Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64Cu-SarAr immunoconjugates.

Abstract

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement (18)F-FDG. Copper-64 ((64)Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1-N-(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6] eicosane-1,8-diamine) for use in developing a new class of tumor-specific (64)Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with (64)Cu resulted in >95% of the (64)Cu being chelated by the immunoconjugate. Specific activities of at least 10 microCi/microg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after (64)Cu labeling. Solid-phase radioimmunoassays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15-20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5-10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (<5% injected dose per gram). MicroPET imaging confirmed significant uptake of the tracer in GD-2-positive tumors, with minimal uptake in GD-2-negative tumors and nontarget tissues such as liver. The (64)Cu-SarAr-mAb system described here is potentially applicable to (64)Cu-PET imaging with a broad range of antibody or peptide-based imaging agents.

• Authors: Stephan D Voss, Suzanne V Smith, Nadine DiBartolo, Lacey J McIntosh, Erika M Cyr, Ali A Bonab, Jason L J Dearling, Edward A Carter, Alan J Fischman, S Ted Treves, Stephen D Gillies, Alan M Sargeson, James S Huston, Alan B Packard
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 44 Pg. 17489-93 (Oct 30 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17954911 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

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
• Copper Radioisotopes
• Immunoconjugates

Topics

• Aniline Compounds (chemistry)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (chemistry)
• Cell Line, Tumor
• Copper Radioisotopes (chemistry)
• Humans
• Immunoconjugates (immunology)
• Melanoma (diagnosis)
• Mice
• Molecular Structure
• Neoplasm Transplantation
• Neuroblastoma (diagnosis)
• Positron-Emission Tomography (methods)