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

Nucl Med Biol. 2014 Mar;41(3):259-67. doi: 10.1016/j.nucmedbio.2013.12.003. Epub 2013 Dec 12.

Abstract

Introduction: 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.

Conclusion: (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.

Keywords: (64)Cu; (68)Ga; Angiogenesis; Cancer; Integrin α(v)β(3); Molecular imaging; NODAGA; RGD dimer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemistry*
  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic*
  • Copper Radioisotopes*
  • Female
  • Gallium Radioisotopes
  • Glioblastoma / blood supply
  • Glioblastoma / diagnostic imaging
  • Glioblastoma / pathology*
  • Heterocyclic Compounds, 1-Ring / chemistry*
  • Humans
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / diagnostic imaging
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacokinetics
  • Positron-Emission Tomography / methods*
  • Radiochemistry
  • Radiometry
  • Tissue Distribution
  • Tomography, X-Ray Computed

Substances

  • 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane
  • Acetates
  • Copper Radioisotopes
  • Gallium Radioisotopes
  • Heterocyclic Compounds, 1-Ring
  • Oligopeptides
  • arginyl-glycyl-aspartic acid