標題: | 設計與開發 1H and 19F MRI 分子影像對比劑 Design and Development of 1H and 19F MRI COntrast Agent for Molecular Imaging |
作者: | 辛加安 Gyan Singh 王 雲銘 Dr. Yun-Ming Wang 分子醫學與生物工程研究所 |
關鍵字: | 甲基汞;分子成像;造影劑;硫化氫;水合狀態;Methylmercury;Molecular Imaging;Contrast agents;Hydrogen sulfide;Hydration status |
公開日期: | 2015 |
摘要: | 近年來,分子成像已經吸引了極大的關注。全身性動物研究與合適的成像技術,可以使我們動力學和分子在其完整和天然的生理狀態生化活性的可視化。為此,在最近幾年,許多螢光探針已經開發了用於檢測生物分子選擇性。然而,由於可能具有強烈的自體螢光,其不需要的光子吸收和散射被厚且不透明的動物組織影響,從而限制了他們用於體內的研究。為了解決這些限制,本論文意欲分別開發1H和19F-MRI造影劑作為甲基汞(CH3Hg+)和硫化氫的檢測(H2S)。造影劑被設計成在CH3Hg+ 和H2S有關的生物事件和轉導這些生物分子的活性在MR對比的變化。磁共振分子成像的應用程序將允許CH3Hg+ 和H2S檢測具有較高的空間(<100微米)和時間(〜1秒)的分辨率,且不使用任何電離輻射。 第一個項目集中在一個新的釓金屬MRI造影劑作為偵測CH3Hg+的合成與表徵。底層設計原理是基於CH3Hg+ 誘導desulferization消去反應。反應機理從而激活[Gd(DO3A-o-diThioAc)]並用FAB質譜和1H NMR光譜驗證結構。以[Eu(DO3A-o-diThioAc)]溶液進行發光壽命的測量,[Gd(DO3A-o-diThioAc)]改變水合狀態(q)值在CH3Hg+ 存在下從0.2到1.9。[Gd(DO3A-o-diThioAc)]顯示當加入1~3當量CH3Hg+時弛豫增強由62%增加至145%。此外以0.1 mmol/kg的[Gd(DO3A-o-diThioAc)]靜脈注射於暴露於CH3Hg+後小鼠,12,15,和22%的平均對比度增強被記錄在肝臟、腎和腸。因此,新設計的造影劑有潛力用於生物醫學應用中。 第二個項目在合成兩個具釓金屬的 19F-MRI造影劑並用於檢測硫化氫。該複合物合理設計於具大環分子的釓金屬錯合物。不幸的是,我們的初步研究表明設計的探針並不與硫化氫反應 Molecular imaging has attracted a great deal of attention in recent years. With suitable imaging techniques, whole-body small animal studies can allow us visualization of dynamics and biochemical activities of molecule in its intact and native physiological state. To this end, in the recent years, many fluorescence probes have been developed to detect biomolecule selectively. However, fluorescence probes due to their undesired photon absorption and scattering by thick, opaque animal tissue result in strong autofluorescence and thus limiting their utilization for in vivo studies. To address these limitations, the present thesis is intended to develop activatable or responsive 1H and 19F-MRI contrast agent for the detection of methyl mercury (CH3Hg+) and hydrogen sulfide (H2S), respectively. Contrast agents are designed to report on the CH3Hg+ and H2S related biological event and transduce the activity of these biomolecule as a change in MR contrast. MR molecular imaging applications will allow CH3Hg+ and H2S detection with high spatial (< 100 µm) and temporal (~1 s) resolution without any use of ionizing radiation. The first project focused on the synthesis and characterization of a new CH3Hg+ responsive Gd3+ based MRI contrast agent. The underlying design principle is based on CH3Hg+ induced desulferization elimination reaction. The reaction mechanism leading to activation of [Gd(DO3A-o-diThioAc)] was validated by fast atom bombardment (FAB) mass spectrometry, and 1H NMR spectroscopy. Luminescence lifetime measurements performed on solutions of [Eu(DO3A-o-diThioAc)] indicate that the hydration state (q) of [Gd(DO3A-o-diThioAc)] changes from 0.2 to 1.9 in the presence of CH3Hg+. [Gd(DO3A-o-diThioAc)] showed a relaxivity enhancement of 62 and 145% in the presence of 1 and 3 equiv. of CH3Hg+, respectively. Moreover, an average contrast enhancement of 12, 15, and 22% was recorded in liver, kidney, and intestine of mice exposed to CH3Hg+ after intravenous injection of [Gd(DO3A-o-diThioAc)] at a dose of 0.1 mmol/kg. Thus, the newly designed contrast agent has potential to be used in both ex vivo and in vivo bio-imaging of CH3Hg+ and could be useful for biomedical applications. The second project focused on the synthesis and characterization of two Gd3+ based 19F-MRI contrast agent for detection H2S. The complexes are rationally designed consisting of macrocyclic Gd3+ complex and a reporter fluorine moiety linked through a short H2S sensitive spacer. Unfortunately, our preliminary study suggest the design probe do not respond to H2S. |
URI: | http://140.113.39.130/cdrfb3/record/nctu/#GT079829805 http://hdl.handle.net/11536/127481 |
Appears in Collections: | Thesis |