The long and short of it: the influence of N-carboxyethyl versusN-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraamine macrocycles.

Academic Article

Abstract

  • A cross-bridged cyclam ligand bearing two N-carboxymethyl pendant arms (1) has been found to form a copper(II) complex that exhibits significantly improved biological behavior in recent research towards (64)Cu-based radiopharmaceuticals. Both the kinetic inertness and resistance to reduction of Cu-1 are believed to be relevant to its enhanced performance. To explore the influence of pendant arm length on these properties, new cross-bridged cyclam and cyclen ligands with longer N-carboxyethyl pendant arms, 2 and 4, and their respective copper(II) complexes have been synthesized. Both mono- as well as di-O-protonated forms of Cu-2 have also been isolated and structurally characterized. The spectral and structural properties of Cu-2 and Cu-4, their kinetic inertness in 5 M HCl, and electrochemical behavior have been obtained and compared to those of their N-carboxymethyl-armed homologs, Cu-1 and Cu-3. Only the cyclam-based Cu-1 and Cu-2 showed unusually high kinetic inertness towards acid decomplexation. While both of these complexes also exhibited quasi-reversible Cu(II)/Cu(I) reductions, Cu-2 is easier to reduce by a substantial margin of +400 mV, bringing it within the realm of physiological reductants. Similarly, of the cyclen-based complexes, Cu-4 is also easier to reduce than Cu-3 though both reductions are irreversible. Biodistribution studies of (64)Cu-labeled 2 and 4 were performed in Sprague Dawley rats. Despite comparable acid inertness to their shorter-armed congeners, both longer-armed ligand complexes have poorer bio-clearance properties. This inferior in vivo behavior may be a consequence of their higher reduction potentials.
  • Authors

  • Heroux, Katie J
  • Woodin, Katrina S
  • Tranchemontagne, David J
  • Widger, Peter CB
  • Southwick, Evan
  • Wong, Edward H
  • Weisman, Gary R
  • Tomellini, Sterling
  • Wadas, Thaddeus J
  • Anderson, Carolyn J
  • Kassel, Scott
  • Golen, James A
  • Rheingold, Arnold L
  • Status

    Publication Date

  • June 7, 2007
  • Keywords

  • Amines
  • Animals
  • Copper
  • Crystallography, X-Ray
  • Electrochemistry
  • Female
  • Kidney
  • Ligands
  • Liver
  • Macrocyclic Compounds
  • Molecular Structure
  • Organometallic Compounds
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Digital Object Identifier (doi)

    Start Page

  • 2150
  • End Page

  • 2162
  • Volume

  • 0
  • Issue

  • 21