Synthesis, Copper(II) Complexation, 64Cu-Labeling, and Bioconjugation of a New Bis(2-pyridylmethyl) Derivative of 1,4,7-Triazacyclononane

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• 作者：Gilles Gasser ; Linda Tjioe ; Bim Graham ; Matthew J. Belousoff ; Stefanie Juran ; Martin Walther ; Jens-Uwe Kü ; nstler ; Ralf Bergmann ; Holger Stephan ; Leone Spiccia
• 刊名：Bioconjugate Chemistry
• 出版年：2008
• 出版时间：March 2008
• 年：2008
• 卷：19
• 期：3
• 页码：719 - 730
• 全文大小：456K
• 年卷期：v.19,no.3(March 2008)
• ISSN：1520-4812

文摘

A new ligand derivative of 1,4,7-triazacyclononane (TACN), 2-[4,7-bis(2-pyridylmethyl)-1,4,7-triazacyclononan-1-yl]acetic acid (6), has been synthesized and its complexation behavior toward Cu²⁺ ions investigated. The ligand 6 has been characterized by spectroscopic methods, and a molecular structure of a corresponding Cu(II) complex has been elucidated by single-crystal X-ray analysis. The suitability of 6 for conjugation to peptide substrates has been shown by amide coupling of 6 to the stabilized derivative of bombesin (BN), βAla-βAla-[Cha¹³, Nle¹⁴]BN(7–14), to give the conjugate 8. The free ligand 6 and the bioconjugate 8 were labeled with ⁶⁴Cu²⁺, and the resulting complexes, ⁶⁴Cu⊂6 and ⁶⁴Cu⊂8, were found to be stable in the presence of a large excess of a competing ligand (cyclam) or copper-seeking superoxide dismutase (SOD), as well as in rat plasma. Biodistribution studies of ⁶⁴Cu⊂8 in Wistar rats showed a high activity uptake into the pancreas (5.76 ± 0.25 SUV, 5 min p.i.; 3.93 ± 0.25 SUV, 1 h p.i.), which is the organ with high levels of gastrin-releasing peptide receptor (GRPR). This receptor is overexpressed in a large number of breast and prostate carcinomas. The novel ⁶⁴Cu⊂6 complex had a dominating influence on the nonspecific activity biodistribution of its BN conjugate, since the distribution data of ⁶⁴Cu⊂6 are similar to those of ⁶⁴Cu⊂8. The ⁶⁴Cu complexes exhibited a low activity accumulation in the liver tissue and an extensive renal clearance, which was distinctively different to the biodistribution of ⁶⁴CuCl₂, suggesting that ⁶⁴Cu⊂6 does not undergo significant demetalation, but rather exhibits high in vivo stability.