Elucidation of the human serum albumin (HSA) binding site for the Cu-PTSM and Cu-ATSM radiopharmaceuticals

Nathan E. Basken, Carla J. Mathias, Mark A. Green

Research output: Contribution to journalArticle

22 Scopus citations


The Cu-PTSM (pyruvaldehyde bis(N4-methylthiosemicarbazonato) copper-(II)) and Cu-ATSM (diacetyl bis(N4-methylthiosemicarbazonato) copper(II)) radiopharmaceuticals exhibit strong, species-dependent binding to human serum albumin (HSA), while Cu-ETS (ethylglyoxal bis(thiosemicarbazonato) copper(II)) appears to only exhibit nonspecific binding to human and animal serum albumins. This study examines the structural basis for HSA binding of Cu-PTSM and Cu-ATSM via competition with drugs having known albumin binding sites. Warfarin, furosemide, ibuprofen, phenylbutazone, benzylpenicillin, and cephmandole were added toHSAsolutions at drug:HSA mole ratios from 0 to 8:1, followed by quantification of radiopharmaceutical binding to HSA by ultrafiltration. Warfarin, a site IIA drug, progressively displaced both [ 64Cu]Cu-PTSM and [64Cu]Cu-ATSM from HSA. At 8:1 warfarin:HSA mole ratios, free [64Cu]Cu-PTSM and [ 64Cu]Cu-ATSM levels increased 300-500%. This was in contrast to solutions containing ibuprofen, a site IIIA drug; no increase in free [ 64Cu]Cu-PTSM or [64Cu]Cu-ATSM was observed except at high ibuprofen:HSA ratios, where secondary ibuprofen binding to the IIA site may cause modest radiopharmaceutical displacement. By contrast, and consistent with earlier findings suggesting Cu-ETS exhibits only nonspecific associations, [64Cu]Cu-ETS binding to HSA was unaffected by the addition of drugs that bind in either site. We conclude that the species-dependence of Cu-PTSM and Cu-ATSM albumin binding arises from interaction(s) with the IIA site of HSA.

Original languageEnglish (US)
Pages (from-to)2170-2179
Number of pages10
JournalJournal of Pharmaceutical Sciences
Issue number6
StatePublished - Jun 2009
Externally publishedYes


  • Albumin
  • Distribution
  • PET
  • Preclinical pharmacokinetics
  • Protein binding

ASJC Scopus subject areas

  • Pharmaceutical Science

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