Species dependence of [⁶⁴Cu]Cu-Bis(thiosemicarbazone) radiopharmaceutical binding to serum albumins☆

Abstract 

Introduction

Interactions of three copper(II) bis(thiosemicarbazone) positron emission tomography radiopharmaceuticals with human serum albumin, and the serum albumins of four additional mammalian species, were evaluated.

Methods

⁶⁴Cu-labeled diacetyl bis(N⁴-methylthiosemicarbazonato)copper(II) (Cu-ATSM), pyruvaldehyde bis(N⁴-methylthiosemicarbazonato)copper(II) (Cu-PTSM) and ethylglyoxal bis(thiosemicarbazonato)copper(II) (Cu-ETS) were synthesized and their binding to human, canine, rat, baboon and porcine serum albumins quantified by ultrafiltration. Protein binding was also measured for each tracer in human, porcine, rat and mouse serum.

Results

The interaction of these neutral, lipophilic copper chelates with serum albumin is highly compound- and species-dependent. Cu-PTSM and Cu-ATSM exhibit particularly high affinity for human serum albumin (HSA), while the albumin binding of Cu-ETS is relatively insensitive to species. At HSA concentrations of 40 mg/ml, “% free” (non-albumin-bound) levels of radiopharmaceutical were 4.0±0.1%, 5.3±0.2% and 38.6±0.8% for Cu-PTSM, Cu-ATSM and Cu-ETS, respectively.

Conclusions

Species-dependent variations in radiopharmaceutical binding to serum albumin may need to be considered when using animal models to predict the distribution and kinetics of these compounds in humans.

Keywords: Copper-64, Cu-PTSM, Cu-ETS, Cu-ATSM, Serum albumin binding