201004651 九、發明說明： 【發明所屬之技術領域】 本發明係有關於一種氟-18-FDDNP自動合成盒方 法，尤指一種可有效降低製藥操作人員之輻射曝露傷害 之氟-18-FDDNP自動合成製程，並提供醫學腦部斷層造 影用之氟-18-FDDNP。 【先前技術】 由於生活型態與生活壓力之改變，及人口結構老化 等問題，國人罹患中樞神經系統疾病係逐年增加，其中 又以精神分裂症（Schizophrenia )、焦慮症、憂鬱症等 精神疾病、阿茲海默氏症（Alzheimer’s Disease)等神 經退化性疾病以及巴金森氏症（Parkinson’s Disease) 等運動失調神經疾病影響國人生命品質及社會資源最 為嚴重。 阿茲海默氏症係一種漸行性腦退化之疾病，又稱為 退化性老年失智症，係一種最常見且無法治癒之失智 症，由於阿茲海默氏症好發於老年人，因此年紀愈大得 病機會愈高，以85歲以上罹患率可達30〜35%。此種 漸進式之疾病，其主要臨床表現包括認知（Cognition )、 行為（Behavior )與精神狀態三方面之退化。其在神經 病理學上係具有特殊之變化，在外觀肉眼上可見到大腦 皮質之萎縮、腦之溝迴變寬、以及腦室擴大等。而其中 診斷為阿茲海默氏症之最重要病理指標則係神經纖維 纏結（Neurofibrillary Tangles, NFT)與老年斑（Senile Plaque, SP )。 201004651 目前國内約有五萬名病患，並且在該些阿茲海默氏 症患者之腦部係發現有許多小小且圓形之沉澱或斑 塊。這些如蜘蛛網般纏結之蛋白質即為類澱粉蛋白，其 已成為探討阿茲海默氏症機制與治療阿茲海默氏症之 重點。 於過去研究中針對阿茲海默氏症之生物標幟係可 區分為三類，分別為styrlbenzenes類之X-34、ISB、 BSB、SB13 及 IMSB ;氨基萘（Aminonaphthalene)類 之 FDDNP及 FENE ;以及組織染料硫磺素 S ❹ （Thioflavin-S，TF-S )類之 6-OH-BTA-1、TZDM 及 IMPY。其中在 aminonaPhthalene 類之 FDDNP ’ 係將其 標幡上放射性同位素氣-18’即可成為氟_18-FDDNP ’能 使用於玉子斷層造影（Positron Emission Tomography， PET)之造影劑之一。目前此氟-18-FDDNP係由美國 UCLA醫院進行推廣，至今已進行至臨床試驗第一階 段。然而，其在標幟中依然係利用操作人員手動標幟， 如此一來人員所接受到之輻射劑量仍然具有對操作人 ❹ 員造成〆定損傷之風險。故’一般習用者係無法符合使 用者於實際使用時之所需。 【發明内容】 本發明之主要目的係在於，消除上述習知方法之缺 失，以一食自動合成盒裝置提供一種診斷腦部用之腦部 造影劑，不僅反應時間縮短、產效高，且操作過程簡單。 本發明之次要目的係在於’提供一種醫學診斷用腦 部造影劑氟-18-FDDNP之自動合成製程’在此全自動合 201004651 成盒裝置中完成製備氟-18-FDDNP，可有效降低製藥操 作人員之輻射曝露以減少傷害。 為達以上之目的，本發明係一種氟-18-FDDNP自動 合成盒方法，經由前置作業程序將所需藥品準備完備， 並在流洗所需瓶子及活化管柱後，進行實際作業程序。 首先吸取一氟-18並裝入一標幟瓶中加熱，當該標幟瓶 内產生汽化現象時，係將先前準備之乙腈（Acetonitrile， ACN )分三次間隔導入於該標幟瓶内，待該標幟瓶内無 殘存水分後’加入預先溶解在乙腈之FDDNP前驅物_ 曱苯磺酰萘丙二腈（DMTEAN)，以進行SN2反應，接 著以乳.氣吹氟降溫之後，將先前準備〇 1N之鹽酸（hq ) 導入該標幟瓶内進行水解反應，並將水解後產生之產物 通過一已活化之C18管柱，再利用水沖洗一遍，最後利 用先前準備之二氣甲烷（CH2C12)將產物自該C18管 柱流洗出來，收集於一收集瓶内得氟_18_FDDNp等滲溶 液之最終成品。 / + 學純度均可達標準值以上（9〇%以上） 方法不僅反應時間短、產效高，且 上述所有反應均在一全自動合成盒裝置内進行不 僅可使操作人員接受劑量減低至最低劑量，且於連續多 次之合成操作過程中，氟_18_FDDNp平均產率均 41.19±5·23%’並在經過肌c分析條件下，其放射化201004651 IX. INSTRUCTIONS: [Technical Field] The present invention relates to a fluorine-18-FDDNP automatic synthesis box method, in particular to an automatic synthesis of fluorine-18-FDDNP which can effectively reduce radiation exposure damage of pharmaceutical operators Process, and provide fluoride-18-FDDNP for medical brain tomography. [Prior Art] Due to the changes in lifestyle and life pressure, and the aging of the population structure, the number of diseases of the central nervous system in the country has increased year by year, including mental disorders such as Schizophrenia, anxiety, and depression. Neurodegenerative diseases such as Alzheimer's Disease and dysfunctional neurological diseases such as Parkinson's Disease affect the quality of life and social resources of Chinese people. Alzheimer's disease is a progressive degenerative disease, also known as degenerative dementia, a most common and incurable dementia, due to Alzheimer's disease in the elderly Therefore, the higher the age, the higher the chance of getting sick, and the attack rate of over 85 years old can reach 30~35%. The main clinical manifestations of this progressive disease include the degradation of cognition, behavior and mental state. It has a special change in neuropathology, and the appearance of the cerebral cortex is atrophy, the sulcus of the brain is widened, and the ventricle is enlarged. The most important pathological indicators for diagnosis of Alzheimer's disease are Neurofibrillary Tangles (NFT) and Senile Plaque (SP). 201004651 There are currently about 50,000 patients in China, and many small, rounded deposits or patches have been found in the brains of these Alzheimer's patients. These spider-like proteins are amyloid-like proteins, which have become the focus of the mechanism of Alzheimer's disease and the treatment of Alzheimer's disease. The biomarkers for Alzheimer's disease in the past studies can be divided into three categories, namely X-34, ISB, BSB, SB13 and IMSB of styrlbenzenes; FDDNP and FENE of Aminonaphthalene; And 6-OH-BTA-1, TZDM and IMPY of the tissue Thioflavin-S (TF-S). Among them, the FDDNP of the aminonaPhthalene type can be used as one of the contrast agents of Positron Emission Tomography (PET). At present, this fluoro-18-FDDNP has been promoted by the UCLA hospital in the United States and has been carried out until the first stage of clinical trials. However, it still uses the operator's manual flag in the flag, so that the radiation dose received by the person still has the risk of causing damage to the operator. Therefore, the general practitioners cannot meet the needs of the user in actual use. SUMMARY OF THE INVENTION The main object of the present invention is to eliminate the above-mentioned lack of the conventional method, and to provide a brain contrast agent for diagnosing the brain with an automatic food synthesizing device, which not only has a short reaction time, high productivity, and operation. The process is simple. The secondary object of the present invention is to provide an automatic synthesis process for a brain diagnostic agent for the diagnosis of fluorine-18-FDDNP, in which the preparation of fluorine-18-FDDNP is completed in the fully automated device of 201004651, which can effectively reduce the pharmaceutical Radiation exposure by the operator to reduce injury. In order to achieve the above object, the present invention is a fluorine-18-FDDNP automatic synthesis box method, which prepares a required drug through a pre-operation procedure, and performs a practical operation procedure after flowing the required bottle and activating the column. First, the fluorine-containing-18 is taken up and heated in a label bottle. When vaporization occurs in the label bottle, the previously prepared acetonitrile (ACN) is introduced into the label bottle three times at intervals. After there is no residual moisture in the label bottle, 'addition of FDDNP precursor _ benzene sulfonyl naphthylmalononitrile (DMTEAN) previously dissolved in acetonitrile to carry out SN2 reaction, followed by cooling with milk and air blowing, the previous preparation 〇1N hydrochloric acid (hq) is introduced into the label bottle for hydrolysis reaction, and the product produced after hydrolysis is passed through an activated C18 column, and then rinsed again with water, and finally the previously prepared di-halogen methane (CH2C12) is used. The product was washed out from the C18 column and collected in a collection bottle to obtain the final product of the fluorine_18_FDDNp isotonic solution. / + The purity of the test can reach the standard value or above (more than 9〇%). The method not only has short reaction time and high productivity, but all the above reactions are carried out in a fully automatic synthesis box device, which not only allows the operator to accept the dose to a minimum. Dose, and the average yield of fluorine_18_FDDNp was 41.19±5·23%' during the continuous synthesis operation, and it was radiozed under the condition of muscle c analysis.
从丨ι⑽取求师作人員之輻射曝露以減少傷害。 201004651 【實施方式】 本發明目前係採用GE公司生產之-18FDG自動合 成盒進行修改，將來必自行製造專屬之自動合成盒。 請參閱『第1圖及第2圖』所示，係分別為本發明 之製作流程示意圖及本發明氟-18-FDDNP合成反應之 流程示意圖》如圖所示：本發明係一種氟-18-FDDNP自 動合成盒方法，其至少包括下列程序及步驟： 前置作業程序 ❹ (A)準備藥品11:分別於一第一藥品瓶3〇加 入碳酸鉀（K2C03)溶液’於一第二藥品瓶3 1加入乙 腈（Acetonitrile, ACN )’於一第三藥品瓶3 2加入水， 於一第四藥品瓶3 3加入二氣甲烷（CH2C12),於一第 五藥品瓶3 4加入0.1N鹽酸（HC1 )，以及於一第六藥 品瓶3 5加入前驅物-三氟甲基磺酸鹽（Trifiate); (B )流洗瓶子1 2 :將每一個使用之瓶子均先以 甲醇（Methanol)流诜一次，並吹乾備用； ⑩ （C )活化管柱1 3 :將一 C18管柱5 〇先以5 毫升乙醇（ethanol )與1 〇毫升水流洗一次，而另一石夕 膠管柱則係先以5毫升二氣曱烷流洗一次； 實際作業程序 (D)吸取氟-181 4 :吸取一氟-18 ( 18F/H2180 )約0.2毫升’並計算當時活度與劑量； (E )裝入標幟瓶並加熱1 5 :將該氟裝入一 標幟瓶4 〇中，並放在一熱之板材上使其升溫至95〇c 201004651 (F )觀察標幟瓶1 6 :觀察該標織瓶4 〇中水分 減少情形’當管柱上出現凝結水氣時，則該標幟瓶4 〇 内係產生汽化現象； (G)導入乙腈1 7 :隨後將該第二藥品觀3 1内 之乙腈分三次共1.5毫升’且每次間隔約2至3分鐘， 導入該標幟瓶4 0内； (Η )進行SN2反應1 8 :待該標織瓶4 〇内幾乎 無殘存水分後，加入該第六藥品瓶中預先溶解在4〇〇微 升乙腈之FDDNP前驅物-曱苯續酰萘丙二腈（DMTE AN )2毫克’並進行95°C15分鐘之SN2反應； (I )降溫並進行水解反應1 9 :繼之，將該標幟 瓶4 0内之反應混合物以氣氣吹氣2分鐘使其降溫之 後’將該第五藥品瓶3 4中15毫升0.1N之鹽酸導入該 標幟瓶40内進行水解反應； (J )水解產物通過C18管柱2 0 :接著，將該標 幟瓶4 0中水解後之產物通過該已活化之C18管柱5 0，並利用該第三藥品瓶3 2内12毫升之水沖洗一遍 ;以及 (K )流洗純化2 1 :最後利用該第四藥品瓶3 4 内4毫升之二氣甲烷將產物自該C18管柱5 0流洗出來 ’收集於一收集瓶6 0内得氟-18-FDDNP等滲溶液之最 終成品，而在此反應過程中產生之廢液則係由一廢液瓶 (Waste) 7 0予以回收。 上述獲得之氟-18-FDDNP，其放射化學純度係利用 一高壓液相層析法 （High Pressure Liquid 201004651Take radiant exposure from 丨ι(10) to reduce the damage. 201004651 [Embodiment] The present invention is currently modified by a -18FDG automatic synthesizing box manufactured by GE, and a proprietary automatic synthesizing box must be manufactured in the future. Please refer to FIG. 1 and FIG. 2, which are respectively a schematic diagram of the production process of the present invention and a schematic diagram of the flow of the fluorine-18-FDDNP synthesis reaction of the present invention. As shown in the figure, the present invention is a fluorine-18- FDDNP automatic synthesis box method, which comprises at least the following procedures and steps: Pre-operation procedure ❹ (A) Preparation of medicine 11: Adding potassium carbonate (K2C03) solution to a second medicine bottle 3 in a first pharmaceutical bottle 3 1 Add acetonitrile (Acetonitrile, ACN)' to a third drug bottle 3 2 to add water, add a second gas methane (CH2C12) to a fourth drug bottle 3 3, and add 0.1 N hydrochloric acid (HC1) to a fifth drug bottle 3 4 And adding a precursor, Trifiate, to a sixth pharmaceutical vial 35; (B) draining the bottle 1 2: flowing each used bottle first with methanol (Methanol) Once and blow dry; 10 (C) Activate the column 13: Wash one C18 column 5 with 5 ml of ethanol and 1 ml of water, and the other is the first 5 ml of dioxane is washed once; the actual working procedure (D) draws fluorine -181 4 : absorbs fluorine - 18 ( 18 F/H2180) about 0.2 ml 'and calculate the current activity and dose; (E) load the label bottle and heat 1 5 : put the fluorine into a label bottle 4 , and place it on a hot plate Let it heat up to 95〇c 201004651 (F) Observe the label bottle 1 6: Observe the water loss in the standard bottle 4 ' 'When condensed water appears on the column, the label bottle 4 〇 internal system Vaporization phenomenon; (G) introduction of acetonitrile 1 7: then the acetonitrile in the second drug view 3 1 is divided into three times a total of 1.5 ml ' and each time interval of about 2 to 3 minutes, into the label bottle 40; The SN2 reaction is carried out. 8: After the residue of the standard woven bottle 4 has almost no residual moisture, the FDDNP precursor pre-dissolved in 4 liters of acetonitrile in the sixth drug bottle is added to the benzophenone naphthylmalononitrile. (DMTE AN) 2 mg' and carry out SN2 reaction at 95 °C for 15 minutes; (I) Cooling down and carrying out hydrolysis reaction 19: Next, the reaction mixture in the label bottle 40 was blown with air for 2 minutes. After the temperature is lowered, '15 ml of 0.1 N hydrochloric acid in the fifth drug bottle 34 is introduced into the label bottle 40 for hydrolysis reaction; (J) the hydrolyzed product passes through the C18 column 2 0: The hydrolyzed product of the label bottle 40 is passed through the activated C18 column 50 and rinsed with 12 ml of water in the third drug bottle 3 2; and (K) flow washed to purify 2 1 : Finally, 4 ml of the two gas methane in the fourth drug bottle 3 4 is used to wash the product from the C18 column 50 to collect the final product of the isotonic solution of fluorine-18-FDDNP collected in a collecting bottle 60. The waste liquid generated during the reaction is recovered from a waste bottle (Waste) 70. The radiochemical purity of the above-obtained fluorine-18-FDDNP is determined by a high pressure liquid chromatography (High Pressure Liquid 201004651).
Chromatography，HPLC)分析。其中，該 HPLC 之分析 管柱係採用Cl8分析級管柱，為4.6x150毫米（mm)， 其流動緩衝液則以四氫呋喃：甲醇：水為4〇:2〇:4〇之比例 ，以流速為0.5毫升/分鐘（ml/min)，以及紫外線為4〇〇 奈米（nm)進行分析。 在本發明所有反應均在一全自動合成盒裝置内進 行下，不僅可使操作人員接受劑量減低至最低劑量，且 於連續多次之合成操作過程中，氟-18_FDDNp平均產率 ❹均達到41.19±5.23%，並在經過上述HpLC分析條件下 ,其放射化學純度均可達標準值以上（9〇%以上），顯 示本發明之方法不僅反應時間短、產效高，且操作過程 簡單，可在提供醫學腦部斷層造影用之氟_丨8_FDDNp同 時，亦可有效降低製藥操作人員之輻射曝露以減少傷害 综上所述，本發明係一種氟-18-FDDNP自動合成合 方法，可有效改善過去操作人員手動標誌之種種缺點皿 ❾其:有反應均在一全自動合成盒裝置内進行，不僅可使 '製藥操作人員接受劑量減低至最低劑量，且於連續多次 之合成操作過程中’氟-HFDDNP平均產率均達到 41.19±5.23% ’並在經過HpLC分析條件下，其放射化 學純度均可標準值以上（9G%以上），㈣本發明之 方法不僅反應時間縮短、產效高，且操作過程簡單，可 在提供醫學腦部斷層造影用之氟-18-FDDNP同時，亦可 有效降低製藥操作人員之㈣曝露以減少傷害，進而使 本發明之産生能更進步、更實用、更符合使用者之所 201004651 須，確已符合發明專利申請之要件，爰依法提出專利 請。 惟以上所述者，僅為本發明之較佳實施例而已，當 不能以此限定本發明實施之範圍；故，凡依本發明申二 專利範圍及發明說明書内容所作之簡單的等效變化^ 修飾，皆應仍屬本發明專利涵蓋之範圍内。 、 【圖式簡單說明1 第1圖’係本發明之製作流程示意圖。 第2圖，係本發明氟-18-FDDNP合成反應之流程示意 ° 圖。 " 【主要元件符號說明】 步驟（A)〜（κ) 11〜21 第一藥品瓶3 〇 第二藥品瓶3 1 第三藥品瓶3 2 第四藥品瓶3 3 ▲ 第五藥品瓶3 4 馨 第六藥品瓶3 5 標幡瓶4 .0 C18管柱5 0 收集瓶6 0 廢液瓶7 0Chromatography, HPLC) analysis. Among them, the analytical column of the HPLC system is a Cl8 analytical grade column, which is 4.6×150 mm (mm), and the flow buffer is in the ratio of tetrahydrofuran:methanol:water to 4〇:2〇:4〇, at a flow rate of Analysis was carried out at 0.5 ml/min (ml/min) and ultraviolet light at 4 〇〇 nanometer (nm). All the reactions in the present invention are carried out in a fully automatic synthesizing device, which not only allows the operator to accept the dose to the lowest dose, but also has an average yield of fluoro-18_FDDNp of 41.19 during successive synthetic operations. ±5.23%, and under the above HpLC analysis conditions, the radiochemical purity can reach above the standard value (more than 9%), indicating that the method of the invention not only has short reaction time, high productivity, and the operation process is simple, While providing fluorine_丨8_FDDNp for medical brain tomography, it can also effectively reduce the radiation exposure of pharmaceutical operators to reduce the damage. The present invention is a fluorine-18-FDDNP automatic synthesis method, which can effectively improve In the past, the operator's manual markings have all the disadvantages: the reaction is carried out in a fully automatic synthesizing box device, which not only allows the 'pharmaceutical operator to accept the dose to the lowest dose, but also in the continuous multiple synthetic operations' The average yield of fluoro-HFDDNP reached 41.19±5.23%' and the radiochemical purity was above the standard value (9G% or more) under HpLC analysis. (4) The method of the invention not only shortens the reaction time, has high production efficiency, and has simple operation process, and can provide the fluorine-18-FDDNP for medical brain tomography, and can also effectively reduce the exposure of the pharmaceutical operator (4) to reduce Injury, in turn, makes the invention more promising, more practical, and more in line with the user's position 201004651. It has indeed met the requirements of the invention patent application, and the patent is filed according to law. However, the above is only the preferred embodiment of the present invention, and the scope of the present invention cannot be limited thereto; therefore, the simple equivalent change made according to the scope of the invention and the contents of the invention description of the present invention ^ Modifications are still within the scope of the invention. [Simplified illustration of the drawing 1 Fig. 1] is a schematic diagram of the production process of the present invention. Fig. 2 is a schematic flow chart showing the synthesis reaction of the fluorine-18-FDDNP of the present invention. " [Main component symbol description] Step (A) ~ (κ) 11~21 First drug bottle 3 〇 Second drug bottle 3 1 Third drug bottle 3 2 Fourth drug bottle 3 3 ▲ Fifth drug bottle 3 4 Xin sixth drug bottle 3 5 standard bottle 4 .0 C18 column 5 0 collection bottle 6 0 waste bottle 7 0