Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A
Department of Radiopharmaceutical Chemistry, Eukui Medical School, Japan.
J Nucl Med. 1997 Jul;38(7):1155-60.
An ideal hypoxia imaging agent should have high membrane permeability for easy access to intracellular mitochondria and low redox potential to confer stability in normal tissue, but it should be able to be reduced by mitochondria with abnormally high electron concentrations in hypoxic cells. In this context, nitroimidazole residues are not considered to be essential. In this study, Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), a 62Cu-bisthiosemicarbazone complex, with high membrane permeability and low redox potential, was evaluated as a possible hypoxia imaging agent, using electron spin resonance spectrometry and the Langendorff isolated perfused rat heart model as well as rat heart left anterior descending occlusion model.
Nonradioactive Cu-ATSM was incubated with rat mitochondria, after which reduction of Cu(II) to Cu(I) was measured with electron spin resonance. As a model of hypoxic mitochondria, rotenone (Complex I inhibitor)-treated mitochondria were used.
In this study, Cu-ATSM was reduced by hypoxic but not by normal mitochondria.
Thus, retention of 62Cu-ATSM was studied serially in perfused rat hearts under conditions of normoxia (95% O2 + 5% CO2), hypoxia (95% N2 + 5% CO2) and reoxygenation (95% O2 + 5% CO2). In normoxia and reoxygenation, 62Cu-ATSM injected as a single bolus showed low retention (23.77% and 22.80%, respectively) 15 min after injection, but retention was increased markedly under hypoxic conditions (81.10%). Also, in the in vivo left anterior descending occluded rat heart model, 62Cu-ATSM retention was inversely correlated with accumulation of 201Tl, a relative myocardial blood flow marker.
理想的缺氧显像剂应具有高膜通透性以便易于进入细胞内线粒体，且具有低氧化还原电位以在正常组织中保持稳定，但它应能够被缺氧细胞中电子浓度异常高的线粒体还原。在这种情况下，硝基咪唑残基不被认为是必需的。在本研究中，使用电子自旋共振光谱法、Langendorff离体灌注大鼠心脏模型以及大鼠心脏左前降支闭塞模型，评估了具有高膜通透性和低氧化还原电位的62Cu-双硫代半卡巴腙配合物Cu（II）-二乙酰基双（N4-甲基硫代半卡巴腙）（Cu-ATSM）作为一种可能的缺氧显像剂。
将非放射性Cu-ATSM与大鼠线粒体孵育，然后用电子自旋共振测量Cu（II）还原为Cu（I）的情况。使用鱼藤酮（复合体I抑制剂）处理的线粒体作为缺氧线粒体的模型。
在本研究中，Cu-ATSM被缺氧线粒体还原，但不被正常线粒体还原。
因此，在常氧（95% O2 + 5% CO2）、缺氧（95% N2 + 5% CO2）和复氧（95% O2 + 5% CO2）条件下，对灌注大鼠心脏中62Cu-ATSM的滞留情况进行了连续研究。在常氧和复氧条件下，单次推注注射的62Cu-ATSM在注射后15分钟时显示出低滞留率（分别为23.77%和22.80%），但在缺氧条件下滞留率显著增加（81.10%）。此外，在体内左前降支闭塞大鼠心脏模型中，62Cu-ATSM的滞留与相对心肌血流标志物201Tl的蓄积呈负相关。
