放射性標幟分子之製備與生物試驗以作為腦瘤與巴金森氏病診斷之應用研究

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研究生：	樊修秀 Farn, Shiou-Shiow
論文名稱：	放射性標幟分子之製備與生物試驗以作為腦瘤與巴金森氏病診斷之應用研究 Preparation and Biological Assessment of Imaging Agents for Diagnosis of Brain Tumor and Parkinson’s Disease
指導教授：	俞鐘山 Yu, Chung-Shan
口試委員:	林俊成 Lin, Chun-Cheng 簡敦誠 Chien, Tun-Cheng 林武智 Lin, Wuu-Jyh 顏若芳 Yen, Ruoh-Fang 鄭澄意 Cheng, Cheng-Yi
學位類別：	博士 Doctor
系所名稱：	原子科學院 - 生醫工程與環境科學系 Department of Biomedical Engineering and Environmental Sciences
論文出版年：	2018
畢業學年度：	106
語文別：	中文
論文頁數：	135
中文關鍵詞：	腦瘤、環氧化酶酵素、多巴胺D2接受體、多巴胺轉運體、芬布芬、分析方法確效、巴金森氏病
外文關鍵詞：	brain tumor, cyclooxygenase enzyme, dopamine receptor, dopamine transporter,, fenbufen, method validation, Parkinson’s disease
相關次數：	點閱：1 下載：0
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腦瘤(brain tumor)與帕金森氏病(Parkinson’s disease)是全球關切注目的健康議題與焦點。本研究分為三部分，第一部分：以環氧化酶酵素作為研究標的，開發[18F]FFOA 5腦瘤正子造影劑。第二部分：以多巴胺轉運體作為研究標的，開發[68Ga]IPCAT-NOTA 28 多巴胺轉運體正子造影劑。第三部分：針對多巴胺D2接受體造影劑[123I]IBZM定量問題，開發[123I]IBZM放射化學純度分析方法與確效。
第一部分：由市售化合物4-bromobiphenyl作為起始物進行Friedel-Crafts reation 合成溴化芬布芬1，產率93 %。下一步進行醯胺耦合反應合成溴化辛基醯胺芬布芬2，產率87 %。再經由鈀金屬催化進行錫化反應合成三甲基錫化辛基醯胺芬布芬3，產率60 %。三步驟合成總產率50 %，放射性合成經由[18F]F2進行親電子性取代，合成最終產物[18F]FFOA 5，放射產率16%，比活度4 GBq/μmole。[18F]FFOA 5對於COX-1及COX-2酵素的半結合抑制值(IC50)，分別是26.5 μM與32.7 μM。從體外安定性試驗與PET影像分析數據來看，相較於[18F]FOFA，[18F]FFOA 5的in vitro藥物安定性長達30分鐘(t1/2 = 30 min)與明顯改善[18F]FOFA的脫氟(defuorination)情形(t1/2 = 10 min)。[18F]FFOA 5明顯的累積在C6 Glioma腦瘤小鼠的肺臟(70 %ID/g)，約為C6 Glioma腦瘤大鼠(30 %ID/g)的兩倍多，而且從C6 Glioma腦瘤大鼠的PET影像分析數據得知，腦部吸收值2.5 %ID/g以及腫瘤吸收值3.9 %ID/g。儘管[18F]FFOA 5半結合抑制值(IC50)僅達到uM等級，但是，內生性COX-2酵素與[18F]FFOA 5結合能力，仍可讓區別腦瘤與正常區域組織之COX-2酵素選擇性指數(SI)達到1.5。
第二部分：以Cocaine為起始物，合成化合物 24，產率為76%。另以ethylene glycol和diethylenetriamine前驅物，合成化合物17與化合物19，將化合物17與化合物19分別與化合物24進行取代反應來獲得產物IPCAT-NOTA 26與IPCET-NOTA 27，合成產率均<5%，化學純度分別為99%與<5%。放射性合成則經由螯合[68Ga]成為最終產物[68Ga]IPCAT-NOTA 28與 [68Ga]IPCET-NOTA 29，放射化學純度均≧90%，比活度3.7 MBq/nmol。選用[68Ga]IPCAT-NOTA 28進行後續生物試驗。[68Ga]IPCAT-NOTA 28生物試驗結果：(1)體外血清安定試驗，在37℃長達60分鐘，仍可維持在85%以上的放射化學純度，顯示68Ga可穩定螯合在NOTA 結構。(2)體外親脂性分析，以搖瓶法測定[68Ga]IPCAT-NOTA 28 LogP值，LogP僅有0.88 ± 0.30，表示[68Ga]IPCAT-NOTA 28是難以通過血腦障壁(BBB)，另以電腦模擬分析亦獲得相似結果。(3)體外結合試驗，[68Ga]IPCAT-NOTA 28之大鼠專一性結合比值SBR(%) 15.76 ± 6.74%以及小鼠專一性結合比值SBR(%)為29.75%。(4)體外競爭結合試驗，[68Ga]IPCAT-NOTA 28與前驅物以1:1、1:100與1:1000的濃度比例，競爭與紋狀體的結合能力，專一性結合比值分別為15.76 ± 3.74 , 7.27 ± 5.53與-11.67 ± 4.65，濃度比例100倍的前驅物濃度，可以達到85%的抑制作用。(5)體內NanoPET影像分析，注射37 MBq [68Ga]IPCAT-NOTA 28後5-15、30-40、60-70 min，紋狀體專一性結合量分別為5.78%、25.42%、61.99%，但整體進腦量僅0.07 %ID/g。(6)體內代謝分析試驗，注射55.5MBq [68Ga]IPCAT-NOTA 28後30分鐘，仍有67.65% [68Ga]IPCAT-NOTA 28存在。
第三部分：採用梯度流洗方式、層析管柱：Zorbax XDB C-18、移動相組成：10 mM 3,3-dimethylglutaric acid (DMGA)與乙晴(pH 7.0)、流速：1.0 mL/min與紫外光/可見光波長λ=254 nm。分析方法確效：(1)系統適用性：拖曳因素0.96±0.03(mean±S.D)、理論板數10,656.11±176.16 (mean±S.D)以及解析度9.37±0.33(mean±S.D)，前述數據值均符合規範(N≧3000, T=0.8–1.3, k′=2–8, Rs≧1.5)，證明本系統適用於後續分析作業。(2)專一性：BZM, IBZM, [123I]IBZM與[123I]NH4I的層析峰滯留時間(Retention Time；Rt)，彼此不受干擾。(3)分析精密度與中間精密度：[123I]IBZM層析滯留時間CV%≦2%。(4)準確度(Accuracy)與回收率(Recovery)：不同天，不同濃度的回收率大多落在88%~100%之間。(5)線性(Linearity)：經由線性迴歸分析所計算出的相關係數r≧0.995。(6)耐變性：變更移動相組成(±5%)、變更溫度(±5%)與變更流速(±10%)溫度，對[123I]IBZM放射化學純度不會有太大的影響。(7)最低偵測極限與最低定量極限(LOD與 LOQ)分別為0.145 ug/mL and 0.50 ug/mL。本法適用於[123I]IBZM放射化學純度分析，可得到極佳之敏感性、再現性、精密度與準確性等。
本研究成功開發新穎COX-2腦瘤正子造影劑與新穎多巴胺轉運體正子造影劑，期許後續進一步評估非特異性的結合情形、不同腦瘤分級動物模式以及變更螯合劑結構，以達到精準診斷功效。此外，本研究成功發展一可靠與準確 [123I]IBZM放射化學純度分析，適用於臨床應用以進行BZM與IBZM的定量分析。

Brain tumor and Parkinson's disease are global health concerns and focus issues. The study was divided into three parts. The first part, cyclooxygenase enzyme was used as the research target to develope [18F]FFOA 5 brain tumor imaging agent. The second part, dopamine transporter was used as the research target to develope [68Ga]IPCAT-NOTA 28 dopamine transporter imaging agent. The third part, the [123I]IBZM radiochemical purity analysis method was developed and validated to quantify the [123I]IBZM dopamine D2 receptor imaging agent
The first part, starting from commercial 4-bromobiphenyl via Friedel Crafts acylation to give bromo-fenbufen 1 in 93 % yield, amide coupling reaction to give bromo-fenbufen octyl amide 2 in 87 % yield, and Pd catalyzed stannylation to give trimethyltin-fenbufen octyl amide 3 in 60 % yield, The totoal yield was 50% [18F]FFOA 5 was obtained by fluoro- destannylation using [18F]F2. Para-[18F]Fluorofenbufen octylamide ([18F]FFOA) 5 was obtained with the radiochemical yield of 16% and specific activity of 4 GBq/μmol, and the IC50 values of COX-1 and COX-2 were 26.5 and 32.7 μM, respectively. The stability of cold FFOA in plasma was significantly improved with a half-life of 30 min, and the uptake ratio of [18F]FFOA 5 in rats with brain tumor was 1.5 as determined from accumulation of 3.9% injection dose (ID/g) in the brain tumor and 2.5% ID/g in the brain. [18F]FFOA 5 with COX-2 micromolar affinity can be used to differentiate between brain tumor and normal region.
The second part, starting from Cocaine, compound 24 was synthesized in 76% yield. Compound 17 and 19 were synthesized form of ethylene glycol and diethylenetriamine as starting precursors, furthoremore, compound 24 react with compound 17 and 19 via substitution reaction to gain IPCAT-NOTA 26 and IPCET-NOTA 27 in less than 5% yield, >99% and less than 5% chemical purity of IPCAT-NOTA 26 and IPCAT-NOTA 27, respectively. [68Ga]IPCAT-NOTA 28 and [68Ga]IPCET-NOTA 29 were obtained with the radiochemical purity of ≧90% and specific activity of 3.7 MBq/nmol, respectively. [68Ga]IPCAT-NOTA 28 was selected for follow-up biological experiments. The biological results of [68Ga]IPCAT-NOTA 28 were shown as follows: (1) In vitro serum stability tests, it still had 85% radiochemical purity at 37°C up to 60 minutes that indicate the 68Ga could be stable chelated to NOTA. (2) In vitro lipophilic test, it was 0.88 by shaking flask method that means the ability of penetrating BBB is less, furemore, we have got the similar results by using computer-aid simulation. (3) In vitro binding assay, the specific binding ratio (%) (SBR(%)) of [68Ga]IPCAT-NOTA 28 were 15.76 ± 6.74 and 29.75, in SD-rat and Balc/c animal model, respectively. (4) In vitro competitive assay, SBR(%) of [68Ga]IPCAT-NOTA 28 for striatum were 15.76 ± 3.74 , 7.27 ± 5.53, and -11.67 ± 4.65 by competing with cold precursor of 1:1, 1:100 and 1:1000 fold, respectively. It can be achieved up to 85% inhibition at 100 fold of cold precursor concentration. (5) In vivo NanoPET imaging, SBR(%) of [68Ga]IPCAT-NOTA 28 for striatum were 5.78%, 25.42% and 61.99% at 5-15, 30-40 and 60-70 min, however, that was only 0.07 %ID/g of brain uptake after injection of 55.5MBq [68Ga]IPCAT-NOTA 28. (6) In vivo Metabolite assay, it still had 67.65% of radiochemical purity at 30 minutes after injection of 55.5MBq [68Ga]IPCAT-NOTA 28.
The third part, gradient elution on a Zorbax XDB C-18 column with a mobile phase that consists of 10 mM 3,3-dimethylglutaric acid (DMGA) and acetonitrile (pH 7.0) were used. The flow rate was 1.0 mL/min with detection at λ=254 nm. The method was validated for system suitability, precision, accuracy, specificity, linearity, robustness, limit of detection (LOD) and limit of quantification (LOQ), as described in ICH guidelines. The results are described as follows: (1) the system suitability includes the tailing factor, theoretical plate number and resolution, which are 0.962, 10656.11 and 9.367, respectively. (2) For specificity, the BZM and [123I]NH4I did not interfere with the retention time of the [123I]IBZM. (3) The percentage coefficient of variation for analysis of precision, including repeatability and intermediate precision, is less than 2.0%. (4) Accuracy of the method is within the range of 85–100%. (5) The range of linearity is from 100% to 70% radiochemical purity (%RCP) of [123I]IBZM, with the correlation coefficient (R) always being above 0.995. (6) The data of method robustness are within acceptance criteria. (7) The LOD and LOQ for impurity (BZM) are 0.145 and 0.50 μg/mL, respectively. All of the analysis results demonstrate that this method is sensitive, specific and suitable for routine analysis of the radiochemical purity in [123I]IBZM preparations.
In this study, a novel COX-2 brain tumour imaging agent and dopamine transporter imaging agent were successfully developed, respectively. It is hoped to verify and achieve accurate diagnostic efficacy through with evaluating the nonspecific binding, different grades of brain tumor animal models and changeing the chelate structure in the further. Furthormore, a reliable and reversed-phase HPLC method using UV/VIS and radiometric detectors has been developed for qualitative analysis of BZM and IBZM and radiochemical purity in [123I]IBZM preparations.

目錄
摘要                                                                    I
Abstract                                                            IV
   Study of [18F]FFOA 5 Brain Tumor Imaging Agent                            IV
   Study of [68Ga]IPCAT-NOTA 28 Dopamine Ransportor Imaging Agent             V
   Study of Method Development and Validaion of Radiochemicalpurity of [123I]IBZM Dopamine D2 ReceptorImaging Agent                                            VI
致謝                                                                    VII
縮寫對照表                                                        IX
目錄                                                                    XIII
圖目錄                                                            XX
表目錄                                                            XXIII
第一章 緒論                                                        1
1分子影像技術在新藥開發所扮演的角色                                            1
1.1    藥品開發的生命週期                                                 1
1.2    分析方法確效觀念與執行                                            4
1.2.1    分析方法確效的定義與適用範圍                                            4
1.2.2    分析方法確效指標                                                5
1.2.2.1    專一性(specificity)                                            5
1.2.2.2    準確度(accuracy)                                            6
1.2.2.3    精密度(precision)                                            6
1.2.2.4    線性(linearity)                                                6
1.2.2.5    分析範圍(range)                                                    6
1.2.2.6    最低檢測濃度(Detection Limit, DL)                                    7
1.2.2.7    最低定量濃度(Quantitation Limit, QL)                                    7
1.2.2.8    耐變性(robustiness)                                                7
1.2.2.9    系統適用性(system suitability)                                        7
1.2.3    常見分析方法確效指標的允收標準                                            8
1.2.4    應用實例                                                        8
1.3    分子影像技術                                                    9
1.3.1    核磁共振造影(MRI)                                                9
1.3.2    核子醫學(Nuclear Medicine)                                    9
1.3.2.1    正子發射斷層掃描(Positron Emission Tomography, PET)                    10
1.3.2.1.1    氟-18(18F)放射性核種                                    11
1.3.2.1.2    鎵-68(68Ga)放射性核種                                    14
1.3.2.2    單光子造影標幟放射性核種的選擇                                            16
1.3.2.2.1    鎝-99m(99mTc)放射性核種                                16
1.3.2.2.2    碘-123(123I)放射性核種                                    18
2    腦瘤(Brain Tumor)                                                20
2.1    腦瘤分級、治療與診斷                                            20
2.2    腦瘤PET造影劑發展現況                                            21
2.2.1    葡萄糖代謝(glucose metabolism)造影劑                                22
2.2.2    氨基酸吸收(amino acid uptake)造影劑                            22
2.2.2.1    [11C]MET造影劑                                            23
2.2.2.2    [18F]FET造影劑                                                    23
2.2.2.3    [18F]FDOPA造影劑                                                23
2.2.3    細胞增生(cell proliferation)造影劑                                    24
2.3    腦瘤與發炎                                                24
2.3.1    還氧化酶(Cyclooxygenase, COX)                                24
2.3.2    芬布芬(Fenbufen)                                            25
3    巴金森氏病(Parkinson’s Disease, PD)                                        28
3.1    巴金森氏病(PD)的臨床影像醫學診斷                                    29
3.2    巴金森氏病(PD)診斷造影劑的發展現況                                        31
3.2.1    突觸前造影劑                                                     32
3.2.1.1    [18F]FDOPA造影劑                                                33
3.2.1.2    (+)-[11C]dihydrotetrabenazine(DTBZ)造影劑                            33
3.2.1.3    [18F]dihydrotetrabenazine(DTBZ)造影劑                                34
3.2.1.4    [123I]-CIT(β−CIT)造影劑                                             34
3.2.1.5    核研多巴胺轉運體造影劑(INER TRODAT-1 Kit)造影劑                            34
3.2.2    突觸後造影劑                                                    34
3.2.2.1    [11C]NNC-112  D1接受體造影劑                                    35
3.2.2.2    [11C]raclopride  D2接受體造影劑                                     35
3.2.2.3    [123I]IBZM  D2接受體造影劑                                         35
3.3    多巴胺轉運體(DAT)造影劑                                             36
3.3.1    單光子多巴胺轉運體造影劑的設計                                            38
3.3.1.1    N-8修飾取代                                                39
3.3.1.1.1    [99mTc] technetium, 13(2-)-N,S,S’]oxo                        40
3.3.1.1.2    2-[[3-[3-(4-chlorophenyl)-4-methoxycarbonyl-8-azabicyclo [3.2.1]octan -8-yl]propyl-(2-sulfidoethyl)amino]acetyl]azanidyl ethanethiolate;oxo[99mTc] technetium
40
3.3.1.1.3    2-[3-[3-(4-chlorophenyl)-4-methoxy carbonyl-8-azabicyclo [3.2.1] octan-8-yl]propyl-(2-sulfidoethyl)amino]-N-(2-sulfidoethyl) ethanemidate;oxo [99mTc] technetium
41
3.3.1.2    C-2修飾取代                                                41
3.3.1.2.1    [99mTc] technetium, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3-)-N2,N2′,S2,S2′]oxo-[1R-(exo-exo)]                                        42
3.3.2    正子多巴胺轉運體造影劑的設計                                            42
3.3.2.1    Microdosing                                                44
3.3.2.2    Drug occupancy at target of interest                                     44
3.3.2.3    Biomarkers of pathophysiology                                        44
3.4    多巴胺D2接受體造影劑                                            45
3.4.1    [123I]IBZM多巴胺D2接受體造影劑之合成                                    46
3.4.2    [123I]IBZM多巴胺D2接受體造影劑之品管分析                                46
3.4.2.1    碘標幟核醫藥物品管分析概念                                         47
3.4.2.2    化學純度(Chemical Purity)與放射化學純度(Radiochemical Purity, %RCP)
47
3.4.2.3    In vitro與Shelf-life的藥物安定性(Stability)                                    47
3.4.2.4    藥物品質的考量(Pharmaceutical Consideration)                              48
3.4.2.5    [123I]IBZM多巴胺D2接受體造影劑之品管分析                                48
4    研究動機與目的                                                         48
4.1    [18F]FFOA 5腦瘤正子造影劑開發                                            49
4.2    [68Ga]IPCAT NOTA 28多巴胺轉運體正子造影劑開發                            49
4.3    [123I]IBZM多巴胺D2接受體之放射化學純度分析方法開發與確效                52
第二章 結果與討論                                                        53
1    [18F]FFOA 5腦瘤正子造影劑開發                                                 53
1.1    [18F]FFOA 5正子造影劑放射化學製備                                        53
1.2    [18F]FFOA 5正子造影劑生物試驗                                            54
1.2.1    In vitro放射性氟-18標幟物之競爭結合試驗                                     54
1.2.2    In vitro FFOA 4 體外安定性測試                                         56
1.2.3    In vivo [18F]FFOA 5正子造影分析                                     57
2    [68Ga]IPCAT-NOTA 28多巴胺轉運體正子造影劑開發                                61
2.1    IPCAT-NOTA 26與IPCET-NOTA 27之放射性鎵-68標幟                                64
2.2    [68Ga]IPCAT-NOTA 28生物試驗                                        65
2.2.1    In vitro體外血清安定性(Serum stability)試驗                              65
2.2.2    In vitro體外親脂性測試(Partition Coefficient)                             65
2.2.3    In vitro體外自動輻射顯影(In vitro Autoradiography)之結合試驗(binding assay)
67
2.2.4    In vitro體外自動輻射顯影(In vitro Autoradiography)試驗之競爭性試驗(Competitive assay)                                                                        68
2.2.5    In vivo體內影像擷取與分析(In vivo NanoPET/CT image)試驗                        69
2.2.6    In vivo體內代謝分析(In vivo Metabolite assay)試驗                         70
2.2.7    In silico多巴胺轉運體-配體之結合親和度分析(In silico Binding Affinity of Dopamine Transporter – Ligands)                                                            71
3    [123I]IBZM多巴胺D2接受體放射化學純度分析方法開發與確效                                73
3.1    分析方法的開發                                                     73
3.1.1    不同種類的緩衝液之影響                                             73
3.1.2    緩衝液pH值的影響                                                 74
3.1.3    移動相的流洗方式對分析物層析之影響                                        76
3.1.3.1    等位流洗方式(isocratic elution)                                         76
3.1.3.2    梯度流洗方式(gradient elution)                                         76
3.1.3.3    階梯式流洗方式(stepwise elution)                                     76
3.1.4    管柱鍵結相對分析物層析之影響                                            77
3.2    分析方法條件確認                                                 78
3.3    分析方法確效(Method Validation)                                    79
3.3.1    系統適用性(System Suitability)                                         79
3.3.2    專一性(Specificity)                                            79
3.3.3    精密度(Precision)                                            79
3.3.4    準確度(Accuracy)與回收率(Recovery)                                    80
3.3.5    線性(Linearity)                                                    80
3.3.6    耐變性(Robustness)                                                81
3.3.6.1    分析管柱的影響                                                    81
3.3.6.2    移動相pH值的影響                                                 81
3.3.6.3    移動相流速的影響                                                82
3.3.7    最低偵測極限與最低定量極限(LOD與 LOQ)                                    82
3.4    建議[123I]IBZM品管分析的放行標準                                     83
第三章 實驗方法                                                             84
1    試劑、溶劑與儀器                                                     84
1.1    非放射性化合物合成試劑、溶劑與儀器                                        84
1.2    非放射性化合物鑑定                                                85
1.3    放射性化合物合成                                                 85
2    [18F]FFOA 5腦瘤正子造影劑之前驅物合成與放射化合物製備                                85
2.1    製備 4-(4’-bromo-[1,1’-biphenyl]-4-yl)-4-oxobutanoic acid 1         86
2.2    製備4-(4'-bromo-[1,1'-biphenyl]-4-yl)-N-octyl-4- oxobutanamide 2     86
2.3    製備N-octyl-4-oxo-4-(4'-(trimethylstannyl)-[1,1'-biphenyl]-4-yl) butanemide 3
88
2.4    製備4-([1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide(FFOA) 4非放射性氟化合物標準品                                                                             88
2.5    製備4-(4'-fluoro-[1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide [18F]FFOA 5
89
2.6    [68Ga]IPCAT NOTA 28多巴胺轉運體正子造影劑之前驅物合成與放射化合物製備
90
2.6.1    製備(E) 3-Iodoacrylic acid 6                                    91
2.6.2    製備(E) Ethyl 3-Iodoprop-2-enoic acid 7                                  91
2.6.3    製備(E) 3-iodoprop-2-en-1-ol 8                                92
2.6.4    製備(E)-3-iodo-2-propenyl-1-methylbenzenesulfonate 9            92
2.6.5    製備NOTA (t-Bu)2 14                                        93
2.6.6    製備N-t-Boc-(O-p-tosyl)-2-aminoethanol 15                            94
2.6.7    製備1,4-di-tert-butyl 2,2’-(7-(2-aminoethyl)-1,4,7-triazonan-1,4-diyl) diacetate 16                                                                        94
2.6.8    製備2,2’-(7-(2-aminoethyl)-1,4,7-triazonan-1,4-diyl)diacetic acid 17    94
2.6.9    製備1,4-di-tert-butyl 2,2’-(7-(2-ethoxyl)-1,4,7-triazonan-1,4-diyl)diacetate 18
95
2.6.10    製備2,2’-(7-(2-ethoxyl)-1,4,7-triazonan-1,4-diyl)diacetic acid 19       95
2.6.11    製備3β-(4-chlorophenyl)-nortropane-2β-carboxylic methyl ester 21    96
2.6.12    製備3β-(4-chlorophenyl)-nortropane-2β-carboxylic methyl ester 22    96
2.6.13    製備(E) N-3-iodo-2-propen-1-yl-2β-carbomethoxy-3β-(4-chlorophenyl)nor- tropane 23                                                        97
2.6.14    製備(E) N-3-iodo-2-propen-1-yl-2β-carboxyl-3β-(4-chlorophenyl)nor- tropane 24                                                                        97
2.6.15    製備8-[(2E)-3-iodo-2-propenyl]-2β-[2-(4,7-bis(2-ethylcarboxyl)-1,4,7- triazonan-1-yl)ethyl]carboxamido-3β-(p-chlorophenyl)nortropane (IPCAT-NOTA) 26
98
2.6.16    製備8-[(2E)-3-iodo-2-propenyl]-2β-[(2-(4,7-bis(2-ethylcarboxyl)- 1,4,7- triazonan-1-yl)ethyl)oxy]carbonyl-3β-(p-chlorophenyl)nortropane (IPCET-NOTA) 27
98
2.6.17    製備[68Ga]IPCAT-NOTA 28與[68Ga]IPCET-NOTA 29                               99
3    [18F]FFOA 5腦瘤正子造影劑之生物實驗                                    99
3.1    FFOA 4體外血清安定性試驗                                                99
3.2    [18F]FFOA 5體外環氧化酶(COX)酵素結合試驗                                100
3.3    [18F]FFOA 5動物正子造影分析                                        101
3.4    C6-glioma-rat and C6-glioma-mouse models腦瘤動物模式建立            101
3.5    In vivo [18F]FFOA 5正子造影分析                                     101
4    [68Ga]IPCAT-NOTA 28多巴胺轉運體正子造影劑之生物試驗                             102
4.1    In vitro體外親脂性測試(Partition Coefficient, PC)                                102
4.2    In vitro體外血清安定性(In vitro Serum stability)試驗                               102
4.3    In vitro體外自動輻射顯影(In Vitro Autoradiography)之結合試驗(binding assay)
102
4.4    In vitro體外自動輻射顯影(In Vitro Autoradiography)試驗之競爭性試驗(Competitive assay)                                                                        103
4.5    Ex vivo體表外自動輻射顯影(Ex vivo Autoradiography)試驗                         103
4.6    In vivo體內影像分析(In Vivo NanoPET/CT image)                         103
4.7    In vivo體內生物體分佈(In vivo Bio-distribution)試驗                             104
4.8    In vivo體內代謝分析(In vivo Metabolite assay)試驗                           104
5    [123I]IBZM多巴胺D2接受體放射化學純度分析方法開發與確效                                104
5.1    標準品與移動相的配製                                               104
5.2    分析樣品的配製                                                    104
5.3    HPLC/UV-Visible detector/Radio detector組裝                              105
1    [18F]FFOA 5腦瘤正子造影劑之開發研究                                     106
2    [68Ga]IPCAT-NOTA 28多巴胺轉運體正子造影劑之開發研究                              106
3    [123I]IBZM多巴胺D2接受體放射化學純度分析方法開發與確效                                 107
第六章 參考文獻                                                                 118

                                

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