Imaging cancer using PET--the effect of the bifunctional chelator on the biodistribution of a (64)Cu-labeled antibody.

Abstract

INTRODUCTION:

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: Jason L J Dearling, Stephan D Voss, Patricia Dunning, Erin Snay, Frederic Fahey, Suzanne V Smith, James S Huston, Claude F Meares, S Ted Treves, Alan B Packard
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 38 Issue 1 Pg. 29-38 (Jan 2011) ISSN: 1872-9614 [Electronic] United States
• PMID: 21220127 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo(6.6.6)eicosane-1,8-diamine
• Aniline Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Chelating Agents
• Copper Radioisotopes
• Cross-Linking Reagents
• Heterocyclic Compounds
• Heterocyclic Compounds, 1-Ring
• Immunoconjugates
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• 1,4,7-triazacyclononane-N,N',N''-triacetic acid

Topics

• Aniline Compounds (chemistry)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (chemistry)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Chelating Agents (chemistry)
• Copper Radioisotopes
• Cross-Linking Reagents (chemistry)
• Female
• Heterocyclic Compounds (chemistry)
• Heterocyclic Compounds, 1-Ring (chemistry)
• Humans
• Immunoconjugates (chemistry, immunology, pharmacokinetics)
• Melanoma (diagnostic imaging, pathology)
• Mice
• Positron-Emission Tomography