Abstract
本論文包括三部份：(1)探討鎝99m標誌亞胺酚系列化合物之化學結構、放 射化學特性與生物分佈的相關性，並評估其中中性、親脂性特性鎝99m標 誌亞胺酚錯合物，作為腦血流灌注造影、心肌血流灌注造影及白血球標記 等之潛力；(2)利用錸之穩定同位素(Re185/186)進行錸-亞胺酚配位化學 的基礎研究、單晶X-ray繞射解析及化學光譜鑑定；(3)利用次細胞分佈試 驗，進行腦血流灌注造影劑Tc99m-d,l-HMPAO滯留腦細胞機制的研究。分 述如下：(1) 鎝99m標誌亞胺酚錯合物具中性、親脂性特性。其親脂性指 標LogP介於1.1至2.78之間，隨錯合物之-N-CnHm-N-骨架碳鏈長度增加而 增加，且骨架碳數增加對親脂性增高的效應，略高於支鏈碳數增加的效 應(即-(CH2)5-＞-(CH2)4-＞-CH2(CH3)2CH2-＞-(CH2)3-)；當錯合物苯環 上增加不同位置的甲氧基時，其對親脂性的影響依序為4-MeO＞5-MeO＞3- MeO。大白鼠動物分佈試驗中，本系列鎝99m標誌錯合物主行肝膽道代謝路 徑。於腦部幾無攝入與滯留現象。心肌攝入量與親脂性指標約為粗略拋物 線趨勢，在LogP=1.93至LogP=2.37之間心臟攝入量顯示高原區，且LogP ＞1.5時心肌一分鐘攝入量大於1%I.D.，顯示部份鎝99m錯合物可被心肌攝 入，然而，心肌攝入後並無滯留現象。選擇Tc99m-Ph(IP)2與Tc99m-d,l- HMPAO、Tc99m-L,L-ECD等進行白血球標記實驗，結果顯示Tc99m-Ph(IP)2 類似Tc99m-d,l-HMPAO具白血球標記之潛力。(2) 錸-亞胺酚與錸-胺酚錯 合物之單晶X-ray繞射解析中，μ-oxo-(ReO-DmPn(IP)2)2晶體的分子式 C38H40N4O7Re2，為綠色單斜晶系雙體結構，空間群族為P21/c，單位晶元 軸長：a= 11.2427A，b= 13.3736A，c= 12.4932A，β角度為108.11°， Z= 2，R=0.0314， Rw=0.0307；FTIR光譜圖譜顯示單一C=N吸收峰，知 DmPn(IP)2上C=N鍵的化學性質相同，即本配位子與Re錯合時四個給電子原 子(2N2O)均在赤道軸上。另一方面，μ-oxo-(ReO-Pn(AP)2)2晶體的分子 式C34H36N4O7Re2，為藍色單斜晶系雙體結構，空間群族為Cc，單位晶元 軸長：a= 13.846A，b= 27.001A，c= 9.689A，β角度為92.25°，Z= 4， R= 0.0439，Rw= 0.0492。以上二晶體均具線型O=Re-O-Re=O的結構，2N2O 與Re扭曲配位錯合形成不共平面形式。(3) 經大白鼠腦次細胞分佈試驗， 比較三種鎝99m錯合物在粒腺體層分佈順序為Tc99m-d,l-HMPAO＞Tc99m- meso-HMPAO＞Tc99m-PnAO。經流洗試驗，被流洗出粒腺體層的Tc99m-d,l- HMPAO物種已經轉成親水性物種(≧95.0%)；反之，Tc99m-meso-HMPAO與 Tc99m-PnAO則尚有55.8%與69.2%為親脂性物種。另在一基礎試驗顯示，存 於氯仿層的Tc99m-d,l-HMPAO與不同 pH值緩衝溶液作用時，較相同作用條 件下的Tc99m-meso-HMPAO與Tc99m-PnAO易於分解。是故吾人推測Tc99m-d, l-HMPAO滯留腦細胞機制為：進入腦細胞粒腺體層後，由於粒腺體膜內外 pH值之差異，而造成其分解為親水性產物，因而滯留於其中。 The thesis consists of three parts: (1) Investigation of quantitative structure-distribution relationships of Tc99m labeled imine phenols and assessment of their applications in nuclear medicine; (2) Synthesis, characterization and X-ray structure determination of rhenium(V)-complexes with tetradentate imine phenols and amine phenols; and (3) Study on retention behavior of the cerebral blood flow imaging agent, Tc99m-d,l-HMPAO, in the brain cells of rats. The contents of the three parts are summarized respectively as below:(1) The Tc99m labeled imine phenols were generally characterized to be neutral-lipophilic and the lipophilicity index (LogP) of the Tc99m-complexes under investigation were found to be in the range between 1.1 and 2.78. Lipophilicity of the Tc99m complexes increased with addition of the methyl groups into the alkylene diamine backbone as the order: -(CH2)5-＞-(CH2)4-＞- CH2(CH3)2CH2-＞-(CH2)3-. Besides, lipophilicity of the 99mTc complexes was enhanced with substitution of the methoxyl groups in the aromatic rings as in the order: 4-MeO＞5-MeO＞3-MeO. In rat biodistribution, the neutral-lipophilic Tc99m-complexes were found to secret predominantly via the hepatobiliary way. The brain uptakes for all the Tc99mcomplexes were negligible. The myocardial uptakes of the Tc99m-complexes were considerable at early period at postinjection and seemingly correlated in parabolic curve with the LogP values with a plateau ranging between 1.93 and 2.37. However, no significant retention in myocardium for the Tc99m imine phenols was found. One of the most stable complexes, Tc99m-Ph(IP)2 was further processed for the leukocytes labeling study. The Tc99m complex exhibited high leukocytes labeling efficiency and low elution rate, being comparable with the efficacy of the commercial leukocytes labeling agent, Tc99m-d,l-HMPAO.(2) In X-ray diffraction study of the Re(V)-complexes, the crystals of u-oxo-(ReO-DmPn(IP)2) with formula C38H40N4O7Re2 was found to be a green monoclinic dimer. The space group is P21c with a= 11.2427A, b= 13.3736A, c= 12.4932A, Beta=108.11, Z= 2, R=0.0314, Rw=0.0307. The FTIR spectrum shows the C=N stretch at 1597cm-1 and the Re=O stretch at 957cm-1, implying that Re is coordinated with 2N2O in the basal plan. The crystals of u-oxo-(ReO-Pn(AP)2) with formula C34H36N4O7Re2 was found to be a blue monoclinic dimers. The space group is Cc with a= 13.846A, b= 27.001A, c= 9.689A, Beta=92.25, Z= 4, R=0.0439, Rw=0.0492. Both of the aforementioned Re(V)-complexes exhibit a similar O=Re-O-Re=O structure and are six coordinated in a octahedron structure. (3) In subcellular distribution study by the brain cells of rats, the percentage of the Tc99m radioactivity of the Tc99m complexes found in mitochondria was in the order: Tc99m-d,l- HMPAO＞Tc99m-meso-HMPAO＞Tc99m-PnAO. The binding of both Tc99m- d,l-HMPAO and Tc99m-meso-HMPAO in the mitochondria was more endurable than Tc99m-PnAO, as evidenced by washing with SEH buffer. The washed-out Tc99m species out of mitochondria became hydrophilic at the extents as the order: ＞95% for Tc99m-d,l- HMPAO; 44.2% for Tc99m-meso-HMPAO; 30.8% for Tc99m-PnAO. In a separate study, Tc99m-d,l-HMPAO was found to be much more easily decomposed to be a hydrophilic Tc99m species owing to susceptibility with H+, compared to Tc99m-meso-HMPAO and Tc99m- PnAO. A hypothesis of the retention mechanism for Tc99m-d,l- HMPAO is suggested from the study as that the originally neutral-lipophilic Tc99m-d,l-HMPAO might readily diffuse into the mitochondria of the brain cells but then immediately be transformed into a hydrophilic Tc99m species in the light of pH gradient between outer and inner mitochondria, thereby being trapped and retained.