title: 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.affiliation: Department of Radiology and Division of Nuclear Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. stephan.voss@childrens.harvard.edu
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Voss
authors.forename: Suzanne V
authors.initials: SV
authors.lastname: Smith
authors.forename: Nadine
authors.initials: N
authors.lastname: DiBartolo
authors.forename: Lacey J
authors.initials: LJ
authors.lastname: McIntosh
authors.forename: Erika M
authors.initials: EM
authors.lastname: Cyr
authors.forename: Ali A
authors.initials: AA
authors.lastname: Bonab
authors.forename: Jason L J
authors.initials: JL
authors.lastname: Dearling
authors.forename: Edward A
authors.initials: EA
authors.lastname: Carter
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fischman
authors.forename: S Ted
authors.initials: ST
authors.lastname: Treves
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.forename: Alan M
authors.initials: AM
authors.lastname: Sargeson
authors.forename: James S
authors.initials: JS
authors.lastname: Huston
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; D003301:Copper Radioisotopes / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology*; D008545:Melanoma / Q000175:diagnosis*; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000175:diagnosis*; D049268:Positron-Emission Tomography / Q000379:methods*
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; D003301:Copper Radioisotopes; D018796:Immunoconjugates