Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential.
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.


CONCLUSIONS
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.
Fujibayashi
Y
Y
Department of Radiopharmaceutical Chemistry, Eukui Medical School, Japan.
Taniuchi
H
H
Yonekura
Y
Y
Ohtani
H
H
Konishi
J
J
Yokoyama
A
A
D000818:Animals; D001921:Brain / Q000378:metabolism; D015687:Cell Hypoxia; D002463:Cell Membrane Permeability; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D004578:Electron Spin Resonance Spectroscopy; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology; D013367:Submitochondrial Particles / Q000378:metabolism; D013882:Thiosemicarbazones / Q000493:pharmacokinetics
D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D012402:Rotenone; C052629:copper pyruvaldehyde bis(N(4)-methylthiosemicarbazone) complex