JP2010235462A - Method and apparatus for producing fluorine f-18 labeled compound using microchip - Google Patents

Method and apparatus for producing fluorine f-18 labeled compound using microchip Download PDF

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JP2010235462A
JP2010235462A JP2009082717A JP2009082717A JP2010235462A JP 2010235462 A JP2010235462 A JP 2010235462A JP 2009082717 A JP2009082717 A JP 2009082717A JP 2009082717 A JP2009082717 A JP 2009082717A JP 2010235462 A JP2010235462 A JP 2010235462A
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JP5431764B2 (en
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Katsuhiko Osaki
勝彦 大崎
Yosuke Mizukawa
陽介 水川
Shigeki Yamazaki
茂樹 山▲崎▼
Takehiko Kitamori
武彦 北森
Kazumasa Motai
和真 馬渡
Yoshikuni Kikutani
善国 菊谷
Shin Aota
新 青田
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Kanagawa Academy of Science and Technology
JFE Engineering Corp
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JFE Engineering Corp
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a fluorine F-18 labeled compound which can integrate, as an efficient operation on a microchip, the synthesis of the fluorine F-18 labeled compound of a multi-stage synthesis process including an evaporation operation. <P>SOLUTION: By using a microchip 1 having gas phase channels 14 in the inside and pooling zones 16 for storing a liquid phase at the bottom of the gas phase channels 14, a solution including a fluorine F-18 ion is introduced into the microchip 1 as the liquid phase. By utilizing the capillary force, the solution including a fluorine F-18 ion is dispersed into the pooling zones 16 of the microchip 1. The gas phase is run into the gas phase channels 14 to evaporate the solution including the fluorine F-18 ion stored in the pooling zones 16 to dryness. Since the evaporation operation with high efficiency can be achieved within the microchip 1, the synthetic process of a fluorine F-18 labeled compound including an evaporation operation such as evaporation to dryness or solvent distilling-away operation can be integrated on the microchip 1 with high efficiency. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

本発明は、ポジトロン放出断層撮影法（Positron emission tomography；ＰＥＴシステム）に用いられるフッ素Ｆ−１８標識化合物のマイクロチップを用いた製造方法及び装置に関する。   The present invention relates to a production method and apparatus using a microchip of a fluorine F-18 labeled compound used in positron emission tomography (PET system).

医療分野において、人体内部の状態を画像によって観察し診断する方法の一つとして、近年、陽電子を放出する物質を用いたＰＥＴシステムによる画像診断法が注目されている。ＣＴやＭＲＩが人体の組織の形態を観察するのに対し、ＰＥＴシステムは人体の機能を観察することに特化されている。ＰＥＴシステムによる画像診断法は、癌診断あるいは脳機能診断に有用であることが示されている。   In the medical field, as a method for observing and diagnosing an internal state of a human body with an image, in recent years, an imaging method using a PET system using a substance that emits positrons has attracted attention. Whereas CT and MRI observe the morphology of human tissue, the PET system is specialized in observing the function of the human body. It has been shown that an image diagnostic method using a PET system is useful for cancer diagnosis or brain function diagnosis.

ＰＥＴシステムで用いる放射性薬剤としては、ＦＤＧ（フルオロデオキシグルコース）などのフッ素Ｆ−１８で標識されたフッ素Ｆ−１８標識化合物、メチオニンなどの炭素Ｃ−１１で標識された炭素Ｃ−１１標識化合物などが挙げられる。これらの標識化合物は、サイクロトロンを用いて製造した短半減期の放射性同位元素（フッ素Ｆ−１８、炭素Ｃ−１１等）を原料として、自動遠隔操作が可能な合成装置を用いて合成される。   Examples of radiopharmaceuticals used in the PET system include fluorine F-18 labeled compounds labeled with fluorine F-18 such as FDG (fluorodeoxyglucose), carbon C-11 labeled compounds labeled with carbon C-11 such as methionine, and the like. Is mentioned. These labeled compounds are synthesized using a short-lived radioisotope (fluorine F-18, carbon C-11, etc.) produced using a cyclotron as a raw material using a synthesizer capable of automatic remote operation.

近年、このような標識化合物のうち、フッ素Ｆ−１８標識化合物の合成にマイクロ化学システムの適用が試みられている。マイクロ化学システムにおいて、反応操作を微小な反応流路内で行うことが提案されている。微小な反応流路を用いて化学反応を行う場合、マイクロチップに微小な流路を形成し、その流路内で試料流体を混合して化学反応を行わせる。この場合のマイクロチップは通常、厚さ数ｍｍ程度の薄い基板に流路が形成されたものである。利点としては除熱に優れ、温度制御が容易であること、使用する試料流体や反応溶媒の量が少量ですむことなどが挙げられる。また、マイクロチップに合成プロセスを集積化することができれば、装置の小型化などの利点が得られる。   In recent years, among such labeled compounds, application of a microchemical system has been attempted for the synthesis of fluorine F-18 labeled compounds. In a microchemical system, it has been proposed to perform a reaction operation in a minute reaction channel. When a chemical reaction is performed using a minute reaction channel, a minute channel is formed on the microchip, and a sample fluid is mixed in the channel to cause a chemical reaction. In this case, the microchip usually has a channel formed on a thin substrate having a thickness of about several mm. Advantages include excellent heat removal, easy temperature control, and a small amount of sample fluid and reaction solvent. Further, if the synthesis process can be integrated on the microchip, advantages such as downsizing of the apparatus can be obtained.

フッ素Ｆ−１８標識化合物のマイクロチップを用いた合成例は、特許文献１及び特許文献２に開示されている。しかしながら、フッ素Ｆ−１８標識化合物の合成はフッ素Ｆ−１８標識反応及び加水分解反応の２反応を含み、その合成プロセスは通常６段階程度の多段階で実施される。フッ素Ｆ−１８標識反応は水分をきらう無水反応であるので、反応に先立ち、水分除去のための蒸発操作を十分に行わなければならない。また、最終薬剤調製のため、反応時に使用した有機溶媒を十分に留去しなければならない。このような蒸発操作については、マイクロチップ内での実施は難しいので、特許文献１及び特許文献２では、どちらの例でも、マイクロチップ内で行っているのは反応操作のみである。すなわち、これらの例では、マイクロチップ外の容器内で溶媒の蒸発操作を行い、マイクロチップ内での蒸発操作は行っていないので、全ての合成プロセスをマイクロチップ上に集積化することができていない。   Examples of synthesis using a microchip of a fluorine F-18 labeled compound are disclosed in Patent Document 1 and Patent Document 2. However, the synthesis of a fluorine F-18 labeled compound includes two reactions of a fluorine F-18 labeling reaction and a hydrolysis reaction, and the synthesis process is usually carried out in multiple steps of about six steps. Since the fluorine F-18 labeling reaction is an anhydrous reaction that dissipates moisture, an evaporation operation for removing water must be sufficiently performed prior to the reaction. Moreover, the organic solvent used at the time of reaction must be distilled off sufficiently for final drug preparation. Since such an evaporation operation is difficult to implement in the microchip, in both Patent Documents 1 and 2, only the reaction operation is performed in the microchip in both examples. That is, in these examples, the solvent evaporation operation is performed in a container outside the microchip, and the evaporation operation is not performed in the microchip, so that all synthesis processes can be integrated on the microchip. Absent.

フッ素Ｆ−１８標識化合物の全ての合成プロセスをマイクロチップ内に集積化する初めての試みが非特許文献１に発表されている。この合成例では、蒸発操作は気体透過膜を介した操作となるため、微量の液体であるにもかかわらず、蒸発に時間がかかり、効率的な蒸発操作が実施できていない。放射性核種であるフッ素Ｆ−１８の半減期は１１０分であるため、このように合成プロセスに時間がかかるとフッ素Ｆ−１８標識化合物の収率が低下する。また、本合成例の方法では、蒸発操作を行う液量が多い場合は、さらに合成プロセスに時間がかかり、収率が低下することとなる。   Non-Patent Document 1 discloses the first attempt to integrate all the synthesis processes of a fluorine F-18 labeled compound in a microchip. In this synthesis example, since the evaporation operation is an operation through the gas permeable membrane, it takes time to evaporate even though it is a very small amount of liquid, and an efficient evaporation operation cannot be performed. Since the half-life of fluorine F-18, which is a radionuclide, is 110 minutes, the yield of the fluorine F-18-labeled compound decreases when the synthesis process takes a long time. Further, in the method of this synthesis example, when the amount of the liquid to be evaporated is large, the synthesis process takes more time and the yield is reduced.

特表２００５−５２０８２７号公報Japanese translation of PCT publication No. 2005-52027 特表２００６−５２７３６７号公報JP-T-2006-527367

ＳＣＩＥＮＣＥ ＶＯＬ３１０ １６ ＤＥＣＥＭＢＥＲ ２００５SCIENCE VOL310 16 DECEMBER 2005

このように、従来は、マイクロチップ内で蒸発操作を効率良く行うことが実現できていない。この発明は、上記のような問題点を解決するためになされたものであり、蒸発操作を含む多段階合成プロセスであるフッ素Ｆ−１８標識化合物の合成を、効率的なマイクロチップ上の操作として集積化することを課題としている。より具体的には、ＦＤＧ等のフッ素Ｆ−１８標識化合物の合成を行うための新しいマイクロチップを用いた製造方法及び装置を提供することを課題とする。   Thus, conventionally, it has not been possible to efficiently perform the evaporation operation in the microchip. The present invention has been made to solve the above-described problems. The synthesis of a fluorine F-18 labeled compound, which is a multi-step synthesis process including an evaporation operation, is performed as an efficient operation on a microchip. The issue is to integrate. More specifically, an object of the present invention is to provide a production method and apparatus using a new microchip for synthesizing a fluorine F-18 labeled compound such as FDG.

上記課題を解決するために、本発明の一態様は、マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法であって、内部に気相の流路を有すると共に、前記気相の流路の底部に液相を溜めるプール部を有するマイクロチップに液相としてフッ素Ｆ−１８イオンを含んだ溶液を導入し、前記マイクロチップの前記プール部に毛管力を利用して前記フッ素Ｆ−１８イオンを含んだ溶液を分散させる工程と、前記気相の流路に気相を流して、前記プール部に溜められた前記フッ素Ｆ−１８イオンを含んだ溶液を蒸発乾固させる工程と、を備えるマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法である。   In order to solve the above-described problems, one embodiment of the present invention is a method for producing a fluorine F-18 labeled compound using a microchip, which has a gas-phase channel therein and the gas-phase channel. A solution containing fluorine F-18 ions as a liquid phase is introduced into a microchip having a pool portion for storing a liquid phase at the bottom of the microchip, and the fluorine F-18 ions are applied to the pool portion of the microchip using capillary force. And a step of evaporating and drying the solution containing the fluorine F-18 ions stored in the pool part by flowing a gas phase through the gas phase flow path. This is a method for producing a fluorine F-18 labeled compound using a microchip.

本発明の他の態様は、マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法であって、内部に気相の流路を有すると共に、前記気相の流路の底部に液相を溜めるプール部を有するマイクロチップに液相として、フッ素Ｆ−１８イオンと前駆体を含んだ溶液とを反応させることにより生じたフッ素Ｆ−１８標識中間体を含んだ溶液を導入し、前記マイクロチップの前記プール部に毛管力を利用して前記フッ素Ｆ−１８標識中間体を含んだ溶液を分散させる工程と、前記気相の流路に気相を流して、前記プール部に溜められた前記フッ素Ｆ−１８標識中間体を含んだ溶液を蒸発させ、前記フッ素Ｆ−１８標識中間体を含んだ溶液より溶媒を除去する工程と、を備えるマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法である。   Another aspect of the present invention is a method for producing a fluorine F-18 labeled compound using a microchip, which has a gas phase flow channel therein and stores a liquid phase at the bottom of the gas phase flow channel. A solution containing a fluorine F-18 labeled intermediate produced by reacting fluorine F-18 ions with a solution containing a precursor as a liquid phase is introduced into a microchip having a pool part, and A step of dispersing the solution containing the fluorine F-18 labeled intermediate in the pool part using capillary force; and a step of flowing a gas phase in the gas phase flow path to store the fluorine in the pool part. Evaporating a solution containing the F-18 labeled intermediate and removing the solvent from the solution containing the fluorine F-18 labeled intermediate, and a method for producing a fluorine F-18 labeled compound using a microchip. It is.

本発明のさらに他の態様は、マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造装置であって、内部に気相の流路を有すると共に、前記気相の流路の底部に液相を溜めるプール部を有するマイクロチップと、前記マイクロチップに液相としてフッ素Ｆ−１８イオンを含んだ溶液を導入し、前記マイクロチップの前記プール部に毛管力を利用して前記フッ素Ｆ−１８イオンを含んだ溶液を分散させる液相導入手段と、前記マイクロチップの前記気相の流路に気相を流して、前記プール部に溜められた前記フッ素Ｆ−１８イオンを含んだ溶液を蒸発乾固させる気相操作手段と、を備えるマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造装置である。   Yet another embodiment of the present invention is a fluorine F-18 labeled compound production apparatus using a microchip, which has a gas phase flow channel inside and a liquid phase at the bottom of the gas phase flow channel. A microchip having a pool part to be pooled, a solution containing fluorine F-18 ions as a liquid phase is introduced into the microchip, and the fluorine F-18 ions are introduced into the pool part of the microchip using capillary force. A liquid phase introducing means for dispersing the contained solution; and a gas phase is caused to flow through the gas phase flow path of the microchip, and the solution containing the fluorine F-18 ions stored in the pool portion is evaporated to dryness. An apparatus for producing a fluorine F-18-labeled compound using a microchip.

本発明のさらに他の態様は、マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造装置であって、内部に気相の流路を有すると共に、前記気相の流路の底部に液相を溜めるプール部を有するマイクロチップと、前記マイクロチップに液相として、フッ素Ｆ−１８イオンと前駆体を含んだ溶液とを反応させることにより生じたフッ素Ｆ−１８標識中間体を含んだ溶液を導入し、前記マイクロチップの前記プール部に毛管力を利用して前記フッ素Ｆ−１８標識中間体を含んだ溶液を分散させる液相導入手段と、前記マイクロチップの前記気相の流路に気相を流して、前記プール部に溜められた前記フッ素Ｆ−１８標識中間体を含んだ溶液を蒸発させ、前記フッ素Ｆ−１８標識中間体を含んだ溶液より溶媒を除去する気相操作手段と、を備えるマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造装置である。   Yet another embodiment of the present invention is a fluorine F-18 labeled compound production apparatus using a microchip, which has a gas phase flow channel inside and a liquid phase at the bottom of the gas phase flow channel. A microchip having a pool portion to be stored and a solution containing a fluorine F-18 labeled intermediate produced by reacting a solution containing fluorine F-18 ions and a precursor as a liquid phase are introduced into the microchip. Liquid phase introducing means for dispersing the solution containing the fluorine F-18 labeled intermediate in the pool portion of the microchip using capillary force; and a gas phase in the gas phase flow path of the microchip. Gas phase operation means for evaporating the solution containing the fluorine F-18 labeled intermediate stored in the pool portion and removing the solvent from the solution containing the fluorine F-18 labeled intermediate; With Microchip an apparatus for manufacturing a fluorine-F-18-labeled compounds using.

本発明によれば、マイクロチップ内での高効率での蒸発操作が実現できるので、蒸発乾固あるいは溶媒留去操作などの蒸発操作を含むフッ素Ｆ−１８標識化合物の合成プロセスを高効率にマイクロチップ上に集積化することが可能になる。   According to the present invention, the highly efficient evaporation operation in the microchip can be realized, so that the process of synthesizing the fluorine F-18 labeled compound including the evaporation operation such as evaporation to dryness or solvent evaporation operation can be performed with high efficiency. It can be integrated on a chip.

本発明の第一の実施形態のフッ素Ｆ−１８標識化合物の製造方法（バッチ方式）に用いられるマイクロチップの概念図The conceptual diagram of the microchip used for the manufacturing method (batch system) of the fluorine F-18 labeled compound of 1st embodiment of this invention. 上記マイクロチップのプール部の断面図Cross-sectional view of the pool part of the microchip 上記マイクロチップの固相ビーズ部の流れ方向に沿った断面図Sectional view along the flow direction of the solid phase bead part of the microchip 本発明の第二の実施形態のフッ素Ｆ−１８標識化合物の製造方法（フロー方式）に用いられるマイクロチップの概念図The conceptual diagram of the microchip used for the manufacturing method (flow system) of the fluorine F-18 labeling compound of 2nd embodiment of this invention.

以下、発明の実施形態を説明する。本発明のフッ素Ｆ−１８標識化合物の製造方法の実施形態には、第一の実施形態のバッチ合成方法と、第二の実施形態のフロー合成方法とがある。まず、第一の実施形態のバッチ合成方法について説明する。   Embodiments of the invention will be described below. Embodiments of the method for producing a fluorine F-18 labeled compound of the present invention include the batch synthesis method of the first embodiment and the flow synthesis method of the second embodiment. First, the batch synthesis method of the first embodiment will be described.

図１は、バッチ合成方法に用いられるマイクロチップ１を示す。マイクロチップ１は、固相ビーズ充填部１３，１５（固相ビーズ充填部１３及び第二の固相ビーズ充填部１５）、プール部１６としての微細加工溝部１６より構成される。   FIG. 1 shows a microchip 1 used in a batch synthesis method. The microchip 1 includes solid phase bead filling portions 13 and 15 (the solid phase bead filling portion 13 and the second solid phase bead filling portion 15) and a microfabricated groove portion 16 as a pool portion 16.

微細加工溝部１６は、マイクロチップの気相の流路１４の底面に形成した溝に毛管力を利用して液相を分散させ、溝に液相を溜めて蒸発操作を行うことを基本操作としている。この蒸発操作は、マイクロチップの流路（マイクロチャンネル）という微小な限定空間内での蒸発操作となり、マイクロチップ内に液相を分散させることにより、比界面積が大きく、蒸発速度が速いという原理的な特徴を有している。   The microfabricated groove 16 has a basic operation in which a liquid phase is dispersed using a capillary force in a groove formed on the bottom surface of the gas phase flow path 14 of the microchip, and an evaporation operation is performed by accumulating the liquid phase in the groove. Yes. This evaporation operation is an evaporation operation in a minute limited space called a microchip channel (microchannel), and the principle is that the liquid phase is dispersed in the microchip, resulting in a large specific interface area and a high evaporation rate. It has the characteristic.

たとえばガラス、セラミックス、シリコン、あるいは樹脂製の基板２の上面には、プール部として、微細加工によって複数の微細加工溝部１６が形成されている。この微細加工溝部１６は、例えばドリルによる加工、レーザ加工、エッチング加工などによって形成される。微細加工溝部１６は、一本の中央溝１６ａと、一本の中央溝１６ａから分岐する複数本の分岐溝１６ｂと、から構成される。複数本の分岐溝１６ｂは、一定の間隔で並列に配列される。微細加工溝部１６の流れ方向の端部には、微細加工溝部１６よりも深いザグリ穴１７が空けられる。この微細加工溝部１６に毛管力によって液相が導入される。   For example, on the upper surface of the substrate 2 made of glass, ceramics, silicon, or resin, a plurality of microfabricated grooves 16 are formed by microfabrication as a pool portion. The finely processed groove 16 is formed by, for example, drilling, laser processing, etching, or the like. The microfabricated groove portion 16 includes a single central groove 16a and a plurality of branch grooves 16b branched from the single central groove 16a. The plurality of branch grooves 16b are arranged in parallel at regular intervals. A counterbore hole 17 deeper than the microfabricated groove 16 is formed at the end of the micromachined groove 16 in the flow direction. A liquid phase is introduced into the microfabricated groove 16 by capillary force.

微細加工溝部１６の大きさや長さについては特に限定はないが、マイクロチップ１上のマイクロ化学システムを構成し、毛管作用を発揮する適宜な設定とする。例えば微細加工溝部１６の流れ方向に直交する断面についてみると、その幅は、５００μｍ、深さは７００μｍ程度を実際的な目安とすることができる。   The size and length of the microfabricated groove 16 are not particularly limited, but the microchemical system on the microchip 1 is configured to have an appropriate setting that exhibits capillary action. For example, looking at a cross section perpendicular to the flow direction of the microfabricated groove 16, a width of about 500 μm and a depth of about 700 μm can be used as a practical guide.

マイクロチップ１は、内部に窒素ガス等の気相の流路１４を有する。マイクロチップ１内の液相の上に気相が導入される。微細加工溝部１６が形成されている基板２上には、側壁である中板３が設けられる。中板３には、微細加工溝部１６の平面形状に合わせた気相の流路１４が形成される。また中板３には、気相及び液相の導入路８、気相及び液相の排出路７が形成される。中板３の上面には、蓋であるカバー上板４が設けられる。カバー上板４には、気相及び液相の導入路８、気相及び液相の排出路７が形成される。これら基板２、中板３、カバー上板４によって、気相および液相が散逸されないようにしている。   The microchip 1 has a gas-phase flow path 14 such as nitrogen gas inside. A gas phase is introduced on the liquid phase in the microchip 1. On the substrate 2 on which the microfabricated grooves 16 are formed, an intermediate plate 3 that is a side wall is provided. The intermediate plate 3 is formed with a gas phase flow path 14 that matches the planar shape of the microfabricated groove 16. The intermediate plate 3 is formed with a gas phase and liquid phase introduction path 8 and a gas phase and liquid phase discharge path 7. A cover upper plate 4 as a lid is provided on the upper surface of the intermediate plate 3. The cover upper plate 4 is formed with a gas phase and liquid phase introduction path 8 and a gas phase and liquid phase discharge path 7. These substrate 2, middle plate 3, and cover upper plate 4 prevent the gas phase and the liquid phase from being dissipated.

シリンジポンプやガス圧ポンプ等の流体制御機構（液相導入手段）を用いて、液相の導入路８に液相を供給すると、図２に示すように、毛管作用により液相が微細加工溝部１６の全体に分散する。微細加工溝部１６の上方の気相の流路１４に気相を流すと、微細加工溝部１６に分散した液相が蒸発する。気相操作手段には、シリンジポンプやガス圧ポンプ等の流体制御機構を用いて、気相の導入路８に窒素ガス等を供給する手段、又は真空ポンプ等の吸引機構を用いて、液相から蒸発した蒸気を気相の排出路７から吸引する手段が採用される。これら流体制御機構、吸引機構を併用してもよい。   When a liquid phase is supplied to the liquid phase introduction path 8 using a fluid control mechanism (liquid phase introduction means) such as a syringe pump or a gas pressure pump, the liquid phase is finely processed by capillary action as shown in FIG. 16 is distributed throughout. When a gas phase is caused to flow in the gas phase flow path 14 above the microfabricated groove portion 16, the liquid phase dispersed in the microfabricated groove portion 16 is evaporated. As the gas phase operation means, a fluid control mechanism such as a syringe pump or a gas pressure pump is used, a means for supplying nitrogen gas or the like to the gas phase introduction path 8, or a suction mechanism such as a vacuum pump is used for the liquid phase. A means for sucking the vapor evaporated from the gas from the gas-phase discharge passage 7 is employed. These fluid control mechanism and suction mechanism may be used in combination.

蒸発操作は、マイクロチップの少なくとも一部を加熱しながら行う。デバイス構成及び加熱操作性の観点から、微細加工溝部１６を設けた基板２の背面部あるいはカバー上板４の表面部にヒータを設けることが望ましい。   The evaporation operation is performed while heating at least a part of the microchip. From the viewpoint of device configuration and heating operability, it is desirable to provide a heater on the back surface portion of the substrate 2 provided with the microfabricated grooves 16 or on the surface portion of the cover upper plate 4.

液相は毛管作用により微細加工溝部１６にとどまり、マイクロチップ１内に分散される。このため、気相の排出路７に気体透過膜を設置しなくても、液相が気相の排出路７から排出されることはない。微細加工溝部１６において液相の少なくとも一部が蒸発し、気相の排出路より排出されるが、気体透過膜が設置されている場合でも、液相により膜を塞ぐことがないため、効率的な蒸発操作が達成される。   The liquid phase remains in the microfabricated grooves 16 by capillary action and is dispersed in the microchip 1. For this reason, even if a gas permeable membrane is not installed in the gas phase discharge path 7, the liquid phase is not discharged from the gas phase discharge path 7. At least a part of the liquid phase evaporates in the microfabricated groove 16 and is discharged from the gas phase discharge path. Even when a gas permeable film is installed, the liquid phase does not block the film, which is efficient. Evaporative operation is achieved.

図１に示すように、中板３の上面には、固相ビーズ充填部１３，１５（固相ビーズ充填部１３，第二の固相ビーズ充填部１５）が切削加工により設けられている。固相ビーズ充填部１３，１５の大きさや長さについて特に限定はないが、マイクロチップ１上のマイクロ化学システムを構成し、十分な分離・精製作用を発揮する適宜な設定とする。例えば固相ビーズ充填部１３，１５の流れ方向に直交する断面についてみると、その幅は、固相ビーズ充填部１３において、幅は１ｍｍ、深さは５００μｍ程度、固相ビーズ充填部１５において、幅は６ｍｍ、深さ１ｍｍ程度を実際的な目安とすることができる。   As shown in FIG. 1, solid phase bead filling portions 13 and 15 (solid phase bead filling portion 13 and second solid phase bead filling portion 15) are provided on the upper surface of the intermediate plate 3 by cutting. There are no particular limitations on the size and length of the solid-phase bead filling portions 13 and 15, but the microchemical system on the microchip 1 is configured to have an appropriate setting that exhibits a sufficient separation and purification action. For example, looking at the cross section orthogonal to the flow direction of the solid phase bead filling portions 13, 15, the width is about 1 mm and the depth is about 500 μm at the solid phase bead filling portion 13. A width of about 6 mm and a depth of about 1 mm can be used as a practical guide.

図３に示すように、固相ビーズ充填部１３，１５は、流れ方向の両端がダム構造となっており、充填された固相ビーズが流出しないようになっている。固相ビーズ充填部１３，１５の液相の流れ方向の両端部には、流路の底面が盛り上がったダム部１３ａ，１５ａが設けられる。ダム部１３ａ，１５ａを設けることにより液相の流路の高さｈは、約３０μｍ程度になり、固相ビーズの直径未満になる。ダム部１３ａ，１５ａは、固相ビーズ充填部を液相が流れるのを許容すると共に、固相ビーズ充填部１３，１５から固相ビーズが流出するのを防止する。固相ビーズ充填部１３には、陰イオン交換樹脂の固相ビーズ１８が充填される。固相ビーズ充填部１５には、固相ビーズ１８として陽イオン交換樹脂、逆相系樹脂、アルミナが順番に層状に充填される。   As shown in FIG. 3, the solid-phase bead filling sections 13 and 15 have a dam structure at both ends in the flow direction so that the filled solid-phase beads do not flow out. At both ends of the solid phase bead filling portions 13 and 15 in the flow direction of the liquid phase, dam portions 13a and 15a with raised bottom surfaces of the flow paths are provided. By providing the dam portions 13a and 15a, the height h of the liquid phase channel is about 30 μm, which is less than the diameter of the solid phase beads. The dam portions 13a and 15a allow the liquid phase to flow through the solid phase bead filling portion and prevent the solid phase beads from flowing out from the solid phase bead filling portions 13 and 15. The solid phase bead filling unit 13 is filled with solid phase beads 18 of anion exchange resin. The solid phase bead filling unit 15 is filled with a cation exchange resin, a reverse phase resin, and alumina in order as a solid phase bead 18.

上記マイクロチップ１を用いた本発明の第一の実施形態のバッチ合成方法は以下のとおりである。   The batch synthesis method of the first embodiment of the present invention using the microchip 1 is as follows.

まず、固相ビーズ充填部１３にフッ素Ｆ−１８を精製するための陰イオン交換樹脂を充填する。固相ビーズ充填部１３にサイクロトロンで製造したフッ素Ｆ−１８イオン含有酸素Ｏ−１８濃縮水を流し、フッ素Ｆ−１８イオンをトラップさせ、炭酸カリウム及び相間移動触媒クリプタンドを含むアセトニトリル／水溶液などの溶離液を流して、フッ素Ｆ−１８イオンを溶離する。このような操作により酸素Ｏ−１８濃縮水の回収及びフッ素Ｆ−１８イオンの精製が可能となる。   First, the solid phase bead filling unit 13 is filled with an anion exchange resin for purifying fluorine F-18. Fluorine F-18 ion-containing oxygen O-18 concentrated water produced by a cyclotron is passed through the solid phase bead filling section 13 to trap fluorine F-18 ions, and elution of acetonitrile / aqueous solution containing potassium carbonate and phase transfer catalyst cryptand, etc. The solution is run to elute fluorine F-18 ions. Such an operation enables recovery of oxygen O-18 concentrated water and purification of fluorine F-18 ions.

次に、微細加工溝部１６にフッ素Ｆ−１８イオンを含んだ溶離液を供給し、プール部を加熱し、窒素ガスを流しながら蒸発乾固を行う。蒸発乾固を行った後、反応前駆体を含んだ溶液を微細加工溝部１６、又は微細加工溝部１６及びチップ内空間（気相の流路）１４に供給し、標識反応を行う。標識反応を行った後、そのまま、窒素ガスを流しながら反応溶媒の留去を行うことが可能である。溶媒留去を行った後、加水分解試薬である水酸化ナトリウムまたは塩酸等を微細加工溝部１６、又は微細加工溝部１６及びチップ内空間１４に供給し、加水分解反応を行う。微細加工溝部１６において加水分解反応を行った後、注射用蒸留水等を微細加工溝部１６及びチップ内空間１４に供給し、加水分解反応生成物を洗い出す。   Next, an eluent containing fluorine F-18 ions is supplied to the microfabricated groove portion 16, the pool portion is heated, and evaporated to dryness while flowing nitrogen gas. After evaporation to dryness, a solution containing a reaction precursor is supplied to the microfabricated groove 16 or the microfabricated groove 16 and the chip internal space (gas phase flow path) 14 to perform a labeling reaction. After carrying out the labeling reaction, it is possible to distill off the reaction solvent while flowing nitrogen gas as it is. After the solvent is distilled off, a hydrolysis reagent such as sodium hydroxide or hydrochloric acid is supplied to the microfabricated groove 16 or the microfabricated groove 16 and the chip internal space 14 to perform a hydrolysis reaction. After performing the hydrolysis reaction in the microfabricated groove portion 16, distilled water for injection or the like is supplied to the microfabricated groove portion 16 and the chip inner space 14 to wash out the hydrolysis reaction product.

固相ビーズ充填部１５にはフッ素Ｆ−１８標識化合物を精製するための陽イオン交換樹脂、逆相系樹脂、アルミナ等が充填される。固相ビーズ充填部１５に合成したフッ素Ｆ−１８標識化合物を流すことにより未加水分解物、未標識反応物などをトラップし、フッ素Ｆ−１８標識化合物を精製することが可能となる。以上が本発明の第一の実施形態のバッチ合成方法である。   The solid phase bead filling portion 15 is filled with a cation exchange resin, a reverse phase resin, alumina or the like for purifying the fluorine F-18 labeled compound. By flowing the fluorine F-18 labeled compound synthesized in the solid phase bead filling portion 15, it is possible to trap unhydrolyzed products, unlabeled reactants, etc., and purify the fluorine F-18 labeled compound. The above is the batch synthesis method of the first embodiment of the present invention.

固相ビーズ充填部１３には、また、フッ素Ｆ−１８をトラップし、標識反応を行うためのピリジニウム塩、ホスホニウム塩等のオニウム塩樹脂を充填することも可能である。この場合、固相ビーズ充填部１３にサイクロトロンで製造したフッ素Ｆ−１８イオン含有酸素Ｏ−１８濃縮水を流し、フッ素Ｆ−１８イオンをトラップさせ、温度をかけて、アセトニトリル等の反応溶媒を流して、フッ素Ｆ−１８イオンを活性化し、反応前駆体を含んだ溶液を固相ビーズ充填部１３に供給し、標識反応を行うことが可能である。標識反応終了後の溶液は、微細加工溝部１６に供給され、その後のプロセスは微細加工溝部１６にて同様に実施することが可能である。   The solid phase bead filling section 13 can also be filled with an onium salt resin such as a pyridinium salt or a phosphonium salt for trapping fluorine F-18 and performing a labeling reaction. In this case, a fluorine F-18 ion-containing oxygen O-18 concentrated water produced by a cyclotron is caused to flow into the solid phase bead filling portion 13 to trap the fluorine F-18 ions, a temperature is applied, and a reaction solvent such as acetonitrile is allowed to flow. Then, it is possible to activate the fluorine F-18 ion and supply a solution containing the reaction precursor to the solid phase bead filling unit 13 to perform the labeling reaction. The solution after completion of the labeling reaction is supplied to the microfabricated groove 16, and the subsequent process can be similarly performed in the microfabricated groove 16.

図４は、本発明の第二の実施形態のフロー合成方法に用いられるマイクロチップを示す。このマイクロチップ２１は、二つの固相ビーズ充填部３９，４６（固相ビーズ充填部３９，第二の固相ビーズ充填部４６）、二つの微細加工溝部４０，４３（プール部４０，第二のプール部４３）、二つのマイクロチャンネル部４２，４５（微細流路部４２、第二の微細流路部４５）より構成される。   FIG. 4 shows a microchip used in the flow synthesis method of the second embodiment of the present invention. The microchip 21 includes two solid-phase bead filling portions 39 and 46 (solid-phase bead filling portion 39 and second solid-phase bead filling portion 46), and two microfabricated groove portions 40 and 43 (pool portion 40 and second solid-phase bead filling portion 46). Pool portion 43) and two microchannel portions 42 and 45 (a fine flow passage portion 42 and a second fine flow passage portion 45).

微細加工溝部４０，４３は、上記マイクロチップ１の微細加工溝部１６と同様に、マイクロチップの気相の流路４１,４４の底面に形成した溝に毛管力を利用して液相を分散させ、溝に液相を溜めて蒸発操作を行うことを基本操作としている。   The microfabricated grooves 40 and 43 disperse the liquid phase using the capillary force in the grooves formed in the bottom surfaces of the gas phase flow channels 41 and 44 of the microchip, similarly to the microfabricated grooves 16 of the microchip 1. The basic operation is to perform the evaporation operation by accumulating the liquid phase in the groove.

基板２２の上面には、固相ビーズ充填部３９，４６が切削加工により設けられる。固相ビーズ充填部３９，４６は、充填された固相ビーズが流出しないように流れ方向の両端がダム構造となっている。固相ビーズ充填部３９，４６には、陰イオン交換樹脂、陽イオン交換樹脂、逆相系樹脂等の固相ビーズが充填される。   On the upper surface of the substrate 22, solid phase bead filling portions 39 and 46 are provided by cutting. The solid-phase bead filling portions 39 and 46 have dam structures at both ends in the flow direction so that the filled solid-phase beads do not flow out. The solid phase bead filling portions 39 and 46 are filled with solid phase beads such as anion exchange resin, cation exchange resin, and reverse phase resin.

マイクロチャンネル部４２，４５は、カバー上板２４の下面に蛇行して形成される溝からなる。このマイクロチャンネル部４２，４５で化学反応が行われる。ビーカーやフラスコを使用する場合と比べて反応スペースが狭いので、拡散距離が短くなり、それだけ反応時間を短縮できる。   The microchannel portions 42 and 45 are grooves formed to meander on the lower surface of the cover upper plate 24. A chemical reaction is performed in the microchannel portions 42 and 45. Compared to the use of a beaker or flask, the reaction space is narrow, so the diffusion distance is shortened and the reaction time can be shortened accordingly.

上記マイクロチップ２１を用いた本発明の第二の実施形態のフロー合成方法は以下のとおりである。   The flow synthesis method of the second embodiment of the present invention using the microchip 21 is as follows.

まず、固相ビーズ充填部３９にフッ素Ｆ−１８を精製するための陰イオン交換樹脂を充填する。固相ビーズ充填部３９にサイクロトロンで製造したフッ素Ｆ−１８イオン含有酸素Ｏ−１８濃縮水を流し、フッ素Ｆ−１８イオンをトラップさせ、炭酸カリウム及び相間移動触媒クリプタンドを含むアセトニトリル／水溶液などの溶離液を流して、フッ素Ｆ−１８イオンを溶離する。このような操作により酸素Ｏ−１８濃縮水の回収及びフッ素Ｆ−１８イオンの精製が可能となる。   First, the solid phase bead filling unit 39 is filled with an anion exchange resin for purifying fluorine F-18. Fluorine F-18 ion-containing oxygen O-18 concentrated water produced by a cyclotron is passed through the solid phase bead filling section 39 to trap the fluorine F-18 ions, and elution of acetonitrile / aqueous solution containing potassium carbonate and phase transfer catalyst cryptand, etc. The solution is run to elute fluorine F-18 ions. Such an operation enables recovery of oxygen O-18 concentrated water and purification of fluorine F-18 ions.

次に、微細加工溝部４０にフッ素Ｆ−１８イオンを含んだ溶離液を供給し、微細加工溝部４０を加熱し、窒素ガスを流しながら蒸発乾固を行う。蒸発乾固を行った後、反応前駆体であるトリフレートを含んだ溶液を微細加工溝部４０、又は微細加工溝部４０及びチップ内空間４１に供給し、溝表面に乾固された物質を洗い出してマイクロチャンネル部４２に通して標識反応を行う。   Next, an eluent containing fluorine F-18 ions is supplied to the microfabricated groove portion 40, the microfabricated groove portion 40 is heated, and evaporated to dryness while flowing nitrogen gas. After evaporating to dryness, a solution containing triflate as a reaction precursor is supplied to the microfabricated groove 40 or the microfabricated groove 40 and the chip internal space 41, and the material dried on the groove surface is washed out. The labeling reaction is performed through the microchannel section 42.

次に、標識反応後のフッ素Ｆ−１８標識中間体をもうひとつの微細加工溝部４３に供給し、窒素ガスを流しながら反応溶媒の留去を行う。溶媒留去を行った後、加水分解試薬である水酸化ナトリウムまたは塩酸等を微細加工溝部４３、又は微細加工溝部４３及びチップ内空間４４に供給し、溝に濃縮された物質を洗い出してマイクロチャンネル部４５に通して加水分解反応を行う。引き続き、注射用蒸留水等を微細加工溝部４３、微細加工溝部４３及びチップ内空間４４に供給し、マイクロチャンネル部４５を通すことにより、加水分解反応生成物を洗い出す。   Next, the fluorine F-18 labeling intermediate after the labeling reaction is supplied to another finely processed groove 43, and the reaction solvent is distilled off while flowing nitrogen gas. After the solvent is distilled off, sodium hydroxide or hydrochloric acid, which is a hydrolysis reagent, is supplied to the microfabricated groove 43, or the microfabricated groove 43 and the chip inner space 44, and the substance concentrated in the groove is washed out to obtain a microchannel. The hydrolysis reaction is conducted through part 45. Subsequently, distilled water for injection or the like is supplied to the microfabricated groove portion 43, the microfabricated groove portion 43, and the chip inner space 44, and the hydrolysis reaction product is washed out through the microchannel portion 45.

以上のように、マイクロチップ内での高効率での蒸発操作が実現できるので、蒸発乾固あるいは溶媒留去操作などの蒸発操作を伴う工程を含むフッ素Ｆ−１８標識化合物の合成プロセスを高効率にマイクロチップ上に集積化することが可能になる。   As described above, since a highly efficient evaporation operation in the microchip can be realized, a highly efficient synthesis process of a fluorine F-18-labeled compound including a process involving an evaporation operation such as evaporation to dryness or a solvent evaporation operation is highly efficient. It is possible to integrate on a microchip.

以下に実施例を示し、マイクロチップ１を用いた例をさらに詳しく説明する。勿論、以下の実施例によって発明が限定されることはない。   Examples will be described below, and an example using the microchip 1 will be described in more detail. Of course, the invention is not limited by the following examples.

図１に示すように、マイクロチップ１は、２つの固相ビーズ充填部１３，１５と微細加工溝部１６より構成される。固相ビーズ充填部１３，１５は両端の高さｈが３０μｍのダム構造となっており、固相ビーズ充填部１３は幅１．０ｍｍ、深さ０．５ｍｍで、陰イオン交換樹脂を充填した。固相ビーズ充填部１５は幅６．０ｍｍ、深さ１．０ｍｍであり、陽イオン交換樹脂、逆相系樹脂、アルミナを充填した。陰イオン交換樹脂の直径は３７−５５μｍ、陽イオン交換樹脂の直径は７５−１５０μｍ、逆相系樹脂の直径５５−１０５μｍ、アルミナの直径は５０−３００μｍ程度である。このマイクロチップ１を用いてフッ素Ｆ−１８標識ＦＤＧの合成を行った。微細加工溝部１６はチャンネル幅３００μｍ、深さ５００μｍである。ザグリ穴１７の深さは８００μｍである。マイクロチップの基板２の厚みは２ｍｍ、中板３の厚みは１ｍｍ、カバー上板４の厚みは２ｍｍ、全体の厚みは５ｍｍである。   As shown in FIG. 1, the microchip 1 includes two solid phase bead filling portions 13 and 15 and a microfabricated groove portion 16. The solid phase bead filling parts 13 and 15 have a dam structure with a height h of 30 μm at both ends, and the solid phase bead filling part 13 is 1.0 mm wide and 0.5 mm deep and filled with an anion exchange resin. . The solid phase bead filling portion 15 has a width of 6.0 mm and a depth of 1.0 mm, and was filled with a cation exchange resin, a reverse phase resin, and alumina. The anion exchange resin has a diameter of 37-55 μm, the cation exchange resin has a diameter of 75-150 μm, the reverse phase resin has a diameter of 55-105 μm, and the alumina has a diameter of about 50-300 μm. Using this microchip 1, fluorine F-18 labeled FDG was synthesized. The microfabricated groove 16 has a channel width of 300 μm and a depth of 500 μm. The depth of the counterbore hole 17 is 800 μm. The thickness of the microchip substrate 2 is 2 mm, the thickness of the intermediate plate 3 is 1 mm, the thickness of the cover upper plate 4 is 2 mm, and the total thickness is 5 mm.

サイクロトロンで製造したフッ素Ｆ−１８イオン含有酸素Ｏ−１８濃縮水を導入路５より固相ビーズ充填部１３に流し、固相ビーズ充填部１３の陰イオン交換樹脂にフッ素Ｆ−１８イオンをトラップさせた。その後、固相ビーズ充填部１３に導入路５より炭酸カリウム及び相間移動触媒クリプタンドを含むアセトニトリル／水溶液を流し、フッ素Ｆ−１８イオンを溶離させ、排出路６から導入路８を通し、微細加工溝部１６に供給した。微細加工溝部１６を１２０℃に加熱し、窒素ガスを導入路８より流しながら蒸発乾固を行った。   Fluorine F-18 ion-containing oxygen O-18 concentrated water produced by a cyclotron is caused to flow from the introduction path 5 to the solid phase bead filling unit 13 to trap the fluorine F-18 ions on the anion exchange resin in the solid phase bead filling unit 13. It was. Thereafter, an acetonitrile / water solution containing potassium carbonate and a phase transfer catalyst cryptand is caused to flow into the solid-phase bead filling portion 13 from the introduction path 5 to elute fluorine F-18 ions, and from the discharge path 6 through the introduction path 8 to the microfabricated groove section. 16 was supplied. The microfabricated groove 16 was heated to 120 ° C. and evaporated to dryness while flowing nitrogen gas from the introduction path 8.

蒸発乾固終了後、反応前駆体である１，３，４，６−テトラ−Ｏ−アセチル−２−Ｏ−トリフルオロメタンスルホニル−β−Ｄ−マンノピラノースを含むアセトニトリル溶液を導入路８より微細加工溝部１６に供給し、１００℃で標識反応を行った。標識反応終了後、導入路８より窒素ガスを流しながら溶媒であるアセトニトリルを留去した。   After the evaporation to dryness, an acetonitrile solution containing 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose which is a reaction precursor is finer than the introduction path 8 It supplied to the processing groove part 16 and performed labeling reaction at 100 degreeC. After completion of the labeling reaction, acetonitrile as the solvent was distilled off while flowing nitrogen gas from the introduction path 8.

次に加水分解試薬である水酸化ナトリウム水溶液を導入路８より微細加工溝部１６に供給し、室温で加水分解反応を行った。反応終了後、注射用蒸留水を導入路８より溝１６及びチップ内空間１４に供給し、排出路７から導入路９を通り、精製用樹脂を充填した固相ビーズ充填部１５を通すことにより排出路１０よりフッ素Ｆ−１８標識ＦＤＧ注射液を得た。   Next, a sodium hydroxide aqueous solution as a hydrolysis reagent was supplied from the introduction path 8 to the microfabricated groove portion 16 to perform a hydrolysis reaction at room temperature. After completion of the reaction, water for injection is supplied from the introduction path 8 to the groove 16 and the chip inner space 14, and from the discharge path 7 through the introduction path 9 and through the solid phase bead filling section 15 filled with the purification resin. A fluorine F-18 labeled FDG injection solution was obtained from the discharge channel 10.

図１のマイクロチップ１を用いてホスホニウム塩樹脂を用いたフッ素Ｆ−１８標識ＦＤＧの合成を行った。この場合、固相ビーズ充填部１３にはトリブチルホスホニウム塩樹脂を充填した。固相ビーズ充填部１５には同様に、陽イオン交換樹脂、逆相系樹脂、アルミナを充填した。   Fluorine F-18 labeled FDG using a phosphonium salt resin was synthesized using the microchip 1 of FIG. In this case, the solid phase bead filling portion 13 was filled with tributylphosphonium salt resin. Similarly, the solid phase bead filling portion 15 was filled with a cation exchange resin, a reverse phase resin, and alumina.

サイクロトロンで製造したフッ素Ｆ−１８イオン含有酸素Ｏ−１８濃縮水を導入路５より固相ビーズ充填部１３に流し、固相ビーズ充填部１３のトリブチルホスホニウム塩樹脂にフッ素Ｆ−１８イオンをトラップさせた。その後、固相ビーズ充填部１３を１００℃に加熱し、導入路５より固相ビーズ充填部１３にアセトニトリルを流し、フッ素Ｆ−１８イオンを活性化させた。流したアセトニトリルは、排出路６から排出した。次に、反応前駆体である１，３，４，６−テトラ−Ｏ−アセチル−２−Ｏ−トリフルオロメタンスルホニル−β−Ｄ−マンノピラノースを含むアセトニトリル溶液を導入路５から供給し、標識反応を行った。反応溶液は排出路６から導入路８を通し、微細加工溝部１６に供給した。微細加工溝部１６を１００℃に加熱し、窒素ガスを導入路８より流しながら溶媒であるアセトニトリルを留去した。   A fluorine F-18 ion-containing oxygen O-18 concentrated water produced by a cyclotron is caused to flow from the introduction path 5 to the solid phase bead filling unit 13 to trap the fluorine F-18 ions in the tributylphosphonium salt resin in the solid phase bead filling unit 13. It was. Thereafter, the solid phase bead filling portion 13 was heated to 100 ° C., and acetonitrile was allowed to flow from the introduction path 5 to the solid phase bead filling portion 13 to activate the fluorine F-18 ions. The flowed acetonitrile was discharged from the discharge path 6. Next, an acetonitrile solution containing 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose, which is a reaction precursor, is supplied from the introduction path 5 and labeled. Reaction was performed. The reaction solution was supplied from the discharge path 6 through the introduction path 8 to the microfabricated groove 16. The microfabricated groove 16 was heated to 100 ° C., and acetonitrile as a solvent was distilled off while flowing nitrogen gas from the introduction path 8.

次に加水分解試薬である水酸化ナトリウム水溶液を導入路８より微細加工溝部１６に供給し、室温で加水分解反応を行った。反応終了後、注射用蒸留水を導入路８より微細加工溝部１６及びチップ内空間１４に供給し、排出路７から導入路９を通り、精製用樹脂を充填した固相ビーズ充填部１５を通すことにより排出路１０よりフッ素Ｆ−１８標識ＦＤＧ注射液を得た。   Next, a sodium hydroxide aqueous solution as a hydrolysis reagent was supplied from the introduction path 8 to the microfabricated groove portion 16 to perform a hydrolysis reaction at room temperature. After completion of the reaction, distilled water for injection is supplied from the introduction path 8 to the microfabricated groove section 16 and the chip internal space 14, passes through the introduction path 9 from the discharge path 7, and passes through the solid phase bead filling section 15 filled with the purification resin. Thus, a fluorine F-18 labeled FDG injection solution was obtained from the discharge passage 10.

図４に示すように、マイクロチップ２１は、２つの固相ビーズ充填部３９，４６と２つの微細加工溝部４０，４３、２つのマイクロチャンネル部４２，４５より構成される。固相ビーズ充填部３９，４６は両端の高さｈが３０μｍのダム構造となっており、固相ビーズ充填部３９は幅１．０ｍｍ、深さ０．５ｍｍで、陰イオン交換樹脂を充填した。固相ビーズ充填部４６は幅６．０ｍｍ、深さ１．０ｍｍであり、陽イオン交換樹脂、逆相系樹脂、アルミナを充填した。陰イオン交換樹脂の直径は３７−５５μｍ、陽イオン交換樹脂の直径は７５−１５０μｍ、逆相系樹脂の直径５５−１０５μｍ、アルミナの直径は５０−３００μｍ程度である。微細加工溝部４０，４３はチャンネル幅３００μｍ、深さ５００μｍで、微細加工溝部４０の溝容量は１０μＬ、微細加工溝部４３の溝容量は８０μＬである。ザグリ穴４７，４８の深さは８００μｍである。マイクロチップの基板２２の厚みは２ｍｍ、中板２３の厚みは０．５ｍｍ、カバー上板２４の厚みは２ｍｍ、全体の厚みは４．５ｍｍである。   As shown in FIG. 4, the microchip 21 includes two solid-phase bead filling portions 39 and 46, two microfabricated groove portions 40 and 43, and two microchannel portions 42 and 45. The solid phase bead filling portions 39 and 46 have a dam structure with a height h of 30 μm at both ends, and the solid phase bead filling portion 39 has a width of 1.0 mm and a depth of 0.5 mm and is filled with an anion exchange resin. . The solid phase bead filling portion 46 has a width of 6.0 mm and a depth of 1.0 mm, and was filled with a cation exchange resin, a reverse phase resin, and alumina. The anion exchange resin has a diameter of 37-55 μm, the cation exchange resin has a diameter of 75-150 μm, the reverse phase resin has a diameter of 55-105 μm, and the alumina has a diameter of about 50-300 μm. The finely processed groove portions 40 and 43 have a channel width of 300 μm and a depth of 500 μm, the finely processed groove portion 40 has a groove capacity of 10 μL, and the finely processed groove portion 43 has a groove capacity of 80 μL. The depth of the counterbore holes 47 and 48 is 800 μm. The thickness of the microchip substrate 22 is 2 mm, the thickness of the intermediate plate 23 is 0.5 mm, the thickness of the cover upper plate 24 is 2 mm, and the overall thickness is 4.5 mm.

マイクロチャンネル部４２は幅１２５μｍ、長さ０．５ｍであり、マイクロチャンネル部４５は幅３００μｍ、長さ１ｍである。   The microchannel portion 42 has a width of 125 μm and a length of 0.5 m, and the microchannel portion 45 has a width of 300 μm and a length of 1 m.

このマイクロチップ２１を用いてフッ素Ｆ−１８標識ＦＤＧの合成を行った。   The microchip 21 was used to synthesize fluorine F-18 labeled FDG.

サイクロトロンで製造したフッ素Ｆ−１８イオン含有酸素Ｏ−１８濃縮水を導入路２５より固相ビーズ充填部３９に流し、固相ビーズ充填部３９に充填された陰イオン交換樹脂にフッ素Ｆ−１８イオンをトラップさせた。その後、固相ビーズ充填部３９に導入路２５より炭酸カリウム及び相間移動触媒クリプタンドを含むアセトニトリル／水溶液を流し、フッ素Ｆ−１８イオンを溶離させ、排出路２６から導入路２８を通して微細加工溝部４０に供給した。微細加工溝部４０を１２０℃に加熱し、導入路２８より窒素ガスを流しながら蒸発乾固を行った。   Fluorine F-18 ion-containing oxygen O-18 concentrated water produced by a cyclotron is flowed from the introduction path 25 to the solid phase bead filling unit 39, and fluorine F-18 ions are added to the anion exchange resin filled in the solid phase bead filling unit 39. Was trapped. Thereafter, an acetonitrile / water solution containing potassium carbonate and a phase transfer catalyst cryptand is caused to flow into the solid phase bead filling portion 39 from the introduction path 25 to elute fluorine F-18 ions, and from the discharge path 26 to the microfabrication groove section 40 through the introduction path 28. Supplied. The microfabricated groove 40 was heated to 120 ° C. and evaporated to dryness while flowing nitrogen gas from the introduction path 28.

蒸発乾固終了後、反応前駆体である１，３，４，６−テトラ−Ｏ−アセチル−２−Ｏ−トリフルオロメタンスルホニル−β−Ｄ−マンノピラノースを含むアセトニトリル溶液を導入路２８より微細加工溝部４０に供給し、排出路２７から導入路２９を通し、１００℃に加熱したマイクロチャンネル部４２に流して標識反応を行った。反応液はそのまま微細加工溝部４３に排出路３０から導入路３２を通して供給し、導入路３２より窒素ガスを流しながら溶媒であるアセトニトリルを留去した。   After completion of evaporation to dryness, an acetonitrile solution containing 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose, which is a reaction precursor, is finer from the introduction path 28. The labeling reaction was performed by supplying the processed groove portion 40, passing the discharge passage 27 through the introduction passage 29, and flowing into the microchannel portion 42 heated to 100 ° C. The reaction solution was supplied as it was to the microfabricated groove 43 from the discharge passage 30 through the introduction passage 32, and acetonitrile as a solvent was distilled off while flowing nitrogen gas from the introduction passage 32.

次に加水分解試薬である水酸化ナトリウム水溶液を導入路３２より微細加工溝部４３に供給し、排出路３１から導入路３３を通して室温に保たれたマイクロチャンネル部４５に流して加水分解反応を行った。反応液はそのまま排出路３４から導入路３６を通して流し、精製用樹脂を充填した固相ビーズ充填部４６を通し、さらに注射用蒸留水を導入路３２より流して洗浄し、排出路３５よりフッ素Ｆ−１８標識ＦＤＧ注射液を得た。   Next, an aqueous solution of sodium hydroxide, which is a hydrolysis reagent, is supplied from the introduction path 32 to the microfabrication groove 43, and flows from the discharge path 31 through the introduction path 33 to the microchannel portion 45 kept at room temperature to perform the hydrolysis reaction. . The reaction solution flows as it is from the discharge passage 34 through the introduction passage 36, passes through the solid phase bead filling portion 46 filled with the purification resin, and further flows by washing with distilled water for injection through the introduction passage 32. A -18 labeled FDG injection was obtained.

１，２１…マイクロチップ
２，２２…基板
３，２３…中板（側壁）
４，２４…カバー上板（蓋）
５，８，９，２５，２８，２９，３２，３３，３６…導入路
６，７，１０，２６，２７，３０，３１，３４，３５…排出路
１１，１２，３７，３８…固相ビーズ充填口
１３，１５，３９，４６…固相ビーズ充填部
１４，４１，４４…気相の流路（チップ内空間）
１６，４０，４３…微細加工溝部（プール部）
１７，４７，４８…ザクリ穴
４２，４５…マイクロチャンネル部（微細流路部） 1, 21 ... Microchip 2,22 ... Substrate 3,23 ... Medium plate (side wall)
4, 24 ... Cover plate (lid)
5, 8, 9, 25, 28, 29, 32, 33, 36... Introduction path 6, 7, 10, 26, 27, 30, 31, 34, 35... Discharge path 11, 12, 37, 38. Bead filling port 13, 15, 39, 46 ... Solid phase bead filling portion 14, 41, 44 ... Gas phase flow path (space in chip)
16, 40, 43 ... Finely processed groove (pool)
17, 47, 48 ... counterbore holes 42, 45 ... microchannel part (fine channel part)

Claims (20)

マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法であって、
内部に気相の流路を有すると共に、前記気相の流路の底部に液相を溜めるプール部を有するマイクロチップに液相としてフッ素Ｆ−１８イオンを含んだ溶液を導入し、前記マイクロチップの前記プール部に毛管力を利用して前記フッ素Ｆ−１８イオンを含んだ溶液を分散させる工程と、
前記気相の流路に気相を流して、前記プール部に溜められた前記フッ素Ｆ−１８イオンを含んだ溶液を蒸発乾固させる工程と、
を備えるマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 A method for producing a fluorine F-18 labeled compound using a microchip,
A solution containing fluorine F-18 ions as a liquid phase is introduced into a microchip having a gas phase flow channel therein and a pool portion for storing a liquid phase at the bottom of the gas phase flow channel. Dispersing the solution containing the fluorine F-18 ions in the pool part using capillary force;
Flowing a gas phase through the gas phase flow path to evaporate and dry the solution containing the fluorine F-18 ions stored in the pool portion;
A method for producing a fluorine F-18 labeled compound using a microchip comprising: 前記マイクロチップはさらに、陰イオン交換樹脂が充填される固相ビーズ充填部を有し、
前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記マイクロチップの前記プール部に前記フッ素Ｆ−１８イオンを含んだ溶液を導入する工程の前に、前記フッ素Ｆ−１８イオンを含んだ溶液を前記固相ビーズ充填部に流し、前記フッ素Ｆ−１８イオンの精製を行う工程、を備えることを特徴とする請求項１に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The microchip further has a solid phase bead filling portion filled with an anion exchange resin,
The method for producing a fluorine F-18 labeled compound using the microchip further includes:
Before the step of introducing the solution containing fluorine F-18 ions into the pool portion of the microchip, the solution containing fluorine F-18 ions is allowed to flow through the solid phase bead filling portion, and the fluorine F− A method for producing a fluorine F-18 labeled compound using a microchip according to claim 1, comprising a step of purifying 18 ions. 前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記フッ素Ｆ−１８イオンを含んだ溶液を蒸発乾固させた前記プール部に新たに前駆体を含んだ溶液を導入し、前記フッ素Ｆ−１８イオンと前記前駆体を含んだ溶液とを標識反応させる工程、を備えることを特徴とする請求項１又は２に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The method for producing a fluorine F-18 labeled compound using the microchip further includes:
A solution containing a new precursor is introduced into the pool part obtained by evaporating and drying the solution containing the fluorine F-18 ions, and the fluorine F-18 ions and the solution containing the precursor are labeled. The method of manufacturing a fluorine F-18 labeling compound using the microchip of Claim 1 or 2 characterized by the above-mentioned. 前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記プール部に溜められた、前記標識反応により生じたフッ素Ｆ−１８標識中間体を含んだ溶液を蒸発させ、前記フッ素Ｆ−１８標識中間体を含んだ溶液より溶媒を除去する工程、を備えることを特徴とする請求項３に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The method for producing a fluorine F-18 labeled compound using the microchip further includes:
And evaporating a solution containing the fluorine F-18 labeled intermediate produced by the labeling reaction, which is stored in the pool, and removing the solvent from the solution containing the fluorine F-18 labeled intermediate. A method for producing a fluorine F-18 labeled compound using the microchip according to claim 3. 前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記溶媒が除去された前記プール部に新たに加水分解試薬を含んだ溶液を導入し、前記フッ素Ｆ−１８標識中間体と前記加水分解試薬を含んだ溶液とを加水分解反応させる工程、を備えることを特徴とする請求項４に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The method for producing a fluorine F-18 labeled compound using the microchip further includes:
A step of newly introducing a solution containing a hydrolysis reagent into the pool part from which the solvent has been removed, and causing the fluorine F-18 labeled intermediate and the solution containing the hydrolysis reagent to undergo a hydrolysis reaction. A method for producing a fluorine F-18 labeled compound using the microchip according to claim 4. 前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記加水分解反応を行った前記プール部に新たに洗い出し液を導入し、前記プール部に溜められた、前記加水分解反応により生じたフッ素Ｆ−１８標識化合物を含んだ溶液を洗い出すことを特徴とする請求項５に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The method for producing a fluorine F-18 labeled compound using the microchip further includes:
A washing solution is newly introduced into the pool portion that has undergone the hydrolysis reaction, and a solution that contains the fluorine F-18-labeled compound produced by the hydrolysis reaction that is stored in the pool portion is washed out. A method for producing a fluorine F-18 labeled compound using the microchip according to claim 5. 前記マイクロチップはさらに、陽イオン交換樹脂、逆相系樹脂、及びアルミナが充填される第二の固相ビーズ充填部を有し、
前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記プール部から洗い出された前記フッ素Ｆ−１８標識化合物を含んだ溶液を前記第二の固相ビーズ充填部に流して、前記フッ素Ｆ−１８標識化合物の精製を行う工程、を備えることを特徴とする請求項６に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The microchip further has a second solid phase bead filling portion filled with a cation exchange resin, a reverse phase resin, and alumina,
The method for producing a fluorine F-18 labeled compound using the microchip further includes:
And a step of purifying the fluorine F-18 labeled compound by flowing a solution containing the fluorine F-18 labeled compound washed out from the pool portion to the second solid phase bead filling portion. A method for producing a fluorine F-18 labeled compound using the microchip according to claim 6. 前記マイクロチップはさらに、フッ素Ｆ−１８イオンと前駆体を含んだ溶液とを標識反応させる前記微細流路部を有し、
前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記フッ素Ｆ−１８イオンが溜められた前記プール部に新たに前駆体を含んだ溶液を導入し、前記プール部に溜められた前記フッ素Ｆ−１８イオンを溶解する工程と、
前記フッ素Ｆ−１８イオンが溶解し、前記前駆体を含んだ溶液を前記微細流路部に流して、前記フッ素Ｆ−１８イオンと前記前駆体を含んだ溶液とを標識反応させる工程と、
を備えることを特徴とする請求項１又は２に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The microchip further includes the fine flow path section for labeling the fluorine F-18 ion and the solution containing the precursor,
The method for producing a fluorine F-18 labeled compound using the microchip further includes:
Introducing a solution containing a new precursor into the pool portion in which the fluorine F-18 ions are stored, and dissolving the fluorine F-18 ions stored in the pool portion;
A step in which the fluorine F-18 ions are dissolved, a solution containing the precursor is caused to flow through the fine channel portion, and the fluorine F-18 ions and the solution containing the precursor are subjected to a labeling reaction;
The manufacturing method of the fluorine F-18 labeling compound using the microchip of Claim 1 or 2 characterized by the above-mentioned. 前記マイクロチップはさらに、内部に第二の気相の流路を有すると共に、この第二の気相の流路の底部に第二の液相を溜める第二のプール部を有し、
前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記第二のプール部に第二の液相として前記標識反応により生じたフッ素Ｆ−１８標識中間体を含んだ溶液を導入し、前記第二のプール部に毛管力を利用して前記フッ素Ｆ−１８標識中間体を含んだ溶液を分散させる工程と、
前記第二の気相の流路に気相を流して、前記第二のプール部に溜められた、前記標識反応により生じたフッ素Ｆ−１８標識中間体を含んだ溶液を蒸発させ、前記フッ素Ｆ−１８標識中間体を含んだ溶液より溶媒を除去する工程と、
を備えることを特徴とする請求項８に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The microchip further has a second gas phase channel inside, and a second pool part for storing the second liquid phase at the bottom of the second gas phase channel,
The method for producing a fluorine F-18 labeled compound using the microchip further includes:
A solution containing a fluorine F-18 labeled intermediate produced by the labeling reaction as a second liquid phase is introduced into the second pool part, and the fluorine F-18 is utilized in the second pool part by utilizing capillary force. Dispersing a solution containing the -18 labeled intermediate;
A gas phase is caused to flow through the second gas phase flow path to evaporate a solution containing the fluorine F-18 labeled intermediate produced by the labeling reaction and stored in the second pool portion, and the fluorine Removing the solvent from the solution containing the F-18 labeled intermediate;
The manufacturing method of the fluorine F-18 labeling compound using the microchip of Claim 8 characterized by the above-mentioned. 前記マイクロチップはさらに、前記フッ素Ｆ−１８標識中間体と加水分解試薬を含んだ溶液とを加水分解反応させる第二の微細流路部を有し、
前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記溶媒が除去された前記第二のプール部に新たに加水分解試薬を含んだ溶液を導入し、前記第二のプール部に溜められた前記フッ素Ｆ−１８標識中間体を溶解する工程と、
前記フッ素Ｆ−１８標識中間体が溶解した前記加水分解試薬を含んだ溶液を前記第二の微細流路部に流して、前記フッ素Ｆ−１８標識中間体と前記加水分解試薬を含んだ溶液とを加水分解反応させる工程と、
を備えることを特徴とする請求項９に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The microchip further includes a second fine channel section that causes a hydrolysis reaction between the fluorine F-18 labeled intermediate and a solution containing a hydrolysis reagent,
The method for producing a fluorine F-18 labeled compound using the microchip further includes:
Introducing a solution containing a hydrolysis reagent newly into the second pool part from which the solvent has been removed, and dissolving the fluorine F-18-labeled intermediate stored in the second pool part;
A solution containing the hydrolysis reagent in which the fluorine F-18 labeled intermediate is dissolved is caused to flow through the second fine channel section, and the solution containing the fluorine F-18 labeled intermediate and the hydrolysis reagent; Hydrolyzing the reaction,
The manufacturing method of the fluorine F-18 labeling compound using the microchip of Claim 9 characterized by the above-mentioned. 前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記第二のプール部に新たに洗い出し液を導入し、前記洗い出し液を前記第二の微細流路部に流して、前記加水分解反応により生じたフッ素Ｆ−１８標識化合物を含んだ溶液を洗い出すことを特徴とする請求項１０に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The method for producing a fluorine F-18 labeled compound using the microchip further includes:
A new washing solution is introduced into the second pool portion, and the washing solution is allowed to flow through the second fine channel portion to wash out a solution containing the fluorine F-18 labeled compound generated by the hydrolysis reaction. A method for producing a fluorine F-18 labeled compound using the microchip according to claim 10. 前記マイクロチップはさらに、陽イオン交換樹脂、逆相系樹脂、及びアルミナが充填される第二の固相ビーズ充填部を有し、
前記マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記第二のプール部及び前記第二の微細流路部から洗い出された前記フッ素Ｆ−１８標識化合物を含んだ溶液を前記第二の固相ビーズ充填部に流し、前記フッ素Ｆ−１８標識化合物の精製を行う工程、を備えることを特徴とする請求項１１に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The microchip further has a second solid phase bead filling portion filled with a cation exchange resin, a reverse phase resin, and alumina,
The method for producing a fluorine F-18 labeled compound using the microchip further includes:
A solution containing the fluorine F-18-labeled compound washed out from the second pool part and the second fine channel part is allowed to flow into the second solid phase bead filling part, and the fluorine F-18 label A method for producing a fluorine F-18 labeled compound using the microchip according to claim 11, comprising a step of purifying the compound. マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法であって、
内部に気相の流路を有すると共に、前記気相の流路の底部に液相を溜めるプール部を有するマイクロチップに液相として、フッ素Ｆ−１８イオンと前駆体を含んだ溶液とを反応させることにより生じたフッ素Ｆ−１８標識中間体を含んだ溶液を導入し、前記マイクロチップの前記プール部に毛管力を利用して前記フッ素Ｆ−１８標識中間体を含んだ溶液を分散させる工程と、
前記気相の流路に気相を流して、前記プール部に溜められた前記フッ素Ｆ−１８標識中間体を含んだ溶液を蒸発させ、前記フッ素Ｆ−１８標識中間体を含んだ溶液より溶媒を除去する工程と、
を備えるマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 A method for producing a fluorine F-18 labeled compound using a microchip,
A microchip having a gas phase flow channel inside and a pool portion for storing a liquid phase at the bottom of the gas phase flow channel reacts with a solution containing fluorine F-18 ions and a precursor as a liquid phase. Introducing a solution containing a fluorine F-18-labeled intermediate produced by dispersing the solution, and dispersing the solution containing the fluorine F-18-labeled intermediate in the pool portion of the microchip using capillary force When,
A gas phase is caused to flow through the gas phase flow path to evaporate the solution containing the fluorine F-18 labeled intermediate stored in the pool, and a solvent is removed from the solution containing the fluorine F-18 labeled intermediate. Removing the
A method for producing a fluorine F-18 labeled compound using a microchip comprising: 前記マイクロチップはさらに、オニウム塩樹脂が充填される固相ビーズ充填部を有し、
マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法はさらに、
前記マイクロチップの前記プール部に前記フッ素Ｆ−１８標識中間体を含んだ溶液を導入する工程の前に、前記フッ素Ｆ−１８イオンと前記前駆体を含んだ溶液を前記固相ビーズ充填部に流し、前記フッ素Ｆ−１８イオンと前記前駆体を含んだ溶液を標識反応させる工程、を備えることを特徴とする請求項１３に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The microchip further has a solid phase bead filling portion filled with an onium salt resin,
The method for producing a fluorine F-18 labeled compound using a microchip further includes:
Prior to the step of introducing the solution containing the fluorine F-18 labeled intermediate into the pool part of the microchip, the solution containing the fluorine F-18 ion and the precursor is added to the solid phase bead filling part. The method for producing a fluorine F-18 labeled compound using a microchip according to claim 13, further comprising a step of causing a labeling reaction of the solution containing the fluorine F-18 ions and the precursor. 前記プール部は、前記気相の流路の底面に形成される溝を有することを特徴とする請求項１又は１３に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。   The said pool part has a groove | channel formed in the bottom face of the said gaseous-phase flow path, The manufacturing method of the fluorine F-18 labeled compound using the microchip of Claim 1 or 13 characterized by the above-mentioned. 前記溝は、並列に配置された複数本の溝からなることを特徴とする請求項１５に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。   16. The method for producing a fluorine F-18 labeled compound using a microchip according to claim 15, wherein the groove comprises a plurality of grooves arranged in parallel. 前記マイクロチップは、前記溝が加工される基板と、基板の上面に設けられる側壁と、側壁の上面に設けられる蓋と、を備え、
前記基板、前記側壁及び前記蓋によって、前記気相の流路が構成されることを特徴とする請求項１５又は１６に記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The microchip includes a substrate on which the groove is processed, a side wall provided on the upper surface of the substrate, and a lid provided on the upper surface of the side wall,
The method for producing a fluorine F-18 labeled compound using a microchip according to claim 15 or 16, wherein the gas phase flow path is constituted by the substrate, the side wall and the lid. 前記固相ビーズ充填部及び／又は前記第二の固相ビーズ充填部は、液相の流れ方向の両端部に流路の底面が盛り上がったダム部を有し、
前記ダム部は、液相が流れるのを許容すると共に、固相ビーズが流出するのを防止することを特徴とする請求項２，７，１２，及び１４のいずれかに記載のマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造方法。 The solid phase bead filling portion and / or the second solid phase bead filling portion has a dam portion where the bottom surface of the flow path is raised at both ends in the flow direction of the liquid phase,
15. The microchip according to claim 2, wherein the dam portion allows a liquid phase to flow and prevents a solid phase bead from flowing out. A process for producing a fluorine F-18 labeled compound. マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造装置であって、
内部に気相の流路を有すると共に、前記気相の流路の底部に液相を溜めるプール部を有するマイクロチップと、
前記マイクロチップに液相としてフッ素Ｆ−１８イオンを含んだ溶液を導入し、前記マイクロチップの前記プール部に毛管力を利用して前記フッ素Ｆ−１８イオンを含んだ溶液を分散させる液相導入手段と、
前記マイクロチップの前記気相の流路に気相を流して、前記プール部に溜められた前記フッ素Ｆ−１８イオンを含んだ溶液を蒸発乾固させる気相操作手段と、
を備えるマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造装置。 An apparatus for producing a fluorine F-18 labeled compound using a microchip,
A microchip having a gas phase flow path therein and a pool portion for storing a liquid phase at the bottom of the gas phase flow path;
Liquid phase introduction in which a solution containing fluorine F-18 ions as a liquid phase is introduced into the microchip, and the solution containing fluorine F-18 ions is dispersed into the pool portion of the microchip using capillary force. Means,
A gas phase operating means for causing a gas phase to flow through the gas phase flow path of the microchip and evaporating and drying the solution containing the fluorine F-18 ions stored in the pool portion;
An apparatus for producing a fluorine F-18 labeled compound using a microchip comprising: マイクロチップを用いたフッ素Ｆ−１８標識化合物の製造装置であって、
内部に気相の流路を有すると共に、前記気相の流路の底部に液相を溜めるプール部を有するマイクロチップと、
前記マイクロチップに液相として、フッ素Ｆ−１８イオンと前駆体を含んだ溶液とを反応させることにより生じたフッ素Ｆ−１８標識中間体を含んだ溶液を導入し、前記マイクロチップの前記プール部に毛管力を利用して前記フッ素Ｆ−１８標識中間体を含んだ溶液を分散させる液相導入手段と、
前記マイクロチップの前記気相の流路に気相を流して、前記プール部に溜められた前記フッ素Ｆ−１８標識中間体を含んだ溶液を蒸発させ、前記フッ素Ｆ−１８標識中間体を含んだ溶液より溶媒を除去する気相操作手段と、
を備えるマイクロチップを用いたフッ素Ｆ−１８標識化合物の製造装置。 An apparatus for producing a fluorine F-18 labeled compound using a microchip,
A microchip having a gas phase flow path therein and a pool portion for storing a liquid phase at the bottom of the gas phase flow path;
A solution containing a fluorine F-18 labeled intermediate produced by reacting fluorine F-18 ions with a solution containing a precursor as a liquid phase is introduced into the microchip, and the pool portion of the microchip A liquid phase introducing means for dispersing the solution containing the fluorine F-18 labeled intermediate using capillary force;
A gas phase is caused to flow through the gas phase flow path of the microchip to evaporate a solution containing the fluorine F-18 labeled intermediate stored in the pool portion, thereby including the fluorine F-18 labeled intermediate. A gas phase operating means for removing the solvent from the solution,
An apparatus for producing a fluorine F-18 labeled compound using a microchip comprising:
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