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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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(a) Cross-bridged tetraazamacrocycles; (b) CB-TE2A; (c−d) Trimethylene cross-bridged tetraazamacrocycles.
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fig1: (a) Cross-bridged tetraazamacrocycles; (b) CB-TE2A; (c−d) Trimethylene cross-bridged tetraazamacrocycles.

Mentions: The family of ethylene cross-bridged tetraamine macrocyclic ligands (Figure 1a) has become valuable as metal chelators in coordination, catalytic, as well as medicinal chemistry.1,2 Their pendant-armed derivatives have been especially useful in endowing corresponding metal complexes with remarkable kinetic inertness. One lead bifunctional chelator for copper radiometals has been the bis-carboxymethyl pendant-armed cross-bridged cyclam, CB-TE2A (Figure 1b). Its 64Cu-labeled bioconjugates have significantly improved in vivo behavior and superior inertness toward radiometal loss and are of interest for positron emission tomography (PET) imaging applications.2,3 We have been developing a second generation of cross-bridged ligands aimed at improving the kinetics of complexation and decreasing nontarget organ accumulation.(4) Springborg and co-workers previously reported an interesting series of trimethylene cross-bridged tetraazamacrocycles and their coordination chemistry (Figure 1c, 1d).1,5


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)

(a) Cross-bridged tetraazamacrocycles; (b) CB-TE2A; (c−d) Trimethylene cross-bridged tetraazamacrocycles.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: (a) Cross-bridged tetraazamacrocycles; (b) CB-TE2A; (c−d) Trimethylene cross-bridged tetraazamacrocycles.
Mentions: The family of ethylene cross-bridged tetraamine macrocyclic ligands (Figure 1a) has become valuable as metal chelators in coordination, catalytic, as well as medicinal chemistry.1,2 Their pendant-armed derivatives have been especially useful in endowing corresponding metal complexes with remarkable kinetic inertness. One lead bifunctional chelator for copper radiometals has been the bis-carboxymethyl pendant-armed cross-bridged cyclam, CB-TE2A (Figure 1b). Its 64Cu-labeled bioconjugates have significantly improved in vivo behavior and superior inertness toward radiometal loss and are of interest for positron emission tomography (PET) imaging applications.2,3 We have been developing a second generation of cross-bridged ligands aimed at improving the kinetics of complexation and decreasing nontarget organ accumulation.(4) Springborg and co-workers previously reported an interesting series of trimethylene cross-bridged tetraazamacrocycles and their coordination chemistry (Figure 1c, 1d).1,5

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