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Copper-62-ATSM: A New Hypoxia Imaging Agent with High Membrane Permeability and Low Redox Potential

Departments of Radiopharmaceutical Chemistry and Biomedicai Imaging and Biomedicai Imaging Research Center, Fukui Medical School, Fukui; Departments of Genetic Biochemistry, Nuclear Medicine and Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, School of Medicine, Kyoto University, Kyoto; The First Department of Internal Medicine, Fukushima Medical College, Fukushima, Japan

Correspondence: For correspondence or reprints contact: Yasuhisa Fujibayashi, PhD, Dept. of Genetic Biochemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, 606, Japan.

ABSTRACT

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. Methods: 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. Results: In this study, Cu-ATSM was reduced by hypoxic but not by normal mitochondria. Conclusion: 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% C0₂). 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 ²⁰¹TI, a relative myocardial blood flow marker.

Key Words: copper-62-ATSM • hypoxia • mitochondria

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