK)](2) showed slightly more stable tumor retention. With the advantage of in-house commercially (68)Ge/(68)Ga generators, (68)Ga-NODAGA-E[c(RGDyK)](2) may be the best choice for future clinical PET imaging in humans.
authors.affiliation: Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark. Electronic address: joxbol@sund.ku.dk.
authors.forename: Jytte
authors.initials: J
authors.lastname: Oxboel
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, DK-2100 Copenhagen, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Brandt-Larsen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, DK-2100 Copenhagen, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Schjoeth-Eskesen
authors.affiliation: Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, DK-2100 Copenhagen, Denmark.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Myschetzky
authors.affiliation: Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
authors.forename: Henrik H
authors.initials: HH
authors.lastname: El-Ali
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, DK-2100 Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Madsen
authors.affiliation: Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, DK-2100 Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjaer
mesh_terms: D000085:Acetates / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003301:Copper Radioisotopes; D005260:Female; D005710:Gallium Radioisotopes; D005909:Glioblastoma / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D011874:Radiometry; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: C572723:1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane; D000085:Acetates; D003301:Copper Radioisotopes; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid
keywords: (64)Cu; (68)Ga; Angiogenesis; Cancer; Integrin α(v)β(3); Molecular imaging; NODAGA; RGD dimer