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Isomeric trimethylene and ethylene pendant-armed cross-bridged tetraazamacrocycles and in vitro/in vivo comparisions of their copper(II) complexes.

Odendaal AY, Fiamengo AL, Ferdani R, Wadas TJ, Hill DC, Peng Y, Heroux KJ, Golen JA, Rheingold AL, Anderson CJ, Weisman GR, Wong EH - Inorg Chem (2011)

Bottom Line: Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible.The reaction conditions for preparing (64)Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to (64)Cu-CB-TR2A (basic ethanol).These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, USA.

ABSTRACT
Ethylene cross-bridged tetraamine macrocycles are useful chelators in coordination, catalytic, medicinal, and radiopharmaceutical chemistry. Springborg and co-workers developed trimethylene cross-bridged analogues, although their pendant-armed derivatives received little attention. We report here the synthesis of a bis-carboxymethyl pendant-armed cyclen with a trimethylene cross-bridge (C3B-DO2A) and its isomeric ethylene-cross-bridged homocyclen ligand (CB-TR2A) as well as their copper(II) complexes. The in vitro and in vivo properties of these complexes are compared with respect to their potential application as (64)Cu-radiopharmaceuticals in positron emission tomography (PET imaging). The inertness of Cu-C3B-DO2A to decomplexation is remarkable, exceeding that of Cu-CB-TE2A. Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible. The reaction conditions for preparing (64)Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to (64)Cu-CB-TR2A (basic ethanol). The in vivo behavior of the (64)Cu complexes was evaluated in normal rats. Rapid and continual clearance of (64)Cu-CB-TR2A through the blood, liver, and kidneys suggests relatively good in vivo stability, albeit inferior to (64)Cu-CB-TE2A. Although (64)Cu-C3B-DO2A clears continually, the initial uptake is high and only about half is excreted within 22 h, suggesting poor stability and transchelation of (64)Cu to proteins in the blood and/or liver. These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.

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Isomeric dicarboxymethyl pendant-armed cross-bridged ligands 1 and 2.
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fig2: Isomeric dicarboxymethyl pendant-armed cross-bridged ligands 1 and 2.

Mentions: A limited number of pendant-armed derivatives of these ligands have been investigated, though none with ionizable functional groups.6,7 We were intrigued whether such a trimethylene cross-bridged tetraamine derivative would have distinct in vitro or in vivo behavior compared to its most closely related ethylene cross-bridged analogues. We report here the synthesis and characterization of a dicarboxymethyl pendant-armed cyclen with such a cross-bridge, C3B-DO2A (1), as well as its isomeric ethylene cross-bridged homocyclen ligand, CB-TR2A (2) (Figure 2). Their copper(II) complexes have been prepared and fully characterized. Finally, 64Cu radiolabeling and animal biodistribution studies have been carried out for comparison with each other, and with the widely used chelator CB-TE2A, with the overall goal of developing the optimal 64Cu-cross-bridged complex for conjugation to biomolecules as potential PET imaging agents.


Isomeric trimethylene and ethylene pendant-armed cross-bridged tetraazamacrocycles and in vitro/in vivo comparisions of their copper(II) complexes.

Odendaal AY, Fiamengo AL, Ferdani R, Wadas TJ, Hill DC, Peng Y, Heroux KJ, Golen JA, Rheingold AL, Anderson CJ, Weisman GR, Wong EH - Inorg Chem (2011)

Isomeric dicarboxymethyl pendant-armed cross-bridged ligands 1 and 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3065210&req=5

fig2: Isomeric dicarboxymethyl pendant-armed cross-bridged ligands 1 and 2.
Mentions: A limited number of pendant-armed derivatives of these ligands have been investigated, though none with ionizable functional groups.6,7 We were intrigued whether such a trimethylene cross-bridged tetraamine derivative would have distinct in vitro or in vivo behavior compared to its most closely related ethylene cross-bridged analogues. We report here the synthesis and characterization of a dicarboxymethyl pendant-armed cyclen with such a cross-bridge, C3B-DO2A (1), as well as its isomeric ethylene cross-bridged homocyclen ligand, CB-TR2A (2) (Figure 2). Their copper(II) complexes have been prepared and fully characterized. Finally, 64Cu radiolabeling and animal biodistribution studies have been carried out for comparison with each other, and with the widely used chelator CB-TE2A, with the overall goal of developing the optimal 64Cu-cross-bridged complex for conjugation to biomolecules as potential PET imaging agents.

Bottom Line: Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible.The reaction conditions for preparing (64)Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to (64)Cu-CB-TR2A (basic ethanol).These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, USA.

ABSTRACT
Ethylene cross-bridged tetraamine macrocycles are useful chelators in coordination, catalytic, medicinal, and radiopharmaceutical chemistry. Springborg and co-workers developed trimethylene cross-bridged analogues, although their pendant-armed derivatives received little attention. We report here the synthesis of a bis-carboxymethyl pendant-armed cyclen with a trimethylene cross-bridge (C3B-DO2A) and its isomeric ethylene-cross-bridged homocyclen ligand (CB-TR2A) as well as their copper(II) complexes. The in vitro and in vivo properties of these complexes are compared with respect to their potential application as (64)Cu-radiopharmaceuticals in positron emission tomography (PET imaging). The inertness of Cu-C3B-DO2A to decomplexation is remarkable, exceeding that of Cu-CB-TE2A. Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible. The reaction conditions for preparing (64)Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to (64)Cu-CB-TR2A (basic ethanol). The in vivo behavior of the (64)Cu complexes was evaluated in normal rats. Rapid and continual clearance of (64)Cu-CB-TR2A through the blood, liver, and kidneys suggests relatively good in vivo stability, albeit inferior to (64)Cu-CB-TE2A. Although (64)Cu-C3B-DO2A clears continually, the initial uptake is high and only about half is excreted within 22 h, suggesting poor stability and transchelation of (64)Cu to proteins in the blood and/or liver. These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.

Show MeSH