Isomeric Trimethylene and Ethylene Pendant-armed Cross-bridged Tetraazamacrocycles and in Vitro/in Vivo Comparisions of their Copper(II) Complexes

Citations Over TimeTop 15% of 2011 papers

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.

Related Papers

• → Selective mono N-alkylations of cyclen in one step syntheses(2007)45 cited
• → Three step vs one pot synthesis and X-ray crystallographic investigation of heptadentate triamide cyclen (1,4,7,10-tetraazacyclododecane) based ligands and some of their lanthanide ion complexes(2003)36 cited
• → Synthesis, characterization and kinetic studies of the cis-[RuCl2(cyclen)]+ complex(2002)20 cited
• → Cyano-bridged molecular squares: Synthesis and structures of [Ni(cyclen)]2[Pt(CN)4]2·6H2O, [Ni(cyclen)]2[Ni(CN)4]2·6H2O and [Mn(cyclen)]2[Ni(CN)4]2·6H2O(2005)24 cited
• → Artificial helix supramolecule by doubly p-xylyl bridged bis(ZnII–cyclen) (cyclen = 1,4,7,10-tetraazacyclododecane)(2023)1 cited