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Synthesis of Cyclen-Based Copper Complexes as a Potential Estrogen Receptor Ligand  

Park, Jeong-Chan (Department of Molecular Medicine Kyungpook National University School of Medicine)
Pandya, Darpan N. (Department of Molecular Medicine Kyungpook National University School of Medicine)
Jeon, Hak-Rim (Department of Molecular Medicine Kyungpook National University School of Medicine)
Lee, Sang-Woo (Department of Nuclear Medicine Kyungpook National University School of Medicine)
Ahn, Byeong-Cheol (Department of Nuclear Medicine Kyungpook National University School of Medicine)
Lee, Jae-Tae (Department of Nuclear Medicine Kyungpook National University School of Medicine)
Yoo, Jeong-Soo (Department of Molecular Medicine Kyungpook National University School of Medicine)
Publication Information
Nuclear Medicine and Molecular Imaging / v.41, no.4, 2007 , pp. 326-334 More about this Journal
Abstract
Purpose: The estrogen receptor (ER), which is over-expressed in ER-positive breast tumors, has been imaged by positron emission tomography (PET) using $[^{18}F]$ labeled estrogen ligands, especially $[^{18}F]FES$. However, $[^{18}F]$ has relatively short-lived half-life ($t_{1/2}$ =1.8 h) and the labeling yield of radio-fluorination is usually low compared with $^{64}Cu\;(t_{1/2}=12.7\;h)$. 1,4,7,10-tetraazacyclododecane (cyclen) is used to form stable metal complexes with copper, indium, gallium, and gadolinium. With these in mind, we prepared cyclen-based Cu complexes which mimic estradiol in aspect of two hydroxyl groups. Materials and Methods: 1.7-Protected cyclen, 1.7-bis (benzyloxycarbonyl)-cyclen was synthesized according to the reported procedure. After introducing two 4-benzyloxybenzyl groups at 4,10-positions, the benzyloxycarbonyl and benzyl groups were removed at the same time by hydrogenation on Pd/C to give 1,7-bis(4-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane (1). Results: The prepared ligand 1 was fully characterized by $^1H,\;^{13}C$ NMR, and mass spectrometer. The synthesized ligand was reacted with copper chloride and copper perchlorate to give copper complexes $[Cu(1)]^{2+}2(CIO_4^-)\;and\;[Cu(1)Cl]^+Cl^-$ which were confirmed by high-resolution mass (FAB). Conclusion: We successfully synthesized a cyclen derivative of which two phenol groups are located on trans position of N-atoms. And, two Cu(ll) complexes of +2 and +1 overall charge, were prepared as a potential PET tracers for ER imaging.
Keywords
estrogen receptor ligand; $^{64}Cu$; positron emission tomography; cyclen derivative;
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