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.
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.
Heroux
Katie J
KJ
Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, USA.
Woodin
Katrina S
KS
Tranchemontagne
David J
DJ
Widger
Peter C B
PC
Southwick
Evan
E
Wong
Edward H
EH
Weisman
Gary R
GR
Tomellini
Sterling A
SA
Wadas
Thaddeus J
TJ
Anderson
Carolyn J
CJ
Kassel
Scott
S
Golen
James A
JA
Rheingold
Arnold L
AL
D000588:Amines / Q000737:chemistry*; D000818:Animals; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D005260:Female; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000588:Amines; D008024:Ligands; D047028:Macrocyclic Compounds; D009942:Organometallic Compounds; D003300:Copper