In vivo transchelation of copper-64 from TETA-octreotide to superoxide dismutase in rat liver
In vivo transchelation of copper-64 from TETA-octreotide to superoxide dismutase in rat liver
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DOI：
10.1021/bc990167l
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发表时间：
2000-07-01
影响因子：
4.7
通讯作者：
Anderson, CJ
中科院分区：
文献类型：
--
作者：
Bass, LA;Wang, M;Anderson, CJ
由于放射性金属标记肽在诊断成像和靶向放射治疗领域的应用，了解它们的代谢命运非常重要。铜的放射性同位素（Cu-64，T-1/2 = 12.7 h；Cu-67，T-1/2 = 62 h）已被标记为单克隆抗体 (mAb) 和肽，并在 PET 成像和癌症靶向放射治疗领域得到应用。 Copper-64-TETA-D-Phe(1)-octreotide ([64Cu]TETA-OC) 已被证明在体外和体内均能与生长抑素受体结合，并且该药物可抑制大鼠体内生长抑素受体阳性肿瘤的生长。然而，Copper-64-TETA-OC 在血液、肝脏和骨髓中表现出活性保留，表明 Cu-64 可能在体内从 TETA-OC 解离。本研究的目的是确定 Cu-64 是否从 [Cu-64]TETA-OC 解离并与大鼠肝脏中的蛋白质超氧化物歧化酶 (SOD) 结合。使用 SOD 特异性凝胶电泳测定和尺寸排阻色谱法检查正常大鼠中 [Cu-64]TETA-OC 的肝脏代谢。尺寸排阻色谱显示，注射后 20 小时大鼠肝脏中的主要代谢物的分子量为 32 kDa。专门用于检测 SOD [硝基蓝四唑 (NBT)] 的凝胶电泳测定表明，从大鼠肝匀浆中分离出的 Cu-64 标记的蛋白质与 SOD 发生共迁移。评估铜放射性药物的代谢命运表明，Cu(II) 从大环螯合剂（如 TETA）中解离，并与高浓度的蛋白质（即大鼠肝脏中的 SOD）结合。
An understanding of the metabolic fate of radiometal-labeled peptides is important due to their application in the areas of diagnostic imaging and targeted radiotherapy. Radioisotopes of copper (Cu-64, T-1/2 = 12.7 h; Cu-67, T-1/2 = 62 h) have been labeled to monoclonal antibodies (mAbs) and peptides and have applications in the areas of PET imaging and targeted radiotherapy of cancer. Copper-64-TETA-D-Phe(1)-octreotide ([64Cu]TETA-OC) has been shown to bind to the somatostatin receptor, both in vitro and in vivo, and this agent inhibited the growth of somatostatin-receptor positive tumors in rats. Copper-64-TETA-OC, however, showed a retention of activity in the blood, liver, and bone marrow, suggesting possible dissociation of Cu-64 from TETA-OC in vivo. The purpose of this study was to determine if Cu-64 dissociates from [Cu-64]TETA-OC and binds to the protein, superoxide dismutase (SOD) in rat liver. The liver metabolism of [Cu-64]TETA-OC was examined in normal rats using a gel-electrophoresis assay specific for SOD and size-exclusion chromatography. The major metabolite in rat liver at 20 h postinjection had a molecular weight of 32 kDa as shown by size-exclusion chromatography. A gel electrophoresis assay specific for the detection of SOD [nitro-blue tetrazolium (NBT)] showed that a Cu-64-labeled protein isolated from rat liver homogenates comigrated with SOD. Evaluating the metabolic fate of copper radiopharmaceuticals demonstrated that Cu(II) dissociates from macrocyclic chelators such as TETA and binds to proteins in high concentrations, namely SOD in rat liver.