Trace Metal Impurities Effects on the Formation of [64Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]Cu-ATSM)

Abstract

[⁶⁴Cu]Cu-diacetyl-bis(N⁴-methylthiosemicarbazone) ([⁶⁴Cu]Cu-ATSM) is a radioactive hypoxia-targeting therapeutic agent being investigated in clinical trials for malignant brain tumors. For the quality management of [⁶⁴Cu]Cu-ATSM, understanding trace metal impurities' effects on the chelate formation of ⁶⁴Cu and ATSM is important. In this study, we conducted coordination chemistry studies on metal-ATSM complexes. First, the effects of nonradioactive metal ions (Cu²⁺, Ni²⁺, Zn²⁺, and Fe²⁺) on the formation of [⁶⁴Cu]Cu-ATSM were evaluated. When the amount of Cu²⁺ or Ni²⁺ added was 1.2 mol or 288 mol, equivalent to ATSM, the labeling yield of [⁶⁴Cu]Cu-ATSM fell below 90%. Little effect was observed even when excess amounts of Zn²⁺ or Fe²⁺ were added to the ATSM. Second, these metals were reacted with ATSM, and chelate formation was measured using ultraviolet-visible (UV-Vis) absorption spectra. UV-Vis spectra showed a rapid formation of Cu²⁺ and the ATSM complex upon mixing. The rate of chelate formation by Ni²⁺ and ATSM was lower than that by Cu-ATSM. Zn²⁺ and Fe²⁺ showed much slower reactions with the ATSM than Ni²⁺. Trace amounts of Ni²⁺, Zn²⁺, and Fe²⁺ showed little effect on [⁶⁴Cu]Cu-ATSM' quality, while the concentration of impurity Cu²⁺ must be controlled. These results can provide process management tools for radiopharmaceuticals.

Keywords: [64Cu]Cu-ATSM; quality management; trace metal impurities.