Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64Cu-SarAr immunoconjugates
Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64Cu-SarAr immunoconjugates
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DOI：
10.1073/pnas.0708436104
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发表时间：
2007-10-30
影响因子：
11.1
通讯作者：
Packard, Alan B.
中科院分区：
文献类型：
--
作者：
Voss, Stephan D.;Smith, Suzanne V.;Packard, Alan B.
正电子发射断层扫描（PET）的发展取决于新的放射性示踪剂的开发，将补充F-18-FDG。铜-64（Cu-64）是一种很有前途的PET放射性核素，特别是用于抗体靶向成像，但常规螯合物的高体内不稳定性限制了其临床应用。本工作的目的是评价新型螯合剂SarAr（1-N-（4-氨基苄基）-3，6，10，13，16，19-六氮杂双环[6.6.6]二十烷-1，8-二胺）用于开发一类新的肿瘤特异性Cu-64放射性药物，用于成像神经母细胞瘤和黑色素瘤。抗GD 2单克隆抗体（mAb）14.G2a及其嵌合衍生物ch14.18靶向神经母细胞瘤和黑色素瘤上过表达的双唾液酸神经节苷脂。使用碳二亚胺偶联将两种mAb缀合至SarAr。用Cu-64进行放射性标记导致>95%的Cu-64被免疫缀合物螯合。常规实现至少10 μ Ci/μ g（1 Ci = 37 GBq）的比活度，并且在Cu-64标记后不需要额外的纯化。固相放射免疫分析和完整细胞结合试验证实保留的生物活性。无胸腺裸小鼠皮下接种的生物分布研究。神经母细胞瘤（IMR-6、NMB-7）和黑色素瘤（M21）异种移植物显示，注射后24小时，每克注射剂量的15-20%在肿瘤中累积，只有5-10%的注射剂量累积在肝脏中，该值低于其他螯合剂通常观察到的值。GD 2阴性肿瘤异种移植物的摄取显著降低（
The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement F-18-FDG. Copper-64 (Cu-64) 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 tumorspecific Cu-64 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 Cu-64 resulted in >95% of the Cu-64 being chelated by the immunoconjugate. Specific activities of at least 10 mu Ci/mu g (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after Cu-64 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 (