title: Cu(II) bis(thiosemicarbazone) radiopharmaceutical binding to serum albumin: further definition of species dependence and associated substituent effects.
abstract: BACKGROUND
  The pyruvaldehyde bis(N(4)-methylthiosemicarbazonato)copper(II) (Cu-PTSM) and diacetyl bis(N(4)-methylthiosemicarbazonato)copper(II) (Cu-ATSM) radiopharmaceuticals exhibit strong, species-dependent binding to the IIA site of human serum albumin (HSA), while the related ethylglyoxal bis(thiosemicarbazonato)copper(II) (Cu-ETS) radiopharmaceutical appears to exhibit only nonspecific binding to HSA and animal serum albumins.
  
  
  METHODS
  To further probe the structural basis for the species dependence of this albumin binding interaction, we examined protein binding of these three radiopharmaceuticals in solutions of albumin and/or serum from a broader array of mammalian species (rat, sheep, donkey, rabbit, cow, pig, dog, baboon, mouse, cat and elephant). We also evaluated the albumin binding of several copper(II) bis(thiosemicarbazone) chelates offering more diverse substitution of the ligand backbone.
  
  
  RESULTS
  Cu-PTSM and Cu-ATSM exhibit a strong interaction with HSA that is not apparent with the albumins of other species, while the binding of Cu-ETS to albumin is much less species dependent. The strong interaction of Cu-PTSM with HSA does not appear to simply correlate with variation, relative to the animal albumins, of a single amino acid lining HSA's IIA site. Those agents that selectively interact with HSA share the common feature of only methyl or hydrogen substitution at the carbon atoms of the diimine fragment of the ligand backbone.
  
  
  CONCLUSIONS
  The interspecies variations in albumin binding of Cu-PTSM and Cu-ATSM are not simply explained by unique amino acid substitutions in the IIA binding pocket of the serum albumins. However, the specific affinity for this region of HSA is disrupted when substituents bulkier than a methyl group appear on the imine carbons of the copper bis(thiosemicarbazone) chelate.
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Basken
authors.forename: Mark A
authors.initials: MA
authors.lastname: Green
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism; D003300:Copper / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity; D013379:Substrate Specificity; D013882:Thiosemicarbazones / Q000737:chemistry*
chemical_list: D002614:Chelating Agents; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D012709:Serum Albumin; D013882:Thiosemicarbazones; D003300:Copper