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研究生:張智偉
研究生(外文):Chi-Wei Chang
論文名稱:機械臂半自動化合成核醫正子造影劑及其在荷腫瘤動物的生物特性與分子造影研究
論文名稱(外文):The robotic syntheses of PET tracers and their biological characterization and molecular imaging in tumor-bearing animal models
指導教授:王信二
指導教授(外文):Hsin-Ell Wang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生物醫學影像暨放射科學系暨研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:103
中文關鍵詞:放射性探針[11C]乙基膽鹼[11C]膽鹼微正子電腦斷層造影
外文關鍵詞:radioprobes[11C]ethylcholine[11C]cholinemicro positron emission tomography (microPET)
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利用機械臂半自動化合成系統合成六種放射性探針 (如[18F]FUdR用於細胞分化、 [11C]ethylcholine及[11C]choline用於細胞膜合成、[18F]FMISO用於缺氧細胞、[18F]FHBG及[18F]FHPG用於HSV1-tk基因表現),作為分子造影劑進行微正子電腦斷層造影研究及生物分布特性研究。經由20Ne(d, α)18F核反應產生[18F]F2氟化標幟劑,標幟有機三丁基錫前驅物,進行放射性氟去錫化反應,合成[18F]FUdR。在帶有NG4TL4肉瘤的FVB/n小鼠上進行生物分布特性研究及微正子電腦斷層造影研究。
經由14N(p, α)11C核反應產生[11C]乙基碘及[11C]甲基碘標幟劑,分別用以合成[11C]ethylcholine及[11C]choline。在[11C]乙基碘製備方法中,使用分子篩乾燥劑[11C]ethylcholine的放射化學產率可獲得改進,[11C]ethylcholine及[11C]choline在兩種腫瘤動物模式中進行放射藥物在小鼠體內的生物分布特性研究,在五種腫瘤動物模式中進行微正子電腦斷層造影研究。
經由18O(p, n)18F核反應產生[18F]HF,以合成[18F]FMISO、[18F]FHBG及 [18F]FHPG,在[11C]ethylcholine、[11C]choline、[18F]FMISO、[18F]FHBG 及[18F]FHPG 的純化方法中使用固相萃取法而不採用HPLC方法,可減少合成時間。在C3H小鼠植入KHT肉瘤14天後,進行小鼠體內[18F]FMISO的生物分布特性研究及微正子電腦斷層造影研究。從微正子電腦斷層造影結果,發現[18F]FMISO在KHT肉瘤中有明顯的吸收,說明KHT肉瘤內存在缺氧細胞。
用於合成放射性探針的機械臂半自動化合成系統,是具有高穩定性、高再現性的系統。使用該系統可以製備出具高放射化學純度及高放射化學產率的分子造影的放射性探針,這些放射性探針已經被應用於臨床前的研究(有些甚至已應用於臨床的研究),並有滿意的結果。
Six radioprobes for molecular imaging with positron emission tomography (PET) (e.g. 5-[18F]fluoro-2’-deoxyuridine ([18F]FUdR) for proliferation; [11C]ethylcholine and [11C]choline for cell membrane synthesis; [18F]FMISO for hypoxia; [18F]FHBG and [18F]FHPG for HSV1-tk gene expression) were synthesized using a semi-automated robotic system. The biological properties of these probes were characterized using biodistribution studies and microPET imaging of appropriate animal models.
The fluorinating agent [18F]F2 was produced via the 20Ne(d, α)18F nuclear reaction for [18F]FUdR synthesis. [18F]FUdR was prepared via fluorodestannylation reaction from its organotin precursor. Biodistribution study and microPET imaging of [18F]FUdR in NG4TL4 sarcoma-bearing FVB/n mice were performed.
The 11C-labeling agents [11C]ethyl iodide and [11C]methyl iodide were produced from [11C]CO2 via the 14N(p, ��)11C nuclear reaction for [11C]ethylcholine and [11C]choline synthesis, respectively. Molecular sieves (4 Å), an alternative drying agent, was used in [11C]ethyl iodide preparation and the radiochemical yield of [11C]ethylcholine was improved. In biodistribution study, two tumor animal models were employed to compare the tumor specificity of [11C]ethylcholine and [11C]choline. The microPET imaging studies were performed in five different tumor-bearing animal models.
[18F]HF was produced via the 18O(p, n)18F reaction for [18F]FMISO, [18F]FHBG and [18F]FHPG synthesis. The solid phase extraction method was employed in the purification of [11C]ethylcholine, [11C]choline, [18F]FMISO, [18F]FHBG and [18F]FHPG without HPLC and the synthesis time was reduced. The biodistribution studies and the microPET imaging of [18F]FMISO were performed on day 14 after KHT sarcoma implantation.
Preparation of radioprobes using the automated robotic system is highly reliable and reproducible. Sufficient radioactivity of molecular imaging probes were prepared with high radiochemical purity (all greater than 97%) and radiochemical yield. The radiation burden for the operators was largely reduced. These self-prepared radiotracers have been subjected to preclinical studies (even for clinical applications, e.g. [18F]FMISO and [11C]choline) and gave satisfactory results.
Contents of Figures
page
Fig. 1 The mechanisms and localization of the tumor imaging agents in
the tumor cell. 8
Fig. 2 Biochemical pathways of FdUrd. 9
Fig. 3 The three major potential metabolic pathways of 11C-choline. 11
Fig. 4 Raiolabeled choline analogs. 12
Fig. 5 The mechanism of intracellular trapping of nitroimidazoles. 13
Fig. 6 18F-labeled analogs of nitroimidazole. 14
Fig. 7 Schematic for imaging herpes simplex virus 1 thymidine kinase
reporter gene (HSV1-tk) expression with reporter probes 124I- or
131I-labeled FIAU and 18F-labeled FHBG. 15
Fig. 8 The scheme of automated robotic synthesis system of [18F]FUdR. 20
Fig. 9 The diagram of the semi-automated robotic system for the
radiosynthesis of [11C]ethylcholine and [11C]choline. 23
Fig. 10 The scheme of automated robotic synthesis system of [18F]FHBG
and [18F]FHPG. 31
Fig. 11 The semi-automated robotic system for synthesis of radiodrugs. 32
Fig. 12 Semi-preparative chromatogram of crude [18F]FUdR. 33
Fig. 13 HPLC chromatograms of [18F]FUdR final product. 34
Fig. 14 Thin layer chromatogram of [18F]FUdR. 34
Fig. 15 [18F]FUdR dynamic imaging of FVB/n mouse (NG4TL4). 36
Fig. 16 (A) Radio-chromatogram of [11C]ethylcholine and [11C]choline by
analytical HPLC. 38
Fig. 16 (B) Ultraviolet chromatogram of authentic ethylcholine and choline
by analytical HPLC. 38
Fig. 17 Biodistribution of [11C]choline (upper) and [11C]ethylcholine (lower)
in C26/tk-luc tumor mouse model after i.v. injection. 40
Fig. 18 Biodistribution of [11C]choline (upper) and [11C]ethylcholine (lower)
in GBM tumor mouse model after i.v. injection. 40
Fig. 19 The dynamic mPET imaging of C26/tk-luc-bearing BALB/c mouse
and HepG2-bearing SCID mouse at 15 min after administration
of 37 MBq of tracer. 41
Fig. 20 The dynamic mPET imaging of ARO-bearing NOD/SCID mouse,
GBM-bearing SCID mouse and HT29-bearing SCID mouse at
15 min after administration of 37 MBq of tracer. 42
Fig. 21 Thin layer chromatogram of [18F]FMISO. 43
Fig. 22 Radio-chromatogram of [18F]FMISO by analytical HPLC. Ultraviolet
chromatogram of authentic FMISO by analytical HPLC. 43
Fig. 23 The microPET imaging of KHT sarcoma-bearing C3H mouse at
30 min, 60 min, 120 min and 240 min after administration of
[18F]FMISO. 45
Fig. 24 (A) Radio-chromatogram of [18F]FHBG by analytical HPLC.
(B) Ultraviolet chromatogram of authentic [19F]FHBG by
analytical HPLC. 47
Fig. 25 (A) Radio-chromatogram of [18F]FHPG by analytical HPLC.
(B) Ultraviolet chromatogram of authentic [19F]FHPG by
analytical HPLC. 47
Fig. 26 Radio-chromatogram of [18F]FHBG and [18F]FHPG by TLC. 48

Contents of Tables
page
Table 1. Molecular and functional alterations in cancer. 7
Table 2. The distribution of radioactivity in organs and tissues of NG4TL4 sarcoma-bearing FVB/n mice after intravenous injection of
[18F]FUdR. 35
Table 3. Reaction parameters and results of batch productions of
[11C]ethylcholine and [11C]choline syntheses. 39
Table 4. Biodistribution of [18F]FMISO in KHT sarcoma -bearing C3H mice
after intravenous injection of 5.5 MBq of [18F]FMISO. 44
Table 5. Radioactivity accumulated in muscle and tumor derived from
microPET images at 240 min post injection of 5.5 MBq of
[18F]FMISO in C3H mice bearing KHT sarcoma. 45



Contents of Schemes
page
Scheme 1. Chemical synthesis of the precursor (3’,5’-di-O-acetyl-5-
tributylstannyl-2’-deoxyuridine) and radiosynthesis of 5-18F-
fluoro-2’-deoxyuridine ([18F]FUdR). 19
Scheme 2. The synthesis scheme of ethylcholine iodide. 22
Scheme 3. The radiosynthesis scheme of [11C]ethylcholine. 23
Scheme 4. The radiosynthesis scheme of [11C]choline. 24
Scheme 5. Synthesis of (2’-nitro-1’-imidazolyl)-2-O-acetyl-3-O-tosylpropanol 26
Scheme 6. Radiosynthesis of [18F]fluoromisonidazole. 28
Scheme 7. Radiosynthesis of [18F]FHBG and [18F]FHPG. 30
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