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

✍ Scribed by Nathan E. Basken; Carla J. Mathias; Mark A. Green

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 140 KB
• Volume: 98
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.21570

✦ Synopsis

The Cu-PTSM (pyruvaldehyde bis(N 4 -methylthiosemicarbazonato)copper-(II)) and Cu-ATSM (diacetyl bis(N 4 -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 to HSA solutions 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 [ 64 Cu]Cu-PTSM and [ 64 Cu]Cu-ATSM from HSA. At 8:1 warfarin:HSA mole ratios, free [ 64 Cu]Cu-PTSM and [ 64 Cu]Cu-ATSM levels increased 300--500%. This was in contrast to solutions containing ibuprofen, a site IIIA drug; no increase in free [ 64 Cu]Cu-PTSM or [ 64 Cu]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, [ 64 Cu]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.