title: Imaging cancer using PET--the effect of the bifunctional chelator on the biodistribution of a (64)Cu-labeled antibody.
abstract: BACKGROUND
  Use of copper radioisotopes in antibody radiolabeling is challenged by reported loss of the radionuclide from the bifunctional chelator used to label the protein. The objective of this study was to investigate the relationship between the thermodynamic stability of the (64)Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with (64)Cu using these chelators in tumor-bearing mice.
  
  
  METHODS
  The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH(2)-Bn-NOTA): 6-[p-(bromoacetamido)benzyl]-1, 4, 8, 11-tetraazacyclotetradecane-N, N', N'', N'''-tetraacetic acid (BAT-6): S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododocane tetraacetic acid (p-NH(2)-Bn-DOTA): 1,4,7,10-tetraazacyclododocane-N, N', N", N"'-tetraacetic acid (DOTA): and 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine (SarAr)] were conjugated to the anti-GD2 antibody ch14.18, and the modified antibody was labeled with (64)Cu and injected into mice bearing subcutaneous human melanoma tumors (M21) (n = 3-5 for each study). Biodistribution data were obtained from positron emission tomography images acquired at 1, 24 and 48 hours post-injection, and at 48 hours post-injection a full ex vivo biodistribution study was carried out.
  
  
  RESULTS
  The biodistribution, including tumor targeting, was similar for all the radioimmunoconjugates. At 48 h post-injection, the only statistically significant differences in radionuclide uptake (p < 0.05) were between blood, liver, spleen and kidney. For example, liver uptake of [(64)Cu]ch14.18-p-NH(2)-Bn-NOTA was 4.74 ± 0.77 per cent of the injected dose per gram of tissue (%ID/g), and for [(64)Cu]ch14.18-SarAr was 8.06 ± 0.77 %ID/g. Differences in tumor targeting correlated with variations in tumor size rather than which BFC was used.
  
  
  CONCLUSIONS
  The results of this study indicate that differences in the thermodynamic stability of these chelator-Cu(II) complexes were not associated with significant differences in uptake of the tracer by the tumor. However, there were significant differences in tracer concentration in other tissues, including those involved in clearance of the radioimmunoconjugate (e.g., liver and spleen).
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA. jason.dearling@childrens.harvard.edu
authors.forename: Jason L J
authors.initials: JL
authors.lastname: Dearling
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Voss
authors.forename: Patricia
authors.initials: P
authors.lastname: Dunning
authors.forename: Erin
authors.initials: E
authors.lastname: Snay
authors.forename: Frederic
authors.initials: F
authors.lastname: Fahey
authors.forename: Suzanne V
authors.initials: SV
authors.lastname: Smith
authors.forename: James S
authors.initials: JS
authors.lastname: Huston
authors.forename: Claude F
authors.initials: CF
authors.lastname: Meares
authors.forename: S Ted
authors.initials: ST
authors.lastname: Treves
authors.forename: Alan B
authors.initials: AB
authors.lastname: Packard
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002614:Chelating Agents / Q000737:chemistry*; D003301:Copper Radioisotopes; D003432:Cross-Linking Reagents / Q000737:chemistry*; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000276:immunology / Q000493:pharmacokinetics*; D008545:Melanoma / Q000000981:diagnostic imaging* / Q000473:pathology; D051379:Mice; D049268:Positron-Emission Tomography
chemical_list: C525132:1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo(6.6.6)eicosane-1,8-diamine; D000814:Aniline Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002614:Chelating Agents; D003301:Copper Radioisotopes; D003432:Cross-Linking Reagents; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid