Cu(II) bis(thiosemicarbazone) radiopharmaceutical binding to serum albumin

further definition of species dependence and associated substituent effects

Nathan E. Basken, Mark Green

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Introduction: The pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II) (Cu-PTSM) and diacetyl bis(N4-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.

Original languageEnglish (US)
Pages (from-to)495-504
Number of pages10
JournalNuclear Medicine and Biology
Volume36
Issue number5
DOIs
StatePublished - Jul 2009
Externally publishedYes

Fingerprint

Thiosemicarbazones
Radiopharmaceuticals
Serum Albumin
Albumins
Copper
Carbon
Ligands
Pyruvaldehyde
Diacetyl
Imines
Equidae
Papio
Amino Acid Substitution
Protein Binding
Hydrogen
Sheep
Cats
Swine
Dogs
Rabbits

Keywords

  • Copper radiopharmaceutical
  • Cu-ATSM
  • Cu-ETS
  • Cu-PTSM
  • PET radiopharmaceuticals
  • Serum albumin binding

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

@article{2745079b37d244a7945198becb589398,
title = "Cu(II) bis(thiosemicarbazone) radiopharmaceutical binding to serum albumin: further definition of species dependence and associated substituent effects",
abstract = "Introduction: The pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II) (Cu-PTSM) and diacetyl bis(N4-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.",
keywords = "Copper radiopharmaceutical, Cu-ATSM, Cu-ETS, Cu-PTSM, PET radiopharmaceuticals, Serum albumin binding",
author = "Basken, {Nathan E.} and Mark Green",
year = "2009",
month = "7",
doi = "10.1016/j.nucmedbio.2009.02.006",
language = "English (US)",
volume = "36",
pages = "495--504",
journal = "Nuclear Medicine and Biology",
issn = "0969-8051",
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TY - JOUR

T1 - Cu(II) bis(thiosemicarbazone) radiopharmaceutical binding to serum albumin

T2 - further definition of species dependence and associated substituent effects

AU - Basken, Nathan E.

AU - Green, Mark

PY - 2009/7

Y1 - 2009/7

N2 - Introduction: The pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II) (Cu-PTSM) and diacetyl bis(N4-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.

AB - Introduction: The pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II) (Cu-PTSM) and diacetyl bis(N4-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.

KW - Copper radiopharmaceutical

KW - Cu-ATSM

KW - Cu-ETS

KW - Cu-PTSM

KW - PET radiopharmaceuticals

KW - Serum albumin binding

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