Abstract
銅(II)與四牙胺酚或亞胺酚的錯化物，推測具電中性、親脂性、小分子量 特性，符合正子放射斷層攝影藥物需求，本研究旨在探討放射性銅(II)標 幟四牙胺酚與亞胺酚系列錯化物之X線晶體結構、放射化學與動物體內分 佈特性，並評估其成為正子放射斷層攝影腦造影藥物之可行性。其中， 銅(II)四牙亞胺酚系列錯化物之放射化學與生物分佈特性，已有文獻報導 ，本研究僅著眼於其X線晶體結構數據；其次，放射性銅標幟四牙胺酚系 列錯化物放射化學與動物體內分佈特性之研究，以較長半化期之銅( II)-64模擬銅(II)-62進行測試。依本研究所獲一系列13個銅(II)亞胺酚 錯化物的X線晶體結構數據，顯示銅(II)亞胺酚多為四配位、單核結構， 具電中性、小分子量特性。增加烯基二胺的碳鏈長度時，將使得此類錯化 物有較大平面扭曲程度、二Cu-O-N平面間夾角與N-Cu-N角度，並使得此類 錯化物傾向採用單核結構。此類錯化物中，與銅(II)親和的水分子、水楊 醛上的氧原子，均可能與溶劑分子形成氫鍵，不利於通過細胞膜，進而影 響其腦細胞攝入量。銅(II)胺酚錯化物易於製備，亦具電中性與親脂性， 其親脂性低於銅(II)亞胺酚錯化物；銅(II)胺酚錯化物的親脂性與烯基二 胺的碳鏈長度、烷基取代基數目成正比。胺酚配位子為一伸展平面結構， 與銅(II)錯合後則為醫摺疊、雙核、平面角錐結構。銅(II)-64胺酚錯化 物的大白鼠動物分佈顯示，血液清除速率快，主要代謝路徑為肝膽道，部 分經由泌尿道排除，腦及心肌等特殊器官無顯著攝入與滯留現象；推測此 現象肇因於銅胺酚錯化物具雙核結構，分子量過大；或肇因於與銅(II)親 和的水分子、配位子上的氧原子與氮原子，均可能與溶劑分子形成氫鍵， 不易通過細胞膜。 Tetradentate imine and amine phenols with an N2O2 donor set can chelate Cu(II) atom to form the Cu(II) complexes with neutral- lipophilicity and low molecular weight, being premised to develop as a cerebral blood flow agent. The main purpose of this study is to identify the crystal structures, chemical, and biological characteristics of the Cu(II) imine and amine phenols. The potential of these Cu(II)-62 complexes has been evaluated as a clinical tracer for Positron Emission Tomography (PET). Preliminary characteristics of the Cu(II) complexes with a series of tetradentate N2O2 ligands, including imine phenols, have been reported lately. Here we have then focused on crystal structures of a series of Cu(II) imine phenols. In addition, because the short half-life of Cu-62 is undesirable for laboratory research, we have employed longer lived Cu-64 readily available from the Tsing Hua open pool reactor (THOR), as the radiocopper in this study. Thirteen Cu(II) imine phenols and methoxyl-substituted imine phenols with varying lengths of the alkylenediamine backbone have been prepared and their structures determined by X-ray diffraction. Most of the Cu(II) imine phenols studied show four-coordinate, mononuclear, and neutral complexes with low molecular weights. Elongation of the alkylenediamine backbone results in the degree of distortion from square plane, the enlargement of dihedral and N-Cu-N angles, and the tendency to adopt a mononuclear structure. The tendency to form H-bonding between the solvent molecule and the phenol O or the water molecule attached to Cu(II) ion limits the diffusibility of the Cu(II) imine phenols to cross the cell membrane. Cu(II) amine phenols are readily formed and are also neutral-lipophilic. These complexes are less lipophilic than those with the corresponding Cu(II) imine phenols. Lipophilicity of the Cu(II) amine phenols is enhanced either by the addition of methyl groups to the alkylenediamine backbone or by the alkyl substitution in the bridging carbon atoms. An alkaline condition to prevent protonation of the amine N atoms and to facilitate deprotonation of the phenol groups is required for the coordination of amine phenol ligands to Cu(II) ion. In solid state, the free ligand exhibits a stretched out, planar conformation which is significantly distinct from the folded, dinuclear, square-planar based pyramidal one upon Cu(II) coordination. In rat biodistribution studies the Cu(II)-64 amine phenols are cleared from the blood rather rapidly and excreted mainly via hepatobiliary way and partially via urinary system. Judging from their very low uptake in any particular organ, none of the Cu(II) complexes studied appears to be suitable for PET imaging. The very low uptake of Cu(II)-64 amine phenols in the brain cells may be attributed to the H- bonding formation of phenol O, amine N atoms, and the solvent molecule attached to Cu(II) ion, as well as the large molecular weight due to the dinuclear association between Cu(II) and phenol O atoms.