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

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• 作者：Antoinette Y. Odendaal ; Ashley L. Fiamengo ; Riccardo Ferdani ; Thaddeus J. Wadas ; Daniel C. Hill ; Yijie Peng ; Katie J. Heroux ; James A. Golen ; Arnold L. Rheingold ; Carolyn J. Anderson ; Gary R. Weisman ; Edward H. Wong
• 刊名：Inorganic Chemistry
• 出版年：2011
• 出版时间：April 4, 2011
• 年：2011
• 卷：50
• 期：7
• 页码：3078-3086
• 全文大小：916K
• 年卷期：v.50,no.7(April 4, 2011)
• ISSN：1520-510X

文摘

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 ⁶⁴Cu-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 ⁶⁴Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to ⁶⁴Cu-CB-TR2A (basic ethanol). The in vivo behavior of the ⁶⁴Cu complexes was evaluated in normal rats. Rapid and continual clearance of ⁶⁴Cu-CB-TR2A through the blood, liver, and kidneys suggests relatively good in vivo stability, albeit inferior to ⁶⁴Cu-CB-TE2A. Although ⁶⁴Cu-C3B-DO2A clears continually, the initial uptake is high and only about half is excreted within 22 h, suggesting poor stability and transchelation of ⁶⁴Cu 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.