TWI597259B - Device for preparing 18f-labelled glutamate derivatives and the preparation thereof - Google Patents
Device for preparing 18f-labelled glutamate derivatives and the preparation thereof Download PDFInfo
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本發明係關於一種腫瘤造影劑的製造裝置,特別是指一種自動合成18F正子放射性同位素標誌麩胺酸衍生物之腫瘤造影劑的裝置,及使用該裝置之自動合成方法。 The present invention relates to a device for manufacturing a tumor contrast agent, and more particularly to a device for automatically synthesizing a tumor contrast agent of a 18 F positron radioisotope marker glutamic acid derivative, and an automatic synthesis method using the device.
除了葡萄醣之外,因其細胞合成需要,腫瘤細胞也會高度攝取氨基酸,例如麩醯胺酸(Glutamine)。而氨基酸一般是藉由位於細胞膜上的轉運器(Transporter)進入細胞內,包含LAT1(L-type Amino Acid Transporter 1)、ASCT(Alanine Serine Cysteine Transporter)或xCT(Cytine/Glutamate Exchange Transporter)。而這些轉運器表現的增加程度也反映了部分癌症的惡化與其不佳的預後,例如膠質瘤、肺臟、攝護腺與直腸等器官相關之癌症。 In addition to glucose, tumor cells also highly ingest amino acids, such as glutamine, because of their cellular synthesis needs. The amino acid is generally introduced into the cell by a transporter located on the cell membrane, and includes LAT1 (L-type Amino Acid Transporter 1), ASCT (Alanine Serine Cysteine Transporter) or xCT (Cytine/Glutamate Exchange Transporter). The increase in the performance of these transporters also reflects the deterioration of some cancers and their poor prognosis, such as glioma, lung, prostate and rectum and other organ-related cancers.
其中,xCT已知與麩胱甘肽(Glutathione)的生物合成路徑有關,而且一般並不大量表現於器官中,除了腦部、胰臟、膽囊與胸腺。而xCT的表現狀況於不同的腫瘤細胞亦有所不同,甚至與腫瘤細胞轉移程度及癌症治療中的化學抗性(Chemoresistance)有一定的關係。此外,xCT也被認為與許多及慢性疾病或癌症有關的氧化壓力有一定的相關性。 Among them, xCT is known to be involved in the biosynthetic pathway of glutathione, and is generally not abundantly expressed in organs except the brain, pancreas, gallbladder and thymus. The performance of xCT is different in different tumor cells, and even has a certain relationship with the degree of tumor cell metastasis and chemical resistance (Chemoresistance) in cancer treatment. In addition, xCT is also thought to have a certain correlation with many oxidative stresses associated with chronic diseases or cancer.
另一方面,麩醯胺酸分解作用(Glutaminolysis)近來已被逐漸認為是一癌症治療的重要標的,且以麩胺酸(Glutamate)為前驅物的麩胱甘肽更已知為細胞存活與成長的重要因子之一。因此,氟18標誌之麩胺酸衍生物,例如(4S)-4-(3-18Ffluoropropyl)-L-glutamate([18F]FSPG,如圖1),也已被用作一具潛力的腫瘤正子造影劑,甚至也許可以作為未來惡性腫瘤之一非侵入性的預後指標。而[18F]FSPG不僅已知其與xCT相關,甚至也已成功應用於臨床。從目前研究結果指出,[18F]FSPG不僅於病人體中耐受性良好,甚至在肝癌與肺癌臨床診斷也出表現極佳的腫瘤偵測效果以及相當高的TB比值(Tumor-to-Background Ratios)。 On the other hand, glutaminolysis has recently been recognized as an important target for cancer treatment, and glutathione, which is a precursor of glutamic acid (Glutamate), is more known as cell survival and growth. One of the important factors. Therefore, the fluoro 18-labeled glutamic acid derivative, such as (4S)-4-(3-18Ffluoropropyl)-L-glutamate ([ 18 F]FSPG, as shown in Figure 1), has also been used as a potential tumor. Positive contrast agents may even serve as a non-invasive prognostic indicator for future malignancies. [ 18 F]FSPG is not only known to be associated with xCT, but has also been successfully used in clinical practice. According to the current research results, [18F]FSPG is not only well tolerated in patients, but also has excellent tumor detection effect and relatively high TB ratio (Tumor-to-Background Ratios) in clinical diagnosis of liver cancer and lung cancer. ).
[18F]FSPG的合成是一兩步驟之反應。首先,將K222/K[18F]F與其前驅物(di-tert-butyl(4S)-N-(tert-butoxycarbonyl)-4-(3-{[(4-nitrophenyl)sulfonyl]oxy}propyl)-L-glutamate)進行氟化反應。之後,再以適量鹽酸進行水解反應以得到[18F]FSPG之粗產品(如圖2)。最後,經水稀釋且混合均勻後,再以一系列固相萃取匣進行純化而得到可應用於臨床之[18F]FSPG注射劑。其中,純化往往是其難以控制之因素。此外,18F為輻射物,若以人工操作進行製備,不但操作麻煩,一次可製備的份量少,無法大量製造,且操作人員需長期暴露在輻射下,對其健康將造成不利的影響。因此為減少操作人員劑量,多使用自動合成裝置以大量製備18F標誌之正子造影劑。自動合成器中,GE TRACERlab FX有很多系列,包含FxFN以及FxFDG。其中,唯一可以合成[18F]FSPG的僅限於有製劑(formulation)裝置之部分合成器,如FxFN。而FxFDG合成器因無相關裝置(如圓底燒瓶或磁力攪拌裝置),故並無法直接用以合成出[18F]FSPG。且[18F]FSPG合成過程的放化產率不穩 定(≦1%),因此對於未來[18F]FSPG使用上之推廣將是一非常大的限制。 The synthesis of [ 18 F]FSPG is a one-step reaction. First, K 222 /K[ 18 F]F and its precursor (di-tert-butyl(4S)-N-(tert-butoxycarbonyl)-4-(3-{[(4-nitrophenyl)sulfonyl]oxy}propyl )-- L- glutamate) is subjected to a fluorination reaction. Thereafter, hydrolysis reaction was carried out with an appropriate amount of hydrochloric acid to obtain a crude product of [ 18 F]FSPG (Fig. 2). Finally, after being diluted with water and uniformly mixed, it is purified by a series of solid phase extraction hydrazine to obtain a clinically applicable [ 18 F]FSPG injection. Among them, purification is often a factor that is difficult to control. In addition, 18 F for the radiation matter, if the manual were prepared, not only operational problems, less weight once made, can not be mass-produced, and that the personnel need long-term exposure to radiation, their health will be adversely affected. Therefore, in order to reduce the operator dose, an automatic synthesizing device is often used to prepare a large number of 18 F-labeled positron contrast agents. Among the automatic synthesizers, GE TRACERlab FX has many series, including Fx FN and Fx FDG . Among them, the only one that can synthesize [ 18 F]FSPG is a part of a synthesizer, such as Fx FN , which has a formulation device. The Fx FDG synthesizer cannot be directly used to synthesize [ 18 F]FSPG because it has no relevant equipment (such as a round bottom flask or a magnetic stirring device). Moreover, the radiochemical yield of the [ 18 F]FSPG synthesis process is unstable (≦1%), so the promotion of the use of [ 18 F]FSPG in the future will be a very large limitation.
故,發明人鑑於過去方法所衍生的困難與限制,乃亟思加以改良創新,並經苦心孤詣潛心研究後,終於成功研發完成本件18F正子放射性同位素標誌麩胺酸衍生物之製造方法及其自動合成裝置,成功改良現有TracerLab FxFDG自動合成器並完成本件18F正子放射性同位素標誌麩胺酸衍生物之製造方法。 Therefore, in view of the difficulties and limitations derived from the past methods, the inventors have improved and innovated, and after painstaking research, they have successfully developed and manufactured the 18 F-positive radioisotope-labeled glutamic acid derivative. Synthetic device, successfully improved the existing TracerLab Fx FDG automatic synthesizer and completed the manufacturing method of the 18 F positron radioisotope label glutamic acid derivative.
本發明提供一種18F正子放射性同位素標誌之標誌麩胺酸衍生物的自動化合成裝置(如圖3)來製造可應用於腫瘤造影之18F標誌麩胺酸衍生物造影劑,簡化製造過程,以符合臨床研究的需求。本發明亦提供一種利用該裝置製造18F正子放射性同位素標誌之標誌麩胺酸衍生物之腫瘤造影劑的方法,係以自動化裝置來製造可應用於腫瘤造影之18F標誌麩胺酸衍生物,以減少操作人員暴露在輻射下的機會。 The present invention provides a positive sub 18 F radioisotope automated synthesis apparatus flag flag of glutamic acid derivative (FIG. 3) may be applied to producing 18 F flag glutamic acid derivative tumor contrast agent contrast, the manufacturing process is simplified to Meet the needs of clinical research. The invention also provides a method for manufacturing a tumor contrast agent of a marker glutamic acid derivative of the 18 F positron radioisotope marker by using the device, which is an automated device for manufacturing an 18 F-mark glutamic acid derivative which can be applied to tumor imaging. To reduce the opportunity for operators to be exposed to radiation.
本發明之一種製造18F正子放射性同位素標誌之麩胺酸衍生物的裝置,包括一控制裝置1及一反應系統2;該控制裝置係用以自動控制該反應系統內各管路之開關;該反應系統包含一真空裝置8、一第一試劑存取裝置21、一第二試劑存取裝置22、一第三試劑存取裝置23、一第四試劑存取裝置24、一第五試劑存取裝置25、一第六試劑存取裝置26、一第七試劑存取裝置27、一第八試劑存取裝置28、一第九試劑存取裝置29、一第一分離裝置31、一第二分離裝置32、一第三分離裝置33、一第四分離裝置34、一第五分離裝置35、一反應裝置41、一第一收集器51、一第二收集器52、一第三收集器53、一第四收集器54、以及一個以上之廢液儲存裝置61、62; 該第一分離裝置31係與該第一試劑存取裝置21連接,以接收並分離該第一試劑存取裝置內存放之溶液,並將不需要的溶液置於一廢液儲存裝置61,而所需之試劑則送至反應裝置41中,該反應裝置並與該第二至六試劑存取裝置22、23、24、25、26連接,以接收該第二至六試劑存取裝置內存放之溶液並進行反應,反應後所得之放射性液體送至第二收集器52中,該第二收集器52並與第二及第三分離裝置32、33連接,第二收集器52中之溶液將送至該第二及第三分離裝置32、33以進行分離,不需要的溶液將置於一廢液儲存裝置62,該第三分離裝置33同樣與第七、八、九試劑存取裝置27、28、29連接,而所需之試劑則送至該第三收集器53中,不需要的溶液亦置於該廢液儲存裝置62,該第三收集器53並與第四及第五分離裝置34、35連接,第三收集器53中之溶液將送至該第四及第五分離裝置34、35以進行純化滅菌,製備完成之產物則送至該第四收集器54中備用。 An apparatus for producing a 18 F positron radioisotope-labeled glutamic acid derivative, comprising a control device 1 and a reaction system 2; the control device is for automatically controlling a switch of each pipeline in the reaction system; The reaction system comprises a vacuum device 8, a first reagent access device 21, a second reagent access device 22, a third reagent access device 23, a fourth reagent access device 24, and a fifth reagent access. The device 25, a sixth reagent access device 26, a seventh reagent access device 27, an eighth reagent access device 28, a ninth reagent access device 29, a first separating device 31, and a second separation The device 32, a third separating device 33, a fourth separating device 34, a fifth separating device 35, a reaction device 41, a first collector 51, a second collector 52, a third collector 53, a fourth collector 54, and one or more waste storage devices 61, 62; the first separation device 31 is coupled to the first reagent access device 21 for receiving and separating the first reagent access device for storage Solution and place the unwanted solution in a waste The device 61 is stored, and the required reagent is sent to the reaction device 41, and the reaction device is connected to the second to sixth reagent access devices 22, 23, 24, 25, 26 to receive the second to sixth reagents. The solution stored in the device is accessed and reacted, and the radioactive liquid obtained after the reaction is sent to the second collector 52, which is connected to the second and third separating devices 32, 33, and the second collector The solution in 52 will be sent to the second and third separation devices 32, 33 for separation, and the unwanted solution will be placed in a waste storage device 62, which is also identical to the seventh, eighth, and ninth The reagent access devices 27, 28, 29 are connected, and the required reagents are sent to the third collector 53, and the unnecessary solution is also placed in the waste liquid storage device 62, and the third collector 53 is combined with The fourth and fifth separating devices 34, 35 are connected, and the solution in the third collector 53 is sent to the fourth and fifth separating devices 34, 35 for purification and sterilization, and the prepared product is sent to the fourth collector. 54 in standby.
上述真空裝置8,包含液態氮及真空幫浦。 The vacuum device 8 described above includes liquid nitrogen and a vacuum pump.
上述第一分離裝置為QMA管柱,第二分離裝置為HR-P Sep-Pak管柱,第三分離裝置為MCX Sep-Pak管柱,第四分離裝置為Alumina-N Sep-Pak管柱,第五分離裝置為微孔濾膜。 The first separating device is a QMA column, the second separating device is an HR-P Sep-Pak column, the third separating device is an MCX Sep-Pak column, and the fourth separating device is an Alumina-N Sep-Pak column. The fifth separation device is a microporous membrane.
上述該第二收集器為一燒瓶,特別是圓底燒瓶。 The second collector described above is a flask, particularly a round bottom flask.
上述裝置另包含至少一個氦氣供給裝置71、72、73、或74,用來產生氣泡而進行液體擾動,形同攪拌的作用。且亦可用於輔助蒸乾溶劑及推送液體。該氦氣供給裝置71、72、73、或74透過管路連接至第一至第九試劑存取裝置21-29、反應裝置41、第二收集器52、及第三收集器53,再透過開關閥122、117、120、或121控制氦氣的供給。 The apparatus further includes at least one helium gas supply means 71, 72, 73, or 74 for generating bubbles for liquid perturbation, in the form of agitation. It can also be used to assist in evaporating the solvent and pushing the liquid. The helium gas supply device 71, 72, 73, or 74 is connected to the first to ninth reagent access devices 21-29, the reaction device 41, the second collector 52, and the third collector 53 through a pipeline, and then transmitted through The switching valve 122, 117, 120, or 121 controls the supply of helium.
上述裝置另包含一迴旋加速器(cyclotron)(未示於圖中)。 The above apparatus additionally includes a cyclotron (not shown).
本發明之裝置與現有之裝置的差異在於加入了圓底燒瓶並採用氣泡方式攪拌,以解決無磁力攪拌問題。所謂氣泡攪拌是以氦氣吹氣方式產生氣泡而進行液體擾動,形同攪拌。 The apparatus of the present invention differs from prior art apparatus in that a round bottom flask is added and agitation is carried out by means of a bubble to solve the problem of no magnetic stirring. The bubble agitation is a bubble generated by a helium gas blowing method to perform liquid perturbation, and is stirred in the same manner.
本發明另提供一種18F正子放射性同位素標誌之標誌麩胺酸衍生物的自動化合成方法,包含步驟:步驟1:將[18F]氟離子/[18O]水之混合溶液傳送至一第一收集器;步驟2:將該第一收集器內之混合溶液通過一第一分離裝置,以吸附該[18F]氟離子,而[18O]水則收集到一廢液儲存裝置;步驟3:將K2CO3/氨基聚醚2.2.2(Kryptofix2.2.2)溶液通過該第一分離裝置,以帶出該[18F]氟離子至一反應裝置內,並於一適當溫度及時間通鈍氣進行乾燥;步驟4:將無水乙腈(Acetontrile)溶液加入至該反應裝置內並於一適當溫度及時間通鈍氣進行乾燥;步驟5:將[18F]FSPG前驅物溶液加到該反應裝置內,並於一適當溫度時間進行氟化反應後;反應一段時間後,冷卻至室溫;步驟6:將HCl溶液加入該反應裝置內,並於一適當溫度下進行水解反應,反應一段時間後再冷卻至室溫;步驟7:將水加入該反應裝置內,並將反應裝置內的溶液收集到一含有水的第二收集器中,且通以氮氣,以氣泡攪拌方式使混合均勻;步驟8:再將水加入該反應裝置內,並將反應裝置內殘餘產物收集到第二收集器中; 步驟9:將該第二收集器內的溶液通過一第二與一第三分離裝置,以去除未反應之[18F]氟離子與前驅物及其他副產物;步驟10:利用生理食鹽水清洗該第三分離裝置,以去除該管柱內殘餘的有機溶劑與不純物;步驟11:再次將生理食鹽水清洗該第三分離裝置,以去除殘餘之有機溶劑;步驟12:將磷酸緩衝溶液通過該第三分離裝置,以帶出[18F]FSPG產物至一第三收集器內;及步驟13:將該產物通過一第四與一第五分離裝置,以帶出滅菌產物至一第四收集器內備用。 The invention further provides an automated synthesis method of a marker glutamic acid derivative of the 18 F positron radioisotope marker, comprising the steps of: Step 1: transferring a mixed solution of [ 18 F]fluoride/[ 18 O]water to a first Collector; Step 2: The mixed solution in the first collector is passed through a first separation device to adsorb the [ 18 F] fluoride ion, and the [ 18 O] water is collected into a waste liquid storage device; : passing a solution of K 2 CO 3 /aminopolyether 2.2.2 (Kryptofix 2.2.2 ) through the first separation device to bring out the [18F] fluoride ion into a reaction device, and pass it at an appropriate temperature and time Drying with a blunt gas; Step 4: Adding an anhydrous acetonitrile (Acetontrile) solution to the reaction apparatus and drying it at a suitable temperature and time by blunt gas; Step 5: adding a [ 18 F]FSPG precursor solution to the reaction After the fluorination reaction is carried out in the apparatus at a suitable temperature; after a period of reaction, it is cooled to room temperature; Step 6: the HCl solution is added to the reaction apparatus, and the hydrolysis reaction is carried out at a suitable temperature for a period of time. Then cool to room temperature again; Step 7: Adding water to the reaction device, and collecting the solution in the reaction device into a second collector containing water, and passing nitrogen gas to make the mixing uniform by bubble stirring; Step 8: adding water to the reaction device And collecting the residual product in the reaction device into the second collector; Step 9: passing the solution in the second collector through a second and a third separation device to remove unreacted [ 18 F] fluorine Ion and precursor and other by-products; Step 10: Washing the third separation device with physiological saline to remove residual organic solvent and impurities in the column; Step 11: Washing the physiological saline again to the third separation device to remove the residual organic solvent; step 12: the phosphate buffer solution through the third separation apparatus, in order to bring out the [18 F] FSPG a third product to the collector; and step 13: the product was purified by a fourth And a fifth separating device to bring out the sterilized product to a fourth collector for use.
1‧‧‧控制裝置 1‧‧‧Control device
2‧‧‧反應系統 2‧‧‧Reaction system
8‧‧‧真空系統 8‧‧‧vacuum system
21‧‧‧第一試劑存取裝置 21‧‧‧First reagent access device
22‧‧‧第二試劑存取裝置 22‧‧‧Second reagent access device
23‧‧‧第三試劑存取裝置 23‧‧‧ Third reagent access device
24‧‧‧第四試劑存取裝置 24‧‧‧fourth reagent access device
25‧‧‧第五試劑存取裝置 25‧‧‧ fifth reagent access device
26‧‧‧第六試劑存取裝置 26‧‧‧ sixth reagent access device
27‧‧‧第七試劑存取裝置 27‧‧‧ seventh reagent access device
28‧‧‧第八試劑存取裝置 28‧‧‧The eighth reagent access device
29‧‧‧第九試劑存取裝置 29‧‧‧Ninth Reagent Access Device
31‧‧‧第一分離裝置(QMA管柱) 31‧‧‧First separation device (QMA column)
32‧‧‧第二分離裝置(HR-P Sep-Pak管柱) 32‧‧‧Second separation device (HR-P Sep-Pak pipe column)
33‧‧‧第三分離裝置(MCX Sep-Pak管柱) 33‧‧‧The third separation device (MCX Sep-Pak pipe column)
34‧‧‧第四分離裝置(Alumina-N Sep-Pak管柱) 34‧‧‧Four separation device (Alumina-N Sep-Pak pipe column)
35‧‧‧第五分離裝置(微孔濾膜) 35‧‧‧ fifth separation device (microporous membrane)
41‧‧‧反應裝置 41‧‧‧Reaction device
51‧‧‧第一收集器 51‧‧‧First Collector
52‧‧‧第二收集器(圓底燒瓶) 52‧‧‧Second collector (round bottom flask)
53‧‧‧第三收集器 53‧‧‧ third collector
54‧‧‧第四收集器 54‧‧‧fourth collector
61‧‧‧廢液儲存裝置 61‧‧‧ Waste storage device
62‧‧‧廢液儲存裝置 62‧‧‧ Waste storage device
71‧‧‧氦氣供給裝置 71‧‧‧氦 gas supply device
72‧‧‧氦氣供給裝置 72‧‧‧氦 gas supply device
73‧‧‧氦氣供給裝置 73‧‧‧氦 gas supply device
74‧‧‧氦氣供給裝置 74‧‧‧氦 gas supply device
101‧‧‧開關閥 101‧‧‧ switch valve
102‧‧‧開關閥 102‧‧‧ switch valve
103‧‧‧開關閥 103‧‧‧ switch valve
104‧‧‧開關閥 104‧‧‧ switch valve
105‧‧‧開關閥 105‧‧‧Switching valve
106‧‧‧開關閥 106‧‧‧Switching valve
107‧‧‧開關閥 107‧‧‧ switch valve
108‧‧‧三向開關閥 108‧‧‧Three-way on-off valve
109‧‧‧三向開關閥 109‧‧‧Three-way on-off valve
110‧‧‧三向開關閥 110‧‧‧Three-way on-off valve
111‧‧‧三向開關閥 111‧‧‧Three-way on-off valve
112‧‧‧開關閥 112‧‧‧ switch valve
113‧‧‧開關閥 113‧‧‧ switch valve
114‧‧‧三向開關閥 114‧‧‧Three-way on-off valve
115‧‧‧三向開關閥 115‧‧‧Three-way on-off valve
116‧‧‧開關閥 116‧‧‧Switching valve
117‧‧‧開關閥 117‧‧‧ switch valve
118‧‧‧開關閥 118‧‧‧ switch valve
119‧‧‧開關閥 119‧‧‧ switch valve
120‧‧‧三向開關閥 120‧‧‧Three-way on-off valve
121‧‧‧三向開關閥 121‧‧‧Three-way switch valve
122‧‧‧開關閥 122‧‧‧Switching valve
圖1為[18F]FSPG結構圖。 Figure 1 is a structural diagram of [ 18 F]FSPG.
圖2為[18F]FSPG合成是兩步驟之反應式。 Figure 2 is a two-step reaction formula for [ 18 F]FSPG synthesis.
圖3為18F正子放射性同位素標誌之標誌麩胺酸衍生物的自動化合成裝置結構圖。 Figure 3 is a structural diagram of an automated synthesis apparatus for the marker glutamate derivative of the 18 F positron radioisotope marker.
請參照圖3,本發明之裝置,包括一控制裝置1及一反應系統2;該控制裝置係用以自動控制該反應系統內各管路之開關;該反應系統包含一真空裝置8、一第一試劑存取裝置21、一第二試劑存取裝置22、一第三試劑存取裝置23、一第四試劑存取裝置24、一第五試劑存取裝置25、一第六試劑存取裝置26、一第七試劑存取裝置27、一第八試劑存取裝置28、一第九試劑存取裝置29、一第一分離裝置31、一第二分離裝置32、一第三分離裝置33、一第四分離裝置34、一第五分離裝置35、一反應裝置41、一第 一收集器51、一第二收集器52、一第三收集器53、一第四收集器54、以及一個以上之廢液儲存裝置61、62;該第一分離裝置31係與該第一試劑存取裝置21連接,以接收並分離該第一試劑存取裝置內存放之溶液,並將不需要的溶液置於一廢液儲存裝置61,而所需之試劑則送至反應裝置41中,該反應裝置並與該第二至六試劑存取裝置22、23、24、25、26連接,以接收該第二至六試劑存取裝置內存放之溶液並進行反應,反應後所得之放射性液體送至第二收集器52中,該第二收集器52並與第二及第三分離裝置32、33連接,第二收集器52中之溶液將送至該第二及第三分離裝置32、33以進行分離,不需要的溶液將置於一廢液儲存裝置62,該第三分離裝置33同樣與第七、八、九試劑存取裝置27、28、29連接,而所需之試劑則送至該第三收集器53中,不需要的溶液亦置於該廢液儲存裝置62,該第三收集器53並與第四及第五分離裝置34、35連接,第三收集器53中之溶液將送至該第四及第五分離裝置34、35以進行純化滅菌,製備完成之產物則送至該第四收集器54中備用。 Referring to FIG. 3, the device of the present invention comprises a control device 1 and a reaction system 2; the control device is used for automatically controlling the switches of the pipelines in the reaction system; the reaction system comprises a vacuum device 8, a first a reagent access device 21, a second reagent access device 22, a third reagent access device 23, a fourth reagent access device 24, a fifth reagent access device 25, and a sixth reagent access device 26, a seventh reagent access device 27, an eighth reagent access device 28, a ninth reagent access device 29, a first separating device 31, a second separating device 32, a third separating device 33, a fourth separating device 34, a fifth separating device 35, a reaction device 41, a first a collector 51, a second collector 52, a third collector 53, a fourth collector 54, and one or more waste storage devices 61, 62; the first separation device 31 is coupled to the first reagent The access device 21 is connected to receive and separate the solution stored in the first reagent access device, and place the undesired solution in a waste liquid storage device 61, and the required reagent is sent to the reaction device 41, The reaction device is connected to the second to sixth reagent access devices 22, 23, 24, 25, 26 to receive the solution stored in the second to sixth reagent access device and react, and the radioactive liquid obtained after the reaction And being sent to the second collector 52, the second collector 52 is connected to the second and third separating devices 32, 33, and the solution in the second collector 52 is sent to the second and third separating devices 32, 33 for separation, the undesired solution will be placed in a waste storage device 62, which is also connected to the seventh, eighth, and nine reagent access devices 27, 28, 29, and the required reagents are And sent to the third collector 53, the unnecessary solution is also placed in the waste storage device 62, the third collector 53 is connected to the fourth and fifth separating devices 34, 35, and the solution in the third collector 53 is sent to the fourth and fifth separating devices 34, 35 for purification and sterilization. The finished product is sent to the fourth collector 54 for use.
上述真空裝置8,包含液態氮及真空幫浦。 The vacuum device 8 described above includes liquid nitrogen and a vacuum pump.
在一較佳實施例中,該第一分離裝置為QMA管柱,第二分離裝置為HR-P Sep-Pak管柱,第三分離裝置為MCX Sep-Pak管柱,第四分離裝置為Alumina-N Sep-Pak管柱,第五分離裝置為微孔濾膜。 In a preferred embodiment, the first separating device is a QMA column, the second separating device is a HR-P Sep-Pak column, the third separating device is a MCX Sep-Pak column, and the fourth separating device is Alumina. -N Sep-Pak column, the fifth separation device is a microporous membrane.
該裝置另包含至少一個氦氣供給裝置71、72、73、或74,用來產生氣泡而進行液體擾動,形同攪拌的作用。且亦可用於輔助蒸乾溶劑及推送液體。該氦氣供給裝置71、72、73、或74透過管路連接至第一至第九試劑存取裝置21-29、反應裝置41、第二收集器52、及第三收集器53,並 透過開關閥122、117、120、或121控制氦氣的供給。 The apparatus further comprises at least one helium supply means 71, 72, 73, or 74 for generating bubbles for liquid perturbation, in the form of agitation. It can also be used to assist in evaporating the solvent and pushing the liquid. The helium gas supply device 71, 72, 73, or 74 is connected to the first to ninth reagent access devices 21-29, the reaction device 41, the second collector 52, and the third collector 53 through a pipeline, and The supply of helium is controlled by the on-off valves 122, 117, 120, or 121.
在一較佳實施例中,該氦氣供給裝置71連接至第一至第九試劑存取裝置21-29,並透過開關閥122控制氦氣供給。該氦氣供給裝置72連接至該反應裝置41,並透過開關閥117控制氦氣供給。該氦氣供給裝置73連接至該第二收集器52,並透過開關閥120控制氦氣供給。該氦氣供給裝置74連接至該第三收集器53,並透過開關閥121控制氦氣供給。 In a preferred embodiment, the helium gas supply device 71 is coupled to the first through ninth reagent access devices 21-29 and controls the helium supply through the switching valve 122. The helium gas supply device 72 is connected to the reaction device 41, and controls the helium gas supply through the switching valve 117. The helium gas supply device 73 is connected to the second collector 52 and controls the helium gas supply through the switching valve 120. The helium gas supply device 74 is connected to the third collector 53 and controls the helium gas supply through the switching valve 121.
在一實施例中,該第二收集器52為一燒瓶。在一較佳實施例中,該燒瓶為圓底燒瓶。 In an embodiment, the second collector 52 is a flask. In a preferred embodiment, the flask is a round bottom flask.
本發明之裝置另包含多個開關閥,用以控制各個元件。開關閥101至109分別控制第一試劑存取裝置至第九試劑存取裝置。在一較佳實施例中,該開關閥108及109為三向開關閥。 The apparatus of the present invention further includes a plurality of on-off valves for controlling the various components. The switching valves 101 to 109 control the first to ninth reagent accessing devices, respectively. In a preferred embodiment, the switching valves 108 and 109 are three-way switching valves.
開關閥的數量、種類、及位置設計可依需求所設置,並不被本發明之實施例所限制。本發明所述之開關閥僅為一示範性例子。 The number, type, and positional design of the on-off valves can be set as desired and are not limited by the embodiments of the present invention. The on-off valve of the present invention is merely an illustrative example.
在一較佳實施例中,本發明之18F正子放射性同位素標誌之標誌麩胺酸衍生物的自動化合成方法包含步驟:步驟1:將[18F]氟離子/[18O]水之混合溶液傳送至一第一收集器;步驟2:將該第一收集器內之混合溶液通過一第一分離裝置,以吸附該[18F]氟離子,而[18O]水則收集到一廢液儲存裝置;步驟3:將K2CO3/氨基聚醚2.2.2(Kryptofix2.2.2)溶液通過該第一分離裝置,以帶出該[18F]氟離子至一反應裝置內,並於一適當溫度及時間通鈍氣進行乾燥;步驟4:將無水乙腈(Acetontrile)溶液至該反應裝置內並於一適當溫度及 時間通鈍氣進行乾燥;步驟5:將前驅物溶液加到該反應裝置內,並於一適當溫度及時間進行氟化反應一段時間後,使溶液冷卻至室溫;步驟6:將HCl溶液加入該反應裝置內,並於一適當溫度下進行水解反應,反應一段時間後再冷卻至室溫;步驟7:將水加入該反應裝置內,並將此含有產物的溶液收集到一含有水的第二收集器中,且通以氮氣,以氣泡方式使混合均勻;步驟8:再將水加入該反應裝置內,並將反應裝置內殘餘產物收集到第二收集器中;步驟9:將該第二收集器內的溶液通過一第二與一第三分離裝置,以去除未反應之[18F]氟離子與前驅物及其他副產物;步驟10:利用生理食鹽水清洗該第三分離裝置,以去除該管柱內殘餘的有機溶劑與不純物;步驟11:再次將生理食鹽水清洗該第三分離裝置,以去除殘餘之有機溶劑;步驟12:將磷酸緩衝溶液通過該第三分離裝置,以帶出該產物至一第三收集器內;及步驟13:將產物通過一第四與一第五分離裝置,以帶出滅菌產物至一第四收集器內備用。 In a preferred embodiment, the method for automated synthesis of the glutamate derivative of the 18 F positron isotope signature of the present invention comprises the steps of: Step 1: Mixing a solution of [ 18 F]fluoride/[ 18 O]water Transfer to a first collector; step 2: pass the mixed solution in the first collector through a first separation device to adsorb the [ 18 F] fluoride ion, and [ 18 O] water collects a waste liquid a storage device; step 3: passing a solution of K 2 CO 3 /aminopolyether 2.2.2 (Kryptofix 2.2.2 ) through the first separation device to bring out the [18F] fluoride ion into a reaction device, and Drying at a suitable temperature and time with an blunt gas; Step 4: drying an anhydrous acetonitrile (Acetontrile) solution into the reaction device and drying it at a suitable temperature and time; Step 5: Adding the precursor solution to the reaction device After the fluorination reaction is carried out at a suitable temperature and time for a period of time, the solution is cooled to room temperature; Step 6: the HCl solution is added to the reaction device, and the hydrolysis reaction is carried out at a suitable temperature for a period of time after the reaction. Cool to room temperature again; Step 7: Will Adding to the reaction device, collecting the product-containing solution into a second collector containing water, and uniformly mixing the mixture by using nitrogen gas; Step 8: adding water to the reaction device, and Collecting residual product in the reaction device into the second collector; Step 9: passing the solution in the second collector through a second and a third separation device to remove unreacted [ 18 F] fluoride ions and precursors And other by-products; Step 10: washing the third separation device with physiological saline to remove residual organic solvent and impurities in the column; Step 11: washing the physiological saline again to the third separation device to remove a residual organic solvent; step 12: passing the phosphate buffer solution through the third separation device to carry the product into a third collector; and step 13: passing the product through a fourth and a fifth separation device Bring the sterilized product out to a fourth collector for use.
在一較佳實施例中,步驟3之適當溫度為110℃;適當時間係指所有溶劑完全蒸乾之時間點,其會因合成器與鈍氣供應量差異而有所不同,其中該步驟所述之鈍氣為氦氣或其他本領域可接受之鈍氣。 In a preferred embodiment, the appropriate temperature for step 3 is 110 ° C; the appropriate time refers to the point at which all of the solvent is completely evaporated, which may vary depending on the difference between the synthesizer and the supply of the blunt gas, wherein the step The blunt gas is helium or other blunt gas acceptable in the art.
在一較佳實施例中,步驟4之適當時間係指所有溶劑完全蒸 乾之時間點。 In a preferred embodiment, the appropriate time for step 4 means that all solvents are completely steamed. When to do it.
在一較佳實施例中,該步驟5的適當溫度為70℃,氟化反應時間為十分鐘。 In a preferred embodiment, the appropriate temperature for step 5 is 70 ° C and the fluorination reaction time is ten minutes.
在一較佳實施例中,該步驟6的水解反應時間為十分鐘;適當溫度為120℃。 In a preferred embodiment, the hydrolysis reaction time of the step 6 is ten minutes; the appropriate temperature is 120 °C.
請參照圖2及圖3,在一較佳實施例中,[18F]FSPG的自動合成,包括有下列步驟:(1)將18O(p,n)18F核反應所製造的[18F]離子水溶液,自一迴旋加速器(cyclotron)(未示於圖中)移至一第一收集器51並填充氦氣;(2)利用真空幫浦抽真空,並在真空環境下打開開關118,[18F]離子水溶液會被吸出該第一收集器,並通過三向開關110及QMA管柱31,然後通過三向開關111,最後,H2 18O會被回收到廢液儲存裝置(61),而[18F]離子則會留在該QMA管柱31內;(3)利用真空幫浦抽真空,並在真空環境下打開開關118,含有K2CO3以及Kryptofix2.2.2的溶液則會自第一試劑存取器21被吸出,通過該三向開關110、該QMA管柱31以及該三向開關111,留在該QMA管柱31內的[18F]離子會被該溶液一併帶出,流到反應裝置41內;(4)將反應裝置41內之溶液置於110℃下蒸發2分鐘,並通以流動氦氣輔助進行溶劑乾燥;(5)將第二試劑存取器22內的無水乙腈在氦氣填充下加到反應裝置41中;(6)在抽真空環境下打開開關118,並將該溶液置於110℃下蒸發2分鐘,並通以流動氦氣進行乾燥; (7)將第三試劑存取器23內的前驅物(di-tert-butyl(4S)-N-(tert-butoxycarbonyl)-4-(3-{[(4-nitrophenyl)sulfonyl]oxy}propyl)-L-glutamate)(該前驅物係溶於無水乙腈)以間接填充氦氣的方式加到含有K[18F]/Kryptofix2.2.2殘留物的反應裝置41中;(8)將該溶液於70℃下進行第一步氟化反應;(9)將第四試劑存取器24內的HCl溶液加到反應裝置41中;(10)將該溶液於120℃下進行第二步水解反應;(11)將第五試劑存取器25內的H2O加到反應裝置41中;(12)打開開關閥112,將反應器41中的溶液在氦氣填充下通到第二收集器52中,且以氦氣持續吹氣攪拌數分鐘;(13)將第六試劑存取器26內的H2O加到反應裝置41中;(14)調整開關閥112,將反應裝置41中的溶液在氦氣填充下到第二收集器52中;(15)將三向開關閥120轉到氦氣來源,並調整開關閥113,在第二收集器52之溶液會通過HR-P Sep-Pak管柱32與MCX Sep-Pak管柱33,然後到廢液儲存裝置62內;(16)調整三向開關114,將第七試劑存取器27內的生理食鹽水在氦氣填充下通過MCX Sep-Pak管柱33,然後到廢液儲存裝置62內;(17)將第八試劑存取器28內的生理食鹽水在氦氣填充下通過MCX Sep-Pak管柱33,然後到廢液儲存裝置62內;(18)將第九試劑存取器29內的磷酸緩衝液在氦氣填充下通過MCX Sep-Pak 管柱33以及三向開關115,然後到第三收集器53內,留在該MCX Sep-Pak管柱33的[18F]FSPG會隨磷酸緩衝液一起流洗到該第三收集裝置53內;(19)將三向開關121轉到氦氣來源,並調整開關閥116,在生理食鹽水內的[18F]FSPG會經由Alumina-N Sep-Pak管柱34與一微孔濾膜35,然後流到第四收集器54備用。 Referring to FIG. 2 and FIG. 3, in a preferred embodiment, the automatic synthesis of [ 18 F]FSPG includes the following steps: (1) [ 18 F produced by 18 O(p,n) 18 F nuclear reaction An aqueous ion solution, moved from a cyclotron (not shown) to a first collector 51 and filled with helium; (2) vacuuming with a vacuum pump and opening the switch 118 in a vacuum environment, The [ 18 F] aqueous ion solution is sucked out of the first collector and passed through the three-way switch 110 and the QMA column 31, and then through the three-way switch 111. Finally, the H 2 18 O is recovered to the waste storage device (61). ), while [ 18 F] ions remain in the QMA column 31; (3) vacuum is applied by a vacuum pump, and the switch 118 is opened in a vacuum environment, and the solution containing K 2 CO 3 and Kryptofix 2.2.2 is opened. The first reagent accessor 21 is sucked out, and the [ 18 F] ions remaining in the QMA column 31 are passed through the three-way switch 110, the QMA column 31, and the three-way switch 111. Putting it out together, flowing into the reaction device 41; (4) evaporating the solution in the reaction device 41 at 110 ° C for 2 minutes, and assisting the solvent drying by flowing helium gas; 5) adding anhydrous acetonitrile in the second reagent accessor 22 to the reaction device 41 under helium gas filling; (6) opening the switch 118 in an evacuated environment, and evaporating the solution at 110 ° C for 2 minutes. And drying with flowing helium; (7) The precursor in the third reagent accessor 23 (di-tert-butyl(4S)-N-(tert-butoxycarbonyl)-4-(3-{[ (4-nitrophenyl)sulfonyl]oxy}propyl)-L-glutamate) (this precursor is dissolved in anhydrous acetonitrile) is added to the reaction containing K[ 18 F]/Kryptofix 2.2.2 residue by indirect filling of helium. In the apparatus 41; (8) the solution is subjected to a first step of fluorination at 70 ° C; (9) the HCl solution in the fourth reagent accessor 24 is added to the reaction device 41; (10) the solution is The second hydrolysis reaction is carried out at 120 ° C; (11) the H 2 O in the fifth reagent accessor 25 is added to the reaction device 41; (12) the on-off valve 112 is opened, and the solution in the reactor 41 is The helium gas is filled into the second collector 52 and continuously blown with helium for several minutes; (13) the H 2 O in the sixth reagent accessor 26 is added to the reaction device 41; (14) Adjusting the switching valve 112 to dissolve the reaction device 41 The helium gas is filled into the second collector 52; (15) the three-way switching valve 120 is turned to the helium source, and the switching valve 113 is adjusted, and the solution at the second collector 52 passes through the HR-P Sep-Pak. The column 32 and the MCX Sep-Pak column 33 are then passed into the waste storage device 62; (16) the three-way switch 114 is adjusted to pass the physiological saline in the seventh reagent accessor 27 through the helium filling through the MCX. a Sep-Pak column 33, and then into the waste storage device 62; (17) passing the physiological saline in the eighth reagent accessor 28 through the MCX Sep-Pak column 33 under helium gas, and then to the waste liquid In the storage device 62; (18) the phosphate buffer in the ninth reagent accessor 29 is passed through the MCX Sep-Pak column 33 and the three-way switch 115 under helium gas filling, and then into the third collector 53, leaving The [ 18 F]FSPG of the MCX Sep-Pak column 33 is flushed with the phosphate buffer into the third collection device 53; (19) the three-way switch 121 is turned to the helium source, and the on-off valve is adjusted. 116, [ 18 F]FSPG in physiological saline will pass through the Alumina-N Sep-Pak column 34 and a microporous membrane 35, and then flow to the fourth collector 54 for use.
第(12)之步驟所述之攪拌時間為5分鐘。 The stirring time described in the step (12) was 5 minutes.
該迴旋加速器為提供18F-Fluoride之儀器,即裝置51之更前端(未示於圖中)。 The cyclotron is an instrument that provides 18F-Fluoride, the front end of device 51 (not shown).
上述之示範性實施例用來對實行本發明之所屬技術領域之人提供本發明特定態樣的說明。這些範例所述之劑量或操作時間等各方面並不用於限制本發明之範圍。在不用進一步的詳述之下,所屬技術領域之人根據本文中之敘述,可以最大程度來利用本發明。所有於本文中所引述之公開發表刊物皆全文併入本文作參考。 The above-described exemplary embodiments are provided to provide a description of specific aspects of the invention to those skilled in the art. The dosages or operating times described in these examples are not intended to limit the scope of the invention. Without departing from the detailed description, those skilled in the art will be able to utilize the present invention to the extent possible. All published publications cited herein are hereby incorporated by reference in their entirety.
1‧‧‧控制裝置 1‧‧‧Control device
2‧‧‧反應系統 2‧‧‧Reaction system
8‧‧‧真空系統 8‧‧‧vacuum system
21‧‧‧第一試劑存取裝置 21‧‧‧First reagent access device
22‧‧‧第二試劑存取裝置 22‧‧‧Second reagent access device
23‧‧‧第三試劑存取裝置 23‧‧‧ Third reagent access device
24‧‧‧第四試劑存取裝置 24‧‧‧fourth reagent access device
25‧‧‧第五試劑存取裝置 25‧‧‧ fifth reagent access device
26‧‧‧第六試劑存取裝置 26‧‧‧ sixth reagent access device
27‧‧‧第七試劑存取裝置 27‧‧‧ seventh reagent access device
28‧‧‧第八試劑存取裝置 28‧‧‧The eighth reagent access device
29‧‧‧第九試劑存取裝置 29‧‧‧Ninth Reagent Access Device
31‧‧‧第一分離裝置(QMA管柱) 31‧‧‧First separation device (QMA column)
32‧‧‧第二分離裝置(HR-P Sep-Pak管柱) 32‧‧‧Second separation device (HR-P Sep-Pak pipe column)
33‧‧‧第三分離裝置(MCX Sep-Pak管柱) 33‧‧‧The third separation device (MCX Sep-Pak pipe column)
34‧‧‧第四分離裝置(Alumina-N Sep-Pak管柱) 34‧‧‧Four separation device (Alumina-N Sep-Pak pipe column)
35‧‧‧第五分離裝置(微孔濾膜) 35‧‧‧ fifth separation device (microporous membrane)
41‧‧‧反應裝置 41‧‧‧Reaction device
51‧‧‧第一收集器 51‧‧‧First Collector
52‧‧‧第二收集器(圓底燒瓶) 52‧‧‧Second collector (round bottom flask)
53‧‧‧第三收集器 53‧‧‧ third collector
54‧‧‧第四收集器 54‧‧‧fourth collector
61‧‧‧廢液儲存裝置 61‧‧‧ Waste storage device
62‧‧‧廢液儲存裝置 62‧‧‧ Waste storage device
71‧‧‧氦氣供給裝置 71‧‧‧氦 gas supply device
72‧‧‧氦氣供給裝置 72‧‧‧氦 gas supply device
73‧‧‧氦氣供給裝置 73‧‧‧氦 gas supply device
74‧‧‧氦氣供給裝置 74‧‧‧氦 gas supply device
101‧‧‧開關閥 101‧‧‧ switch valve
102‧‧‧開關閥 102‧‧‧ switch valve
103‧‧‧開關閥 103‧‧‧ switch valve
104‧‧‧開關閥 104‧‧‧ switch valve
105‧‧‧開關閥 105‧‧‧Switching valve
106‧‧‧開關閥 106‧‧‧Switching valve
107‧‧‧開關閥 107‧‧‧ switch valve
108‧‧‧三向開關閥 108‧‧‧Three-way on-off valve
109‧‧‧三向開關閥 109‧‧‧Three-way on-off valve
110‧‧‧三向開關閥 110‧‧‧Three-way on-off valve
111‧‧‧三向開關閥 111‧‧‧Three-way on-off valve
112‧‧‧開關閥 112‧‧‧ switch valve
113‧‧‧開關閥 113‧‧‧ switch valve
114‧‧‧三向開關閥 114‧‧‧Three-way on-off valve
115‧‧‧三向開關閥 115‧‧‧Three-way on-off valve
116‧‧‧開關閥 116‧‧‧Switching valve
117‧‧‧開關閥 117‧‧‧ switch valve
118‧‧‧開關閥 118‧‧‧ switch valve
119‧‧‧開關閥 119‧‧‧ switch valve
120‧‧‧三向開關閥 120‧‧‧Three-way on-off valve
121‧‧‧三向開關閥 121‧‧‧Three-way switch valve
122‧‧‧開關閥 122‧‧‧Switching valve
Claims (8)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW105120764A TWI597259B (en) | 2016-06-30 | 2016-06-30 | Device for preparing 18f-labelled glutamate derivatives and the preparation thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW105120764A TWI597259B (en) | 2016-06-30 | 2016-06-30 | Device for preparing 18f-labelled glutamate derivatives and the preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
TWI597259B true TWI597259B (en) | 2017-09-01 |
TW201800369A TW201800369A (en) | 2018-01-01 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW105120764A TWI597259B (en) | 2016-06-30 | 2016-06-30 | Device for preparing 18f-labelled glutamate derivatives and the preparation thereof |
Country Status (1)
Country | Link |
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TW (1) | TWI597259B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI696598B (en) * | 2019-02-15 | 2020-06-21 | 國立臺灣大學醫學院附設醫院 | METHOD FOR AUTOMATED PRODUCTION OF 68Ga-LABELLED RADIOPHARMACEUTICALS AND CASSETTE KIT FOR HORIZONTAL-TYPE CASSETTE-BASED SYNTHESIZERS |
-
2016
- 2016-06-30 TW TW105120764A patent/TWI597259B/en active
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI696598B (en) * | 2019-02-15 | 2020-06-21 | 國立臺灣大學醫學院附設醫院 | METHOD FOR AUTOMATED PRODUCTION OF 68Ga-LABELLED RADIOPHARMACEUTICALS AND CASSETTE KIT FOR HORIZONTAL-TYPE CASSETTE-BASED SYNTHESIZERS |
Also Published As
Publication number | Publication date |
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TW201800369A (en) | 2018-01-01 |
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