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The long and short of it: the influence of N-carboxyethyl versus N-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...
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Published in: | Dalton transactions : an international journal of inorganic chemistry 2007-01 (21), p.2150-2162 |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 1477-9226 1477-9234 |
DOI: | 10.1039/b702938a |