JP5322527B2 - Compounds suitable for detecting apoptosis - Google Patents
Compounds suitable for detecting apoptosis Download PDFInfo
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- JP5322527B2 JP5322527B2 JP2008186378A JP2008186378A JP5322527B2 JP 5322527 B2 JP5322527 B2 JP 5322527B2 JP 2008186378 A JP2008186378 A JP 2008186378A JP 2008186378 A JP2008186378 A JP 2008186378A JP 5322527 B2 JP5322527 B2 JP 5322527B2
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- apoptosis
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- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 229960001479 tosylchloramide sodium Drugs 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Description
本発明は、アポトーシスの検出に適した化合物に関する。 The present invention relates to compounds suitable for the detection of apoptosis.
アポトーシスとは、生理的条件下で細胞が自ら引き起こす細胞死のことである。癌化した細胞も通常はアポトーシスで排除されるが、何らかの原因によりその機序が働かなくなると悪性腫瘍へと成長する。脳梗塞等の虚血性疾患並びにアルツハイマー病及びパーキンソン病等の神経変性疾患においては、アポトーシスにより神経細胞の脱落が起こっていると考えられている（非特許文献１、２及び３）。また、脳梗塞を治療する際に血栓溶解剤を投与して脳の血流を元に戻してもアポトーシスが生じ、やはり神経細胞が脱落する（非特許文献１、４及び５）。 Apoptosis is cell death caused by cells themselves under physiological conditions. Cancerated cells are also usually eliminated by apoptosis, but if the mechanism fails for some reason, they grow into malignant tumors. In ischemic diseases such as cerebral infarction and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, it is considered that neuronal cells are lost due to apoptosis (Non-patent Documents 1, 2 and 3). In addition, even when a thrombolytic agent is administered to treat cerebral infarction to restore the blood flow in the brain, apoptosis occurs, and nerve cells also fall off (Non-Patent Documents 1, 4 and 5).
アポトーシスが生じる機構については、ミトコンドリア外膜上に存在する種々のタンパク質が互いに結合してホモダイマーやヘテロダイマーを形成することでアポトーシスを抑制又は誘導することが知られており、これらのタンパク質を利用してアポトーシスを制御する研究が行われてきた（非特許文献１及び６）。 Regarding the mechanism of apoptosis, it is known that various proteins existing on the outer mitochondrial membrane bind to each other to form homodimers and heterodimers, thereby suppressing or inducing apoptosis. Studies have been conducted to control apoptosis (Non-patent Documents 1 and 6).
アポトーシスの制御は、癌治療や虚血性疾患及び神経変性疾患における治療につながる。例えば、癌細胞でアポトーシスを積極的に生じさせる抗癌剤は癌治療に用いられている。また、アポトーシスを抑制するアポトーシス抑制剤は、虚血性疾患や神経変性疾患における神経細胞の脱落を阻止するために用いられる。疾患の治療においては、これらの薬剤が生体内で有効に作用しているかどうかを評価することが重要であり、この評価を可能にするための技術が求められている。
アポトーシス制御を利用した薬剤の薬効を評価するために、被験者の生体内で生じているアポトーシスを可視化することが有効であると考えられる。従って、本発明の目的の一つは、アポトーシスが生体内で生じていることを可視化するために用いられる物質を提供することである。 In order to evaluate the efficacy of a drug using apoptosis control, it is considered effective to visualize apoptosis occurring in a subject's living body. Accordingly, one of the objects of the present invention is to provide a substance that can be used to visualize that apoptosis is occurring in vivo.
本発明は、下記一般式（I）で表される化合物を提供する。
（式（Ｉ）中、Ｘはヨウ素原子又は臭素原子であり、Ｙは水酸基又はメトキシ基である。）
The present invention provides a compound represented by the following general formula (I).
(In formula (I), X is an iodine atom or a bromine atom, and Y is a hydroxyl group or a methoxy group.)
式（I）で表される化合物はアポトーシスが生じている細胞に集積する傾向がある。また、式（I）で表される化合物により放出されるポジトロンはすぐに電子と結合してγ線（消滅放射線）を放出するため、このγ線を陽電子放出型断層撮影装置（以下、「ＰＥＴ」という）で測定することにより、式（I）で表される化合物の体内分布を定量的かつ経時的に画像化することができる。従って上記式（I）で表される化合物を用いることで、被験者の生体内でアポトーシスが生じている部位を経時的に可視化できる。 Compounds represented by formula (I) tend to accumulate in cells undergoing apoptosis. Further, since the positron emitted by the compound represented by the formula (I) is immediately combined with an electron to emit γ-rays (annihilation radiation), the γ-rays are emitted from a positron emission tomography apparatus (hereinafter referred to as “PET”). ”), The biodistribution of the compound represented by the formula (I) can be quantitatively imaged over time. Therefore, by using the compound represented by the above formula (I), it is possible to visualize the site where apoptosis occurs in the subject's body over time.
本発明は下記一般式（ＩＩ）で表される化合物を提供する。
（式（ＩＩ）中、Ｘはヨウ素原子又は臭素原子であり、Ｙは水酸基又はメトキシ基である。）
The present invention provides a compound represented by the following general formula (II).
(In formula (II), X is an iodine atom or a bromine atom, and Y is a hydroxyl group or a methoxy group.)
式（ＩＩ）で表される化合物をポジトロン核種で標識することにより、効率良く式（Ｉ）で表される化合物を提供することができる。 By labeling the compound represented by the formula (II) with a positron nuclide, the compound represented by the formula (I) can be efficiently provided.
式（Ｉ）で表される化合物は、アポトーシスの検出用試薬として有用である。該アポトーシスの検出用試薬によれば、簡便に生体中のアポトーシスが生じている部位を検出することができる。 The compound represented by the formula (I) is useful as a reagent for detecting apoptosis. According to the reagent for detecting apoptosis, a site where apoptosis occurs in a living body can be easily detected.
式（Ｉ）で表される化合物は、抗癌剤の薬効評価用試薬としても用いられる。該抗癌剤の薬効評価用試薬によれば、癌細胞でアポトーシスが生じているかどうかを患者が生存した状態で検出することができるために、癌患者に適用して抗癌剤の薬効評価をすることができる。 The compound represented by the formula (I) is also used as a reagent for evaluating the efficacy of anticancer agents. According to the reagent for evaluating the efficacy of the anticancer agent, since it is possible to detect whether apoptosis has occurred in the cancer cells in a state where the patient is alive, the efficacy of the anticancer agent can be evaluated by applying it to a cancer patient. .
式（Ｉ）で表される化合物は、アポトーシス抑制剤の評価用試薬としても有用である。アポトーシス抑制剤は虚血性疾患や神経変性疾患等における神経脱落を予防するのに用いられる。アポトーシス抑制剤の上記評価用試薬によれば、アポトーシス抑制剤により生体中でアポトーシスが効果的に抑制されているかどうかを経時的に評価することができる。 The compound represented by the formula (I) is also useful as a reagent for evaluating an apoptosis inhibitor. Apoptosis inhibitors are used to prevent nerve loss in ischemic diseases, neurodegenerative diseases and the like. According to the above-described evaluation reagent for an apoptosis inhibitor, it can be evaluated over time whether apoptosis is effectively suppressed in the living body by the apoptosis inhibitor.
本発明によれば、アポトーシスが生体内で生じていることを可視化するために用いられる物質が提供される。更に、アポトーシス検出用試薬、抗癌剤の薬効評価試薬及びアポトーシス抑制剤の薬効評価用試薬が提供される。 According to the present invention, a substance used for visualizing that apoptosis occurs in vivo is provided. Furthermore, a reagent for detecting apoptosis, a reagent for evaluating the efficacy of anticancer agents, and a reagent for evaluating the efficacy of apoptosis inhibitors are provided.
本発明の化合物は、下記一般式（Ｉ）：
（式（Ｉ）中、Ｘはヨウ素原子又は臭素原子であり、Ｙは水酸基又はメトキシ基である。）で表され、より具体的には、
下記一般式（Ｉ−ａ）;
で表されるＮ−｛２−クロロ−５−（４−［１８Ｆ］フルオロフェニルスルホニル）フェニル｝−５−クロロ−２−ヒドロキシ−３−ヨードベンズアミド（以下「［１８Ｆ］ＦＢＨＩ」という）、
下記一般式（Ｉ−ｂ）；
で表されるＮ−｛２−クロロ−５−（４−［１８Ｆ］フルオロフェニルスルホニル）フェニル｝−３−ブロモ−５−クロロ−２−ヒドロキシベンズアミド（以下「［１８Ｆ］ＦＢＨＢ」という）、
下記一般式（Ｉ−ｃ）；
で表されるＮ−｛２−クロロ−５−（４−［１８Ｆ］フルオロフェニルスルホニル）フェニル｝−５−クロロ−３−ヨード−２−メトキシベンズアミド（以下「［１８Ｆ］ＦＢＭＩ」という）、及び、
下記一般式（Ｉ−ｄ）；
で表されるＮ−｛２−クロロ−５−（４−［１８Ｆ］フルオロフェニルスルホニル）フェニル｝−３−ブロモ−５−クロロ−２−メトキシベンズアミド（以下「［１８Ｆ］ＦＢＭＢ」という）である。
The compound of the present invention has the following general formula (I):
(In the formula (I), X is an iodine atom or a bromine atom, and Y is a hydroxyl group or a methoxy group.) More specifically,
The following general formula (Ia);
N- {2-chloro-5- (4- [ 18 F] fluorophenylsulfonyl) phenyl} -5-chloro-2-hydroxy-3-iodobenzamide (hereinafter referred to as “[ 18 F] FBHI”) ,
The following general formula (Ib);
N- {2-chloro-5- (4- [ 18 F] fluorophenylsulfonyl) phenyl} -3-bromo-5-chloro-2-hydroxybenzamide (hereinafter referred to as “[ 18 F] FBHB”) ,
The following general formula (Ic);
N- {2-chloro-5- (4- [ 18 F] fluorophenylsulfonyl) phenyl} -5-chloro-3-iodo-2-methoxybenzamide (hereinafter referred to as “[ 18 F] FBMI”) ,as well as,
The following general formula (Id);
N- {2-chloro-5- (4- [ 18 F] fluorophenylsulfonyl) phenyl} -3-bromo-5-chloro-2-methoxybenzamide (hereinafter referred to as “[ 18 F] FBMB”) It is.
下記一般式（ＩＩ）で表される化合物（以下、「化合物（ＩＩ）」という）は、上記一般式（Ｉ）で表される化合物（以下、「化合物（Ｉ）」という）の前駆体である。
（式（ＩＩ）中、Ｘはヨウ素原子又は臭素原子であり、Ｙは水酸基又はメトキシ基である。）
A compound represented by the following general formula (II) (hereinafter referred to as “compound (II)”) is a precursor of a compound represented by the above general formula (I) (hereinafter referred to as “compound (I)”). is there.
(In formula (II), X is an iodine atom or a bromine atom, and Y is a hydroxyl group or a methoxy group.)
化合物（Ｉ）は化合物（ＩＩ）から、下記反応式（ＩＩＩ）を経て合成できる。
（式（ＩＩＩ）中、Ｘはヨウ素原子又は臭素原子であり、Ｙは水酸基又はメトキシ基である。）
Compound (I) can be synthesized from compound (II) through the following reaction formula (III).
(In formula (III), X is an iodine atom or a bromine atom, and Y is a hydroxyl group or a methoxy group.)
化合物（ＩＩ）は実施例１に記載の方法で化学合成でき、化合物（Ｉ）は実施例２に記載の方法で化学合成できる。 Compound (II) can be chemically synthesized by the method described in Example 1, and compound (I) can be chemically synthesized by the method described in Example 2.
化合物（Ｉ）は、生体に投与した場合、アポトーシスが生じている細胞に集積する傾向がある。また、化合物（Ｉ）により放出されるポジトロンはすぐに電子と結合してγ線を放出するため、このγ線をＰＥＴで測定することにより、化合物（Ｉ）の体内分布を定量的に画像化することができる。したがって、化合物（Ｉ）を用いることで、被験者の生体内でアポトーシスが生じている部位を検出し、その度合い、変化を経時的に可視化できる。 Compound (I) tends to accumulate in cells undergoing apoptosis when administered to a living body. In addition, positrons emitted by compound (I) immediately combine with electrons and emit γ-rays. By measuring these γ-rays with PET, the distribution of compound (I) in the body can be quantitatively imaged. can do. Therefore, by using Compound (I), it is possible to detect a site where apoptosis occurs in the body of the subject and visualize the degree and change over time.
化合物（Ｉ）は、アポトーシスの検出用試薬として有用である。ここで、本発明のアポトーシス検出用試薬は、化合物（Ｉ）を含み、生体に投与されると、生体中の化合物（Ｉ）から放出されるγ線をＰＥＴで計測することにより、アポトーシスが生じている部位を検出できる。 Compound (I) is useful as a reagent for detecting apoptosis. Here, the reagent for detecting apoptosis of the present invention contains compound (I), and when administered to a living body, apoptosis occurs by measuring γ-rays released from compound (I) in the living body with PET. Can be detected.
化合物（Ｉ）は、抗癌剤の薬効評価用試薬としても有用である。ここで、「抗癌剤の薬効評価用試薬」とは、生体に投与された抗癌剤がその薬効により生体中の癌細胞をアポトーシスで消失させる機能が働いているかどうかを評価する試薬である。本発明の抗癌剤の薬効評価用試薬は化合物（Ｉ）を含むため、抗癌剤で治療中の生体に投与すると、癌細胞でアポトーシスが生じていれば、患部に化合物（Ｉ）が集積する。集積した化合物（Ｉ）から放出されるγ線をＰＥＴで計測することにより、癌細胞でアポトーシスが生じているかどうかを判断できる。従って、抗癌剤が効いているかどうかを本発明の抗癌剤の薬効評価用試薬により判断できる。 Compound (I) is also useful as a reagent for evaluating the efficacy of anticancer agents. Here, the “reagent for evaluation of drug efficacy of anticancer agent” is a reagent for evaluating whether or not the anticancer agent administered to the living body has a function of eliminating cancer cells in the living body by apoptosis due to its drug efficacy. Since the reagent for evaluating the efficacy of the anticancer agent of the present invention contains Compound (I), when administered to a living body being treated with the anticancer agent, Compound (I) accumulates in the affected area if apoptosis occurs in cancer cells. By measuring γ-rays released from the accumulated compound (I) with PET, it is possible to determine whether apoptosis has occurred in cancer cells. Therefore, whether or not the anticancer agent is effective can be determined by the drug efficacy evaluation reagent of the anticancer agent of the present invention.
上記抗癌剤の薬効評価用試薬に含まれる化合物（Ｉ）として、［１８Ｆ］ＦＢＭＢ又は［１８Ｆ］ＦＢＭＩが好ましい。これらの化合物は、特に癌細胞で生じるアポトーシスに対して集積する傾向がある。 [ 18 F] FBMB or [ 18 F] FBMI is preferred as the compound (I) contained in the drug efficacy evaluation reagent of the anticancer agent. These compounds tend to accumulate especially against apoptosis that occurs in cancer cells.
化合物（Ｉ）は、アポトーシス抑制剤の評価用試薬として使用できる。ここで、「アポトーシス抑制剤の評価用試薬」とは、生体に投与されたアポトーシス抑制剤によってアポトーシスが該生体内の標的部で抑制されているかどうかを、評価する試薬である。アポトーシス抑制剤を生体に投与し、該アポトーシス抑制剤の薬効が標的部で有効であれば、標的部でアポトーシスが抑制される。そこで本発明のアポトーシス抑制剤の評価用試薬を該生体に投与し、ＰＥＴ計測をすると、本発明のアポトーシス抑制剤は化合物（Ｉ）を含むにもかかわらず、γ線が該標的部から放出されていないこと、すなわち、化合物（Ｉ）が標的部に集積していないことがわかる。化合物（Ｉ）が集積していないことから、アポトーシスが抑制されており、アポトーシス抑制剤の薬効が有効であることを判断できる。逆にアポトーシス抑制剤が標的部で有効に作用していなければ、本発明の評価剤に含まれる化合物（Ｉ）が標的部に集積することから、アポトーシスが生じていること、すなわちアポトーシス抑制剤が効いていないことを判断できる。 Compound (I) can be used as a reagent for evaluating an apoptosis inhibitor. Here, the “reagent for evaluation of apoptosis inhibitor” is a reagent for evaluating whether apoptosis is suppressed at the target site in the living body by the apoptosis inhibitor administered to the living body. When an apoptosis inhibitor is administered to a living body, and the medicinal effect of the apoptosis inhibitor is effective at the target part, apoptosis is suppressed at the target part. Accordingly, when the reagent for evaluating the apoptosis inhibitor of the present invention is administered to the living body and measured by PET, γ rays are released from the target portion even though the apoptosis inhibitor of the present invention contains the compound (I). It can be seen that the compound (I) is not accumulated in the target portion. Since compound (I) is not accumulated, it can be judged that apoptosis is suppressed and the efficacy of the apoptosis inhibitor is effective. On the other hand, if the apoptosis inhibitor is not acting effectively at the target part, the compound (I) contained in the evaluation agent of the present invention accumulates at the target part. Judge that it is not working.
アポトーシス抑制剤の薬効評価用試薬に含まれる化合物（Ｉ）として、［１８Ｆ］ＦＢＨＢ又は［１８Ｆ］ＦＢＨＩが好ましい。これらの化合物は、特に神経変性疾患、虚血性疾患で生じるアポトーシスに対して集積する傾向がある。アポトーシス抑制剤は神経変性疾患や虚血性疾患で生じる神経細胞の脱落の予防に主に用いられ、そのような神経変性疾患や虚血性疾患におけるアポトーシス抑制剤の薬効評価用試薬は有効である。 [ 18 F] FBHB or [ 18 F] FBHI is preferred as the compound (I) contained in the reagent for evaluating the efficacy of an apoptosis inhibitor. These compounds tend to accumulate especially against apoptosis that occurs in neurodegenerative diseases and ischemic diseases. Apoptosis inhibitors are mainly used for prevention of neuronal loss caused by neurodegenerative diseases and ischemic diseases, and reagents for evaluating the efficacy of apoptosis inhibitors in such neurodegenerative diseases and ischemic diseases are effective.
上記アポトーシス検出用試薬、上記抗癌剤の薬効評価用試薬又は上記アポトーシス抑制剤の薬効評価用試薬は、例えば、化合物（Ｉ）を任意の緩衝液に溶解することにより製造することができる。かかる場合、当該試薬は溶液として提供され、上記の緩衝成分の他、界面活性剤、防腐剤、安定化剤等のその他の成分を含有させることもできる。投与方法は、通常、静脈内投与である。 The reagent for detecting apoptosis, the reagent for evaluating the efficacy of the anticancer agent, or the reagent for evaluating the efficacy of the apoptosis inhibitor can be produced, for example, by dissolving the compound (I) in an arbitrary buffer solution. In such a case, the reagent is provided as a solution and may contain other components such as a surfactant, a preservative, and a stabilizer in addition to the buffer component. The administration method is usually intravenous administration.
また、上記アポトーシス検出用試薬、上記抗癌剤の薬効評価用試薬又は上記アポトーシス抑制剤の薬効評価用試薬の対象として、ヒトを含む動物の脳、器官、臓器、組織、細胞等を挙げることができるがこれらに限定されるものではない。また、本発明の化合物（Ｉ）を用いてＰＥＴ測定を行うに際し、その測定方法は特に制限されず、公知の方法に準じて実施することができる。 Examples of the target for the apoptosis detection reagent, the drug efficacy evaluation reagent for the anticancer agent, or the drug efficacy evaluation reagent for the apoptosis inhibitor include brains, organs, organs, tissues, cells, and the like of animals including humans. It is not limited to these. Moreover, when performing PET measurement using the compound (I) of this invention, the measuring method in particular is not restrict | limited, It can implement according to a well-known method.
（実施例１）化合物（ＩＩ）の化学合成
（１−１ａ）［１８Ｆ］ＦＢＨＩの前駆体の化学合成
［１８Ｆ］ＦＢＨＩの前駆体であるＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−５−クロロ−２−ヒドロキシ−３−ヨードベンズアミド トリフルオロメタンスルホン酸塩（下記式（ＩＶ）中に示す化合物（ＩＩ−ａ））を以下のように作製した。下記式（ＩＶ）に、合成スキームを示す。
上記式（ＩＶ）において、まず化合物（３Ｈ−Ｉ）を以下のように作製した。ジムロート冷却管及び温度計を取り付けた３００ｍＬ４つ口コルベンに、５−クロロサリチル酸３０．０ｇ（０．１７ｍｏｌ）及び酢酸１５０ｍＬを仕込み加熱撹拌した。この懸濁溶液中に塩化ヨウ素３２．０ｇ（０．１８ｍｏｌ）の酢酸溶液９０ｍＬを１．５時間かけて滴下し、１００℃にて５時間撹拌した。この溶液を室温まで放冷後、５％亜硫酸ナトリウム水溶液４００ｍＬへ投入した。この溶液を３０分間撹拌後、析出した白色結晶を濾取した。この結晶を減圧乾燥し、２５ｇの粗精製物を得た。酢酸１８０ｍＬにて再結晶を行い、上記式（ＩＶ）中に示す化合物（３Ｈ−Ｉ）１４ｇ（収率２７％）を得た。 In the above formula (IV), first, compound (3H-I) was prepared as follows. In a 300 mL four-necked Kolben equipped with a Dimroth condenser and a thermometer, 30.0 g (0.17 mol) of 5-chlorosalicylic acid and 150 mL of acetic acid were charged and stirred. 90 mL of an acetic acid solution of 32.0 g (0.18 mol) of iodine chloride was dropped into this suspension solution over 1.5 hours, and the mixture was stirred at 100 ° C. for 5 hours. The solution was allowed to cool to room temperature and then poured into 400 mL of 5% aqueous sodium sulfite solution. The solution was stirred for 30 minutes, and the precipitated white crystals were collected by filtration. The crystals were dried under reduced pressure to obtain 25 g of a crude product. Recrystallization was performed with 180 mL of acetic acid to obtain 14 g (yield 27%) of the compound (3H-I) shown in the above formula (IV).
ジムロート冷却管を取り付けた１００ｍＬナスコルベンに、室温で、化合物（３Ｈ−Ｉ）３．８７ｇ（１３ｍｍｏｌ）、下記式（ＶＩＩＩ）中に示す化合物（７）４．００ｇ（１３ｍｍｏｌ）及びトルエン５０ｍＬを入れ、９０℃に加熱し、均一溶液とした。この溶液にＰＯＣｌ３２．０ｇ（１３ｍｍｏｌ）／トルエン５．０ｍＬを滴下した。１８時間加熱還流後、全ての溶媒を留去し、得られた固体をシリカゲルカラムクロマトグラフィー（クロロホルム／アセトン＝１０／１）で精製し、上記式（ＩＶ）中に示す化合物（９Ｈ-Ｉ）１．３ｇ（収率１７％）を得た。 In a 100 mL eggplant corben equipped with a Dimroth condenser, 3.87 g (13 mmol) of the compound (3H-I), 4.00 g (13 mmol) of the compound (7) shown in the following formula (VIII) and 50 mL of toluene were added, Heated to 90 ° C. to obtain a homogeneous solution. To this solution was added dropwise POCl 3 2.0 g (13 mmol) / toluene 5.0 mL. After heating under reflux for 18 hours, all the solvent was distilled off, and the resulting solid was purified by silica gel column chromatography (chloroform / acetone = 10/1) to obtain the compound (9H-I) represented by the above formula (IV). 1.3 g (yield 17%) was obtained.
１００ｍＬナスコルベンに、室温で、化合物（９Ｈ−Ｉ）１．３ｇ（２．２ｍｍｏｌ）を脱水ジクロロメタン５０ｍＬに溶解した。この溶液にトリフルオロメタンスルホン酸メチル０．４０ｇ（２．４２ｍｍｏｌ）×２回／脱水ジクロロメタン５ｍＬを加えて、室温で２０時間攪拌した。析出物を濾過し、濾物をジクロロメタン１０ｍＬで洗浄し、真空乾燥することにより、［１８Ｆ］ＦＢＨＩの前駆体であるＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−５−クロロ−２−ヒドロキシ−３−ヨードベンズアミド トリフルオロメタンスルホン酸塩（上記式（ＩＶ）中に示す化合物（ＩＩ−ａ））０．７０ｇ（収率４２％、純度９９％）を得た。 In 100 mL eggplant colben, 1.3 g (2.2 mmol) of the compound (9H-I) was dissolved in 50 mL of dehydrated dichloromethane at room temperature. To this solution, 0.40 g (2.42 mmol) of methyl trifluoromethanesulfonate × twice / 5 mL of dehydrated dichloromethane was added and stirred at room temperature for 20 hours. The precipitate was filtered, and the filtrate was washed with 10 mL of dichloromethane and dried in vacuo, whereby N- {2-chloro-5- (4-trimethylammoniumphenylsulfonyl) phenyl} which is a precursor of [ 18 F] FBHI 0.70 g (yield 42%, purity 99%) of -5-chloro-2-hydroxy-3-iodobenzamide trifluoromethanesulfonate (compound (II-a) shown in the above formula (IV)) was obtained. .
（１−１ｂ）［１８Ｆ］ＦＢＨＢの前駆体の化学合成
［１８Ｆ］ＦＢＨＢの前駆体であるＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−３−ブロモ−５−クロロ−２−ヒドロキシベンズアミド トリフルオロメタンスルホン酸塩（下記式（Ｖ）中に示す化合物（ＩＩ−ｂ））を以下のように作製した。下記式（Ｖ）に、合成スキームを示す。
上記式（Ｖ）において、まず化合物（１）を以下のように作製した。メカニカルスターラー、ジムロート冷却管、温度計を取り付けた１Ｌ４つ口コルベンに、室温で５−クロロサリチル酸５０．０ｇ（２８９．７ｍｍｏｌ）とメタノール５００ｍＬを入れ、攪拌しながら、濃硫酸３ｍＬを添加した。この溶液を１５分かけて内温７２℃まで昇温、還流状態とし、同温にて攪拌した。１４時間後、この溶液を室温まで冷却し、溶媒留去を行うと無色固体が得られた。この固体をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製することにより無色固体として上記式（Ｖ）中に示す化合物（１）４１．８ｇ（収率７７％、純度９９．５％）を得た。 In the above formula (V), compound (1) was first prepared as follows. To a 1 L four-necked Kolben equipped with a mechanical stirrer, a Dimroth condenser, and a thermometer, 50.0 g (289.7 mmol) of 5-chlorosalicylic acid and 500 mL of methanol were added at room temperature, and 3 mL of concentrated sulfuric acid was added while stirring. The solution was heated to an internal temperature of 72 ° C. over 15 minutes, brought to a reflux state, and stirred at the same temperature. After 14 hours, the solution was cooled to room temperature and the solvent was distilled off to obtain a colorless solid. This solid was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 41.8 g (yield 77%, purity 99.5) of the compound (1) shown in the above formula (V) as a colorless solid. %).
メカニカルスターラー、ジムロート冷却管、温度計を取り付けた５０ｍＬ四つ口コルベンに、室温で、化合物（１）１５．０ｇ（８０．４ｍｍｏｌ）、４０％ＨＢｒ−酢酸溶液９ｍＬ及び酢酸９ｍＬを入れ、攪拌しながら、６０℃に加温した。この溶液に、ＮａＣｌＯ３３．５ｇ／蒸留水２０ｍＬを５分かけて滴下すると、臭素の発生が確認され、固体が析出した。溶液を８時間加熱した後、得られた固体を濾取することにより、淡黄色固体として上記式（Ｖ）中に示す化合物（２−Ｂｒ）２２．４ｇ（収率１０５％）を得た。 At room temperature, 15.0 g (80.4 mmol) of Compound (1), 9 mL of 40% HBr-acetic acid solution and 9 mL of acetic acid were placed in a 50 mL four-necked Kolben equipped with a mechanical stirrer, Dimroth condenser, and thermometer, and stirred. The mixture was heated to 60 ° C. To this solution was added drop wise over 5 minutes NaClO 3 3.5 g / distilled water 20 mL, generation of bromine was confirmed, the solid was precipitated. After heating the solution for 8 hours, the obtained solid was collected by filtration to obtain 22.4 g (yield 105%) of the compound (2-Br) represented by the above formula (V) as a pale yellow solid.
メカニカルスターラー、ジムロート冷却管、温度計を取り付けた３００ｍＬ４つ口コルベンに、化合物（２−Ｂｒ）２２．４ｇ（８４．４ｍｍｏｌ）、メタノール１００ｍＬ及び２Ｎ水酸化ナトリウム水溶液１００ｍＬを入れ、攪拌した。この溶液を１５分かけて還流状態とし、同温にて攪拌した。２４時間後、この溶液を室温まで冷却し、液量を１／５まで濃縮した。この溶液に６Ｎ塩酸５０ｍＬを加え、ｐＨ２程度にした。析出している固体を濾別し、水１００ｍＬで洗浄し、真空乾燥することにより、無色結晶として上記式（Ｖ）中に示す化合物（３Ｈ−Ｂｒ）１８．３ｇ（収率８３％）を得た。 In a 300 mL four-necked Kolben equipped with a mechanical stirrer, a Dimroth condenser, and a thermometer, 22.4 g (84.4 mmol) of the compound (2-Br), 100 mL of methanol and 100 mL of 2N aqueous sodium hydroxide solution were added and stirred. The solution was brought to reflux for 15 minutes and stirred at the same temperature. After 24 hours, the solution was cooled to room temperature and concentrated to 1/5. To this solution, 50 mL of 6N hydrochloric acid was added to adjust the pH to about 2. The precipitated solid is separated by filtration, washed with 100 mL of water, and dried under vacuum to obtain 18.3 g (yield 83%) of the compound (3H-Br) shown in the above formula (V) as colorless crystals. It was.
ジムロート冷却管を取り付けた１Ｌナスコルベンに、室温で、化合物（３Ｈ−Ｂｒ）７．５０ｇ（２９．８ｍｍｏｌ）、下記式（ＶＩＩＩ）中に示す化合物（７）９．３６ｇ（３０．１ｍｍｏｌ）及びトルエン５００ｍＬを入れ、９０℃に加熱し、均一溶液とした。この溶液にＰＯＣｌ３１０ｍＬ／トルエン１００ｍＬを１時間かけて滴下した。この溶液を２４時間加熱還流後、全ての溶媒を留去し、得られた固体をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で分離し、濃縮後、得られた固体をクロロホルム／メタノールから再結晶することにより、無色固体として上記式（Ｖ）中に示す化合物（９Ｈ−Ｂｒ）３．２４ｇ（収率２０％、純度９８％）を得た。 To 1 L NASCORBEN fitted with a Dimroth condenser, 7.50 g (29.8 mmol) of compound (3H-Br), 9.36 g (30.1 mmol) of compound (7) shown in the following formula (VIII) and toluene at room temperature 500 mL was added and heated to 90 ° C. to obtain a uniform solution. To this solution was added dropwise over 1 hour POCl 3 10 mL / toluene 100 mL. After heating and refluxing this solution for 24 hours, all the solvent was distilled off, and the resulting solid was separated by silica gel column chromatography (hexane / ethyl acetate = 1/1) and concentrated. By recrystallization from methanol, 3.24 g (yield 20%, purity 98%) of the compound (9H-Br) shown in the above formula (V) as a colorless solid was obtained.
３００ｍＬナスコルベンに、室温で、化合物（９Ｈ−Ｂｒ）３．０２ｇ（５．５５ｍｍｏｌ）を脱水ジクロロメタン２００ｍＬに溶解した。この溶液にトリフルオロメタンスルホン酸メチル１．００ｇ／脱水ジクロロメタン１ｍＬを加えて、室温で２６時間攪拌した。析出物を濾過し、濾物を熱したテトラヒドロフラン（ＴＨＦ）４０ｍＬに溶解し、ジクロロメタン１０ｍＬを加えて、静置し、析出した固体を濾過し、ＴＨＦ１０ｍＬで洗浄した後、真空乾燥することで無色固体として［１８Ｆ］ＦＢＨＢの前駆体であるＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−３−ブロモ−５−クロロ−２−ヒドロキシベンズアミド トリフルオロメタンスルホン酸塩（上記式（Ｖ）中に示す化合物（ＩＩ−ｂ））１．３８ｇ（収率３５％、純度９９％）を得た。 In 300 mL eggplant colben, 3.02 g (5.55 mmol) of the compound (9H-Br) was dissolved in 200 mL of dehydrated dichloromethane at room temperature. To this solution was added 1.00 g of methyl trifluoromethanesulfonate / 1 mL of dehydrated dichloromethane, and the mixture was stirred at room temperature for 26 hours. The precipitate was filtered, the filtrate was dissolved in 40 mL of hot tetrahydrofuran (THF), 10 mL of dichloromethane was added, and the mixture was allowed to stand. The precipitated solid was filtered, washed with 10 mL of THF, and then vacuum dried to obtain a colorless solid. N- {2-Chloro-5- (4-trimethylammoniumphenylsulfonyl) phenyl} -3-bromo-5-chloro-2-hydroxybenzamide trifluoromethanesulfonate (predecessor of [ 18 F] FBHB) 1.38 g (yield 35%, purity 99%) of compound (II-b) shown in formula (V) was obtained.
（１−１ｃ）［１８Ｆ］ＦＢＭＩの前駆体の化学合成
［１８Ｆ］ＦＢＭＩの前駆体であるＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−５−クロロ−３−ヨード−２−メトキシベンズアミド トリフルオロメタンスルホン酸塩（下記式（ＶＩ）中に示す化合物（ＩＩ−ｃ））を以下のように作製した。下記式（ＶＩ）に、合成スキームを示す。
上記化学式（ＶＩ）において化合物（１）を、上記（１−１ｂ）［１８Ｆ］ＦＢＨＢの前駆体の化学合成における化合物（１）の合成と同様の方法で合成した。こうして合成した化合物（１）３７．３ｇ（１９９．９ｍｍｏｌ）を、ヨウ化ナトリウム３０．４ｇ（２０２．８ｍｍｏｌ）及びＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ）４００ｍＬと共に、室温で、メカニカルスターラー、ジムロート冷却管、温度計を取り付けた１Ｌ４つ口コルベンに入れ、攪拌しながら、クロラミン−Ｔ ｎ水和物４５．６ｇ（２００．３ｍｍｏｌ）を４５分かけてこの溶液に添加した。この溶液を室温にて１．５時間攪拌した後、氷水２Ｌと飽和チオ硫酸ナトリウム水溶液１００ｍＬに注ぎ込み、酢酸エチル４Ｌで抽出した。有機層を無水硫酸マグネシウムで乾燥後、有機層を溶媒留去した。得られた黄色固体と黄色油状物に９０％メタノール２００ｍＬを加え、１５分攪拌した。析出した固体を濾過し、メタノール２００ｍＬで２回洗浄した後、真空乾燥することにより、無色結晶として上記式（ＶＩ）中に示す化合物（２−Ｉ）４２．１ｇ（収率８３％）を得た。 In the chemical formula (VI), the compound (1) was synthesized in the same manner as the synthesis of the compound (1) in the chemical synthesis of the precursor of (1-1b) [ 18 F] FBHB. The compound (1) thus synthesized (37.3 g, 199.9 mmol) was mixed with sodium iodide (30.4 g, 202.8 mmol) and N, N-dimethylformamide (DMF) (400 mL) at room temperature at a mechanical stirrer, Dimroth condenser. Into a 1 L 4-neck Kolben equipped with a thermometer, 45.6 g (200.3 mmol) of chloramine-T n hydrate was added to this solution over 45 minutes while stirring. The solution was stirred at room temperature for 1.5 hours, poured into 2 L of ice water and 100 mL of a saturated aqueous sodium thiosulfate solution, and extracted with 4 L of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the organic layer was evaporated. To the resulting yellow solid and yellow oil, 200 mL of 90% methanol was added and stirred for 15 minutes. The precipitated solid was filtered, washed twice with 200 mL of methanol, and then vacuum-dried to obtain 42.1 g (yield 83%) of the compound (2-I) shown in the above formula (VI) as colorless crystals. It was.
メカニカルスターラー、ジムロート冷却管、温度計を取り付けた２Ｌ４つ口コルベンに、室温で、化合物（２−Ｉ）３５．０ｇ（１１２．０ｍｍｏｌ）、炭酸カリウム５５．２ｇ（３９９．４ｍｍｏｌ）及びアセトン１．３Ｌを入れ、攪拌しながら、ジメチル硫酸２６．９ｇ（２１３．３ｍｍｏｌ）を添加した。この溶液を１５分かけて還流状態とし、同温にて攪拌した。１４時間後、この溶液を室温まで冷却し、析出している固体を濾別し、濾液を濃縮した。得られた赤色油状物４０．０ｇをシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１０／１）で精製することにより、橙色油状物として上記式（ＶＩ）に示す化合物（３−Ｉ）３４．３ｇ（収率９４％、純度９８％）を得た。 To a 2 L four-necked Kolben equipped with a mechanical stirrer, a Dimroth condenser, and a thermometer, at room temperature, 35.0 g (112.0 mmol) of compound (2-I), 55.2 g (399.4 mmol) of potassium carbonate, and acetone 1. 3L was added and 26.9 g (213.3 mmol) of dimethyl sulfate was added with stirring. The solution was brought to reflux for 15 minutes and stirred at the same temperature. After 14 hours, the solution was cooled to room temperature, the precipitated solid was filtered off, and the filtrate was concentrated. The obtained red oily substance (40.0 g) was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 34.3 g of the compound (3-I) represented by the above formula (VI) as an orange oily substance. (Yield 94%, purity 98%) was obtained.
メカニカルスターラー、ジムロート冷却管、温度計を取り付けた１Ｌ四つ口コルベンに、室温で、化合物（３−Ｉ）３０．０ｇ（９１．９ｍｍｏｌ）、エタノール３００ｍＬ及び２Ｎ水酸化ナトリウム水溶液３００ｍＬを入れ、攪拌した。この溶液を１５分かけて還流状態とし、同温にて攪拌した。４時間後、この溶液を室温まで冷却し、濃塩酸４０ｍＬを加え、溶液をｐＨ２程度にした。析出している固体を濾別し、真空乾燥することにより、無色結晶として上記式（ＶＩ）中に示す化合物（４−Ｉ）２３．９ｇ（収率８３％）を得た。 A 1 L four-necked Kolben equipped with a mechanical stirrer, Dimroth condenser, and thermometer was charged with 30.0 g (91.9 mmol) of compound (3-I), 300 mL of ethanol and 300 mL of 2N aqueous sodium hydroxide solution at room temperature and stirred. did. The solution was brought to reflux for 15 minutes and stirred at the same temperature. After 4 hours, the solution was cooled to room temperature, and 40 mL of concentrated hydrochloric acid was added to bring the solution to about pH2. The precipitated solid was separated by filtration and vacuum dried to obtain 23.9 g (yield 83%) of the compound (4-I) represented by the above formula (VI) as colorless crystals.
ジムロート冷却管を取り付けた１００ｍＬナスコルベンに、室温で、化合物（４−Ｉ）２．９１ｇ（９．３１ｍｍｏｌ）、塩化チオニル４．０ｍＬ及びトルエン３０ｍＬを入れた。この溶液にＤＭＦ５滴を加えて、１００℃で４時間、加熱攪拌した。この溶液を室温まで冷却し、溶媒を留去することで、中間体を黄色油状物として得た。この中間体を脱水ＴＨＦ５０ｍＬに溶解し、下記式（ＶＩＩＩ）に示す化合物（７）２．９１ｇ（９．３１ｍｍｏｌ）を添加した。トリエチルアミン１．５６ｍＬを滴下して、室温で４時間攪拌した。この溶液を水１００ｍＬに注ぎ込み、クロロホルム３００ｍＬで抽出し、有機層を水１００ｍＬで２回洗浄した。有機層を無水硫酸マグネシウムで乾燥後、溶媒留去し、無色固体を得た。この固体にエーテル１００ｍＬを加えて５分間超音波洗浄を行い、析出物を濾過、真空乾燥することにより、無色固体として上記式（ＶＩ）に示す化合物（９−Ｉ）３．８４ｇ（収率６８％、純度９９％）を得た。 Compound (4-I) 2.91 g (9.31 mmol), thionyl chloride 4.0 mL and toluene 30 mL were placed in a 100 mL eggplant colben equipped with a Dimroth condenser at room temperature. To this solution, 5 drops of DMF was added, and the mixture was heated and stirred at 100 ° C. for 4 hours. The solution was cooled to room temperature, and the solvent was distilled off to obtain an intermediate as a yellow oil. This intermediate was dissolved in 50 mL of dehydrated THF, and 2.91 g (9.31 mmol) of the compound (7) represented by the following formula (VIII) was added. Triethylamine 1.56mL was dripped and it stirred at room temperature for 4 hours. This solution was poured into 100 mL of water, extracted with 300 mL of chloroform, and the organic layer was washed twice with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a colorless solid. 100 mL of ether was added to this solid, and ultrasonic cleaning was performed for 5 minutes. The precipitate was filtered and vacuum-dried to obtain 3.84 g (yield 68) of the compound (9-1) represented by the above formula (VI) as a colorless solid. %, Purity 99%).
３００ｍＬナスコルベンに、室温で、化合物（９−Ｉ）３．０２ｇ（４．９９ｍｍｏｌ）を脱水ジクロロメタン１５０ｍＬに溶解した。この溶液にトリフルオロメタンスルホン酸メチル１．００ｇ／脱水ジクロロメタン１ｍＬを加えて、室温で２６時間攪拌した。析出物を濾過し、濾物をジクロロメタン２０ｍＬで洗浄後、真空乾燥することにより、無色固体として［１８Ｆ］ＦＢＭＩの前駆体であるＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−５−クロロ−３−ヨード−２−メトキシベンズアミド トリフルオロメタンスルホン酸塩（上記式（ＶＩ）中に示す、化合物（ＩＩ−ｃ））２．５９ｇ（収率６７％、純度９９％）を得た。 In 300 mL eggplant colben, 3.02 g (4.99 mmol) of the compound (9-1) was dissolved in 150 mL of dehydrated dichloromethane at room temperature. To this solution was added 1.00 g of methyl trifluoromethanesulfonate / 1 mL of dehydrated dichloromethane, and the mixture was stirred at room temperature for 26 hours. The precipitate was filtered, and the filtrate was washed with 20 mL of dichloromethane and then vacuum-dried, whereby N- {2-chloro-5- (4-trimethylammonium phenylsulfonyl), a precursor of [ 18 F] FBMI, was obtained as a colorless solid. ) Phenyl} -5-chloro-3-iodo-2-methoxybenzamide trifluoromethanesulfonate (compound (II-c) shown in the above formula (VI)) 2.59 g (yield 67%, purity 99%) )
（１−１ｄ）［１８Ｆ］ＦＢＭＢの前駆体の化学合成
［１８Ｆ］ＦＢＭＢの前駆体であるＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−３−ブロモ−５−クロロ−２−メトキシベンズアミド トリフルオロメタンスルホン酸塩（下記式（ＶＩＩ）中に示す化合物（ＩＩ−ｄ））は以下のように作製した。下記式（ＶＩＩ）に、合成スキームを示す。
上記式（ＶＩＩ）において化合物（２−Ｂｒ）を、上記（１−１ｂ）［１８Ｆ］ＦＢＨＢの前駆体の化学合成における化合物（２−Ｂｒ）の合成と同様の方法で合成した。こうして合成した化合物（２−Ｂｒ）３０．０ｇ（０．１１ｍｏｌ）と共に炭酸カリウム４６．９ｇ(０．３４ｍｏｌ)及びアセトン１．３Ｌを、メカニカルスターラー、ジムロート冷却管、温度計を取り付けた２Ｌ四つ口コルベンに室温で入れ、攪拌しながら、ジメチル硫酸２７．１ｇ（０．２１ｍｏｌ）を添加した。この溶液を１５分かけて還流状態とし、同温にて攪拌した。１４時間後、この溶液を室温まで冷却し、析出している固体を濾別し、濾液を濃縮した。得られた赤色油状物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１０／１）で精製することにより、橙色油状物として上記式（ＶＩＩ）中に示す化合物（３−Ｂｒ）２８．４ｇ（収率９０％）を得た。 In the formula (VII), the compound (2-Br) was synthesized in the same manner as the synthesis of the compound (2-Br) in the chemical synthesis of the precursor of (1-1b) [ 18 F] FBHB. 40.0 g (0.34 mol) of potassium carbonate and 1.3 L of acetone together with 30.0 g (0.11 mol) of the compound (2-Br) synthesized in this way, four 2 L units equipped with a mechanical stirrer, Dimroth condenser, and thermometer. In a mouth Kolben at room temperature, 27.1 g (0.21 mol) of dimethyl sulfate was added with stirring. The solution was brought to reflux for 15 minutes and stirred at the same temperature. After 14 hours, the solution was cooled to room temperature, the precipitated solid was filtered off, and the filtrate was concentrated. The obtained red oil was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 28.4 g (yield) of the compound (3-Br) represented by the above formula (VII) as an orange oil. 90%).
メカニカルスターラー、ジムロート冷却管、温度計を取り付けた１Ｌ４つ口コルベンに、室温で、化合物（３−Ｂｒ）２５．６ｇ（９１．９ｍｍｏｌ）、エタノール３００ｍＬ及び２Ｎ水酸化ナトリウム水溶液３００ｍＬを入れ、攪拌した。この溶液を１５分かけて還流状態とし、同温にて攪拌した。４時間後、この溶液を室温まで冷却し、濃塩酸４０ｍＬを加え、溶液をｐＨ２程度にした。析出している固体を濾別し、真空乾燥することにより無色結晶として上記式（ＶＩＩ）中に示す化合物（４−Ｂｒ）１９．５ｇ（収率８０％）を得た。 At room temperature, 25.6 g (91.9 mmol) of compound (3-Br), 300 mL of ethanol and 300 mL of 2N aqueous sodium hydroxide solution were added to a 1 L four-necked Kolben equipped with a mechanical stirrer, Dimroth condenser, and thermometer, and stirred. . The solution was brought to reflux for 15 minutes and stirred at the same temperature. After 4 hours, the solution was cooled to room temperature, and 40 mL of concentrated hydrochloric acid was added to bring the solution to about pH2. The precipitated solid was separated by filtration and vacuum dried to obtain 19.5 g (yield 80%) of the compound (4-Br) represented by the above formula (VII) as colorless crystals.
ジムロート冷却管を取り付けた１００ｍＬナスコルベンに、室温で、化合物（４−Ｂｒ）２．４７ｇ（９．３１ｍｍｏｌ）及び塩化チオニル４．０ｍＬ、トルエン３０ｍＬを入れた。この溶液にＤＭＦ５滴を加えて、１００℃で４時間、加熱攪拌した。この溶液を室温まで冷却し、溶媒を留去することで、中間体を黄色油状物として得た。この中間体を脱水ＴＨＦ５０ｍＬに溶解し、下記式（ＶＩＩＩ）中に示す化合物（７）を２．９１ｇ（９．３１ｍｍｏｌ）添加した。この溶液にトリエチルアミン１．５６ｍＬを滴下して、室温で４時間攪拌した。この溶液を水１００ｍＬに注ぎ込み、クロロホルム３００ｍＬで抽出し、有機層を水１００ｍＬで２回洗浄した。有機層を無水硫酸マグネシウムで乾燥後、溶媒留去し、無色固体を得た。この固体にエーテル１００ｍＬを加えて５分間超音波洗浄を行い、析出物を濾過、真空乾燥することにより、無色固体として上記式（ＶＩＩ）中に示す化合物（９−Ｂｒ）２．９５ｇ（収率６０％、純度９９％）を得た。 In a 100 mL eggplant corben equipped with a Dimroth condenser, 2.47 g (9.31 mmol) of the compound (4-Br), 4.0 mL of thionyl chloride, and 30 mL of toluene were added at room temperature. To this solution, 5 drops of DMF was added, and the mixture was heated and stirred at 100 ° C. for 4 hours. The solution was cooled to room temperature, and the solvent was distilled off to obtain an intermediate as a yellow oil. This intermediate was dissolved in 50 mL of dehydrated THF, and 2.91 g (9.31 mmol) of compound (7) represented by the following formula (VIII) was added. To this solution, 1.56 mL of triethylamine was added dropwise and stirred at room temperature for 4 hours. This solution was poured into 100 mL of water, extracted with 300 mL of chloroform, and the organic layer was washed twice with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a colorless solid. 100 mL of ether was added to this solid, ultrasonic cleaning was performed for 5 minutes, and the precipitate was filtered and dried under vacuum to give 2.95 g of compound (9-Br) represented by the above formula (VII) as a colorless solid (yield 60%, purity 99%).
３００ｍＬナスコルベンに、室温で、化合物(９−Ｂｒ)２．６３ｇ(４．９９ｍｍｏｌ)を脱水ジクロロメタン１５０ｍＬに溶解した。この溶液にトリフルオロメタンスルホン酸メチル１．００ｇ／脱水ジクロロメタン１ｍＬを加えて、室温で２６時間攪拌した。析出物を濾過し、濾物をジクロロメタン２０ｍＬで洗浄後、真空乾燥することにより、［１８Ｆ］ＦＢＭＢの前駆体として、無色固体のＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−３−ブロモ−５−クロロ−２−メトキシベンズアミド トリフルオロメタンスルホン酸塩（上記式（ＶＩＩ）中に示す化合物（ＩＩ−ｄ））１．８０ｇ（収率５０％、純度９９％）を得た。 In 300 mL eggplant colben, 2.63 g (4.99 mmol) of the compound (9-Br) was dissolved in 150 mL of dehydrated dichloromethane at room temperature. To this solution was added 1.00 g of methyl trifluoromethanesulfonate / 1 mL of dehydrated dichloromethane, and the mixture was stirred at room temperature for 26 hours. The precipitate was filtered, and the filtrate was washed with 20 mL of dichloromethane and then vacuum-dried to give a colorless solid N- {2-chloro-5- (4-trimethylammonium phenylsulfonyl) as a precursor of [ 18 F] FBMB. ) Phenyl} -3-bromo-5-chloro-2-methoxybenzamide trifluoromethanesulfonate (compound (II-d) shown in the above formula (VII)) 1.80 g (yield 50%, purity 99%) Got.
なお、上記［１８Ｆ］ＦＢＨＢの前駆体、［１８Ｆ］ＦＢＭＩの前駆体及び［１８Ｆ］ＦＢＭＢの前駆体を作製する際に用いた化合物（７）は下記式（ＶＩＩＩ）で示す合成スキームにより作製した。
上記式（ＶＩＩＩ）に示す化合物（５）は以下のようにして合成した。メカニカルスターラー、ジムロート冷却管、温度計を取り付けた１Ｌ４つ口コルベンに、室温で、４−クロロ−３−ニトロベンゼンスルホニルクロリド５０．０ｇ（１９５ｍｍｏｌ）及びフルオロベンゼン２００ｍＬを入れ、攪拌しながら、無水塩化アルミニウム３０．０ｇ（２２４．８ｍｍｏｌ）を３０分かけて添加した。この溶液を５０℃に加温しながら１８時間反応させた。この溶液を室温まで冷却し、氷水５００ｍＬに注ぎ込み、濃塩酸１００ｍＬを加えて攪拌した。この溶液を酢酸エチル１Ｌで抽出し、有機層を水５００ｍＬで洗浄後、飽和重曹水５００ｍＬ及び水５００ｍＬで洗浄した。有機層を無水硫酸マグネシウムで乾燥後、溶媒留去し、赤色固体を得た。シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝４／１）で精製することにより、橙色油状物として上記式（ＶＩＩＩ）に示す化合物（５）３４．６ｇ（収率５６％、純度９２％）を得た。 Compound (5) represented by the above formula (VIII) was synthesized as follows. To a 1 L four-necked Kolben equipped with a mechanical stirrer, Dimroth condenser, and thermometer, at room temperature, 50.0 g (195 mmol) of 4-chloro-3-nitrobenzenesulfonyl chloride and 200 mL of fluorobenzene were added and stirred with anhydrous aluminum chloride. 30.0 g (224.8 mmol) was added over 30 minutes. The solution was reacted for 18 hours while warming to 50 ° C. The solution was cooled to room temperature, poured into 500 mL of ice water, and 100 mL of concentrated hydrochloric acid was added and stirred. This solution was extracted with 1 L of ethyl acetate, and the organic layer was washed with 500 mL of water, and then washed with 500 mL of saturated aqueous sodium bicarbonate and 500 mL of water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a red solid. Purification by silica gel column chromatography (hexane / ethyl acetate = 4/1) gave 34.6 g (yield 56%, purity 92%) of the compound (5) represented by the above formula (VIII) as an orange oil. It was.
メカニカルスターラー、ジムロート冷却管、温度計を取り付けた５００ｍＬ４つ口コルベンに、室温で、化合物（５）１０．５ｇ（３３．３ｍｍｏｌ）、エタノール１６０ｍＬ、酢酸１６０ｍＬ及び蒸留水８０ｍＬを入れ、攪拌しながら、６０℃に加温した。この溶液に還元鉄１３．０ｇ（２３２．８ｍｍｏｌ）を１３回に分けて添加し、さらに同温で１０分間攪拌した。この溶液に濃塩酸１ｍＬを添加後、７０℃で２時間加熱すると原料の消失が確認された。この溶液を室温まで冷却し、氷水１Ｌに注ぎ込み、飽和重曹水５００ｍＬで中和し、酢酸エチル１Ｌで抽出し、有機層を水５００ｍＬで３回洗浄した。有機層を無水硫酸マグネシウムで乾燥後、溶媒留去し、黄白色固体を得た。ヘキサン１００ｍＬを加えて５分間超音波洗浄を行い、析出物を濾過、真空乾燥することにより、無色固体として上記式（ＶＩＩＩ）中に示す化合物（６）９．３４ｇ（収率９８％、純度９２％）を得た。 In a 500 mL four-necked Kolben equipped with a mechanical stirrer, Dimroth condenser, and thermometer, at room temperature, 10.5 g (33.3 mmol) of compound (5), 160 mL of ethanol, 160 mL of acetic acid and 80 mL of distilled water were added and stirred. Warmed to 60 ° C. To this solution, 13.0 g (232.8 mmol) of reduced iron was added in 13 portions, and the mixture was further stirred at the same temperature for 10 minutes. When 1 mL of concentrated hydrochloric acid was added to this solution and heated at 70 ° C. for 2 hours, disappearance of the raw materials was confirmed. The solution was cooled to room temperature, poured into 1 L of ice water, neutralized with 500 mL of saturated aqueous sodium bicarbonate, extracted with 1 L of ethyl acetate, and the organic layer was washed 3 times with 500 mL of water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a yellowish white solid. 100 mL of hexane was added and ultrasonic cleaning was performed for 5 minutes, and the precipitate was filtered and dried under vacuum to obtain 9.34 g (yield 98%, purity 92) of the compound (6) shown in the above formula (VIII) as a colorless solid. %).
ジムロート冷却管、温度計を取り付けた１００ｍＬ４つ口コルベンに、室温で、化合物（６）９．００ｇ（３１．５ｍｍｏｌ）及びヘキサメチルリン酸トリアミド（ＨＭＰＡ）７５ｍＬを入れ、１６０℃で２０時間、加熱攪拌した。この溶液を室温まで冷却し、氷水５００ｍＬに注ぎ込み、酢酸エチル１．５Ｌで抽出し、有機層を水５００ｍＬで３回洗浄した。有機層を無水硫酸マグネシウムで乾燥後、溶媒留去し、褐色油状物を得た。これをシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製し、濃縮後に得られた固体にヘキサン５０ｍＬを加えて５分間超音波洗浄を行い、析出物を濾過、真空乾燥することにより、無色固体として上記式（ＶＩＩＩ）中に示す化合物（７）７．３０ｇ（収率７５％、純度９９％）を得た。こうして得られた化合物（７）を、［１８Ｆ］ＦＢＨＢの前駆体、［１８Ｆ］ＦＢＭＩの前駆体及び［１８Ｆ］ＦＢＭＢの前駆体の化学合成に用いた。 A 100 mL four-necked Kolben equipped with a Dimroth condenser and thermometer was charged with 9.00 g (31.5 mmol) of compound (6) and 75 mL of hexamethylphosphoric triamide (HMPA) at room temperature and heated at 160 ° C. for 20 hours. Stir. The solution was cooled to room temperature, poured into 500 mL of ice water, extracted with 1.5 L of ethyl acetate, and the organic layer was washed 3 times with 500 mL of water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a brown oil. This is purified by silica gel column chromatography (hexane / ethyl acetate = 1/1), 50 mL of hexane is added to the solid obtained after concentration, ultrasonic cleaning is performed for 5 minutes, and the precipitate is filtered and vacuum dried. As a colorless solid, 7.30 g (yield 75%, purity 99%) of the compound (7) represented by the above formula (VIII) was obtained. The thus obtained compound (7), the precursor of [18 F] FBHB, was used for chemical synthesis of precursors and [18 F] FBMB precursors of [18 F] FBMI.
（実施例２）化合物（Ｉ）の化学合成
（２−１）［１８Ｆ］の作製
サイクロトロン（ＨＭ−１８、住友重機械工業製）にて１８ＭｅＶに加速した陽子を２０μＡの電流値で、１８Ｏ−Ｈ２Ｏおよそ２ｍＬを封入したターゲット水に照射して、１８Ｏ（ｐ，ｎ）１８Ｆ核反応により［１８Ｆ］を生成させた。ターゲット水中で［１８Ｆ］は［１８Ｆ］Ｆ−の化学形で存在する。生成された［１８Ｆ］Ｆ−を含むターゲット水を自動合成装置に導入した。［１８Ｆ］Ｆ−を含むターゲット水をＨｅ圧でトラップ用イオン交換樹脂カラムを通過させて、［１８Ｆ］Ｆ−イオンを樹脂に吸着させた。この樹脂に０．５ｍｇＫ２ＣＯ３水溶液０．５ｍＬを導入して［１８Ｆ］Ｆ−イオンを脱着し、反応容器に［１８Ｆ］ＫＦ水溶液として回収した。反応容器内の［１８Ｆ］ＫＦ水溶液に３ｍｇの４，７，１３，１６，２１，２４−Ｈｅｘａｏｘａ−１，１０−ｄｉａｚａｂｉｃｙｃｌｏ［８，８，８］ｈｅｘａｃｏｓａｎｅ（商品名：Ｋｒｙｐｔｏｆｉｘ（商標）２２２、メルク社）を含むアセトニトリル２ｍＬ（Ｋｒｙｐｔｏｆｉｘ３ｍｇ／アセトニトリル２ｍＬ）を加えてＨｅ気流下に加熱して５分間共沸脱水し、アセトニトリル１ｍＬを追加して２分間共沸脱水を続けた。さらにアセトニトリル１ｍＬを追加して乾固するまで共沸脱水し、真空ポンプで９０秒間減圧留去し、９０秒間Ｈｅパージを行って系内の水分を完全に除き、残渣を室温付近まで冷却した。
Example 2 Chemical Synthesis of Compound (I) (2-1) Preparation of [ 18 F] A proton accelerated to 18 MeV with a cyclotron (HM-18, manufactured by Sumitomo Heavy Industries, Ltd.) at a current value of 20 μA, 18 [ 18 F] was generated by 18 O (p, n) 18 F nuclear reaction by irradiating target water in which approximately 2 mL of O—H 2 O was sealed. Target water [18 F] is present in [18 F] F- chemical type. The produced target water containing [ 18 F] F- was introduced into an automatic synthesizer. The target water containing [ 18 F] F − was passed through a trap ion exchange resin column at He pressure to adsorb the [ 18 F] F − ions to the resin. 0.5 mL of a 0.5 mg K 2 CO 3 aqueous solution was introduced into this resin to desorb [ 18 F] F-ion, and the reaction vessel was recovered as an [ 18 F] KF aqueous solution. 3 mg of 4,7,13,16,21,24-Hexoxa-1,10-diazabiccyclo [8,8,8] hexocasane (trade name: Kryptofix (trademark) 222), [ 18 F] KF aqueous solution in the reaction vessel Merck) containing 2 mL of acetonitrile (Kryptofix 3 mg / acetonitrile 2 mL) was added and heated under a He stream to azeotropically dehydrate for 5 minutes, and 1 mL of acetonitrile was added to continue azeotropic dehydration for 2 minutes. Further, 1 mL of acetonitrile was added and azeotropic dehydration was carried out until it was solidified, followed by distilling off the pressure for 90 seconds with a vacuum pump, performing He purge for 90 seconds to completely remove water in the system, and the residue was cooled to near room temperature.
（２−２ａ）［１８Ｆ］ＦＢＨＩの合成
（２−１）で得た残渣に、上記（１−１ａ）で合成した［１８Ｆ］ＦＢＨＩの前駆体Ｎ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−５−クロロ−２−ヒドロキシ−３−ヨードベンズアミド トリフルオロメタンスルホン酸塩４ｍｇ／ＤＭＳＯ０．３ｍＬ溶液を加え、１００℃で１０分間フッ素化を行い、反応終了後、生成物を高速液体クロマトグラフィー（ＨＰＬＣ）の移動相として用いるものと同じ溶媒で希釈し、Ｓｅｐ−Ｐａｋ Ｐｌｕｓ Ａｌｕｍｉｎａ Ｎカラムで未反応の［１８Ｆ］Ｆ−イオンを取り除き、溶出液をＨＰＬＣにて精製した。カラムとしてμＢｏｎｄａ−Ｐａｋ Ｃ１８（カラム内径７．８ｍｍ、カラム長３００ｍｍ、Ｗａｔｅｒｓ社）、移動相としてアセトニトリル／０．１Ｍ酢酸ナトリウム／酢酸＝４００／６００／１を用い、流速６ｍＬ／ｍｉｎ、検出波長２５４ｎｍで分取を行った。［１８Ｆ］ＦＢＨＩのフラクションを２５μＬのＴｗｅｅｎ８０を添加したナスコルベンに分取し、加熱減圧下でＨＰＬＣの溶媒を留去した。さらに残渣を注射用生理食塩水に再溶解し、無菌バイアルに［１８Ｆ］ＦＢＨＩを回収した。
(2-2a) Synthesis of [ 18 F] FBHI To the residue obtained in (2-1), the precursor of [ 18 F] FBHI synthesized in (1-1a) above, N- {2-chloro-5- ( 4-trimethylammoniumphenylsulfonyl) phenyl} -5-chloro-2-hydroxy-3-iodobenzamide trifluoromethanesulfonate 4 mg / DMSO 0.3 mL solution was added and fluorinated at 100 ° C. for 10 minutes. The product is diluted with the same solvent used as the mobile phase of high performance liquid chromatography (HPLC), unreacted [ 18 F] F- ions are removed with a Sep-Pak Plus Alumina N column, and the eluate is analyzed by HPLC. Purified. ΜBonda-Pak C18 (column inner diameter 7.8 mm, column length 300 mm, Waters) was used as the column, acetonitrile / 0.1 M sodium acetate / acetic acid = 400/600/1 as the mobile phase, flow rate 6 mL / min, detection wavelength 254 nm. Sorted by The fraction of [ 18 F] FBHI was fractionated into nascorbene to which 25 μL of Tween 80 was added, and the HPLC solvent was distilled off under heating and reduced pressure. Further, the residue was redissolved in physiological saline for injection, and [ 18 F] FBHI was recovered in a sterile vial.
（２−２ｂ）［１８Ｆ］ＦＢＨＢの合成
上記（２−１）と同様にサイクロトロン（ＨＭ−１８、住友重機械工業製）にて１８Ｏ−Ｈ２Ｏを用いて生成させた［１８Ｆ］Ｆ−を含むターゲット水を自動合成装置に導入した。［１８Ｆ］Ｆ−を含むターゲット水をＨｅ圧でトラップ用イオン交換樹脂カラムを通過させて、［１８Ｆ］Ｆ−イオンを樹脂に吸着させた。この樹脂にＴｅｔｒａｂｕｔｙｌａｍｍｏｎｉｕｍ ｈｙｄｒｏｇｅｎ ｃａｒｂｏｎａｔｅ水溶液／アセトニトリル（１／１）溶液０．５ｍＬを導入して［１８Ｆ］Ｆ−イオンを樹脂から脱着し、反応容器に回収した。反応容器内の［１８Ｆ］水溶液にアセトニトリル２ｍＬを加え、Ｈｅ気流下加熱して５分間共沸脱水した。アセトニトリル１ｍＬを追加して２分間共沸脱水を続けた。さらにアセトニトリル１ｍＬを追加して乾固するまで共沸脱水し、真空ポンプで９０秒間減圧留去し、Ｈｅパージを９０秒間行って系内の水分を完全に除き、残渣を室温付近まで冷却した。この残渣に、［１８Ｆ］ＦＢＨＢの前駆体として上記（１−１ｂ）で合成したＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−３−ブロモ−５−クロロ−２−ヒドロキシベンズアミド トリフルオロメタンスルホン酸塩０．５ｍｇ／ＤＭＳＯ０．３ｍＬ溶液を加え、１００℃で１０分間フッ素化を行った。フッ素化後、ＨＰＬＣの移動相としてアセトニトリル／０．１Ｍ酢酸ナトリウム／酢酸＝３５０／６５０／１を用いたこと以外は上記（２−２ａ）［１８Ｆ］ＦＢＨＩの合成と同様にＨＰＬＣで精製して［１８Ｆ］ＦＢＨＢを得た。
(2-2b) [18 F] Synthesis of (2-1) as well as cyclotrons FBHB (HM-18, manufactured by Sumitomo Heavy Industries) was generated using the 18 O-H 2 O at [18 F ] Target water containing F- was introduced into the automatic synthesizer. The target water containing [ 18 F] F − was passed through a trap ion exchange resin column at He pressure to adsorb the [ 18 F] F − ions to the resin. To this resin, 0.5 mL of an aqueous solution of tetrabutylammonium hydrogen carbonate / acetonitrile (1/1) was introduced to desorb [ 18 F] F-ion from the resin and collect it in a reaction vessel. 2 mL of acetonitrile was added to the [ 18 F] aqueous solution in the reaction vessel, and azeotropic dehydration was performed for 5 minutes by heating in a He stream. Acetonitrile dehydration was continued for 2 minutes by adding 1 mL of acetonitrile. Further, 1 mL of acetonitrile was added and azeotropic dehydration was carried out until it was solidified, and it was distilled off under reduced pressure with a vacuum pump for 90 seconds. He purge was performed for 90 seconds to completely remove water in the system, and the residue was cooled to near room temperature. To this residue, N- {2-chloro-5- (4-trimethylammoniumphenylsulfonyl) phenyl} -3-bromo-5-chloro-synthesized in (1-1b) above as a precursor of [ 18 F] FBHB 2-hydroxybenzamide trifluoromethanesulfonate 0.5 mg / DMSO 0.3 mL solution was added, and fluorination was performed at 100 ° C. for 10 minutes. After fluorination, it was purified by HPLC in the same manner as the synthesis of (2-2a) [ 18 F] FBHI except that acetonitrile / 0.1 M sodium acetate / acetic acid = 350/650/1 was used as the mobile phase of HPLC. [ 18 F] FBHB was obtained.
（２−２ｃ）［１８Ｆ］ＦＢＭＩの合成
（２−１）で得た残渣に、［１８Ｆ］ＦＢＭＩの前駆体として上記（１−１ｃ）で合成したＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−５−クロロ−３−ヨード−２−メトキシベンズアミド トリフルオロメタンスルホン酸塩４ｍｇ／ＤＭＳＯ０．３ｍＬ溶液を加え、ＨＰＬＣの移動相としてアセトニトリル／０．１Ｍ酢酸ナトリウム／酢酸＝５８０／４２０／１を用いたこと以外は上記（２−２ａ）［１８Ｆ］ＦＢＨＩの合成と同様にして［１８Ｆ］ＦＢＭＩを得た。
(2-2c) Synthesis of [ 18 F] FBMI To the residue obtained in (2-1), N- {2-chloro-5-synthesized in (1-1c) above as a precursor of [ 18 F] FBMI. (4-Trimethylammoniumphenylsulfonyl) phenyl} -5-chloro-3-iodo-2-methoxybenzamide trifluoromethanesulfonate 4 mg / DMSO 0.3 mL solution was added and acetonitrile / 0.1 M sodium acetate / [ 18 F] FBMI was obtained in the same manner as the synthesis of (2-2a) [ 18 F] FBHI except that acetic acid = 580/420/1 was used.
（２−２ｄ）［１８Ｆ］ＦＢＭＢの合成
（２−１）で得た残渣に、［１８Ｆ］ＦＢＭＢの前駆体として上記（１−１ｄ）で合成したＮ−｛２−クロロ−５−（４−トリメチルアンモニウムフェニルスルホニル）フェニル｝−３−ブロモ−５−クロロ−２−メトキシベンズアミド トリフルオロメタンスルホン酸塩４ｍｇ／ＤＭＳＯ０．３ｍＬ溶液を加え、ＨＰＬＣの移動相としてアセトニトリル／０．１Ｍ酢酸ナトリウム／酢酸＝５８０／４２０／１を用いたこと以外は上記（２−２ａ）［１８Ｆ］ＦＢＨＩの合成と同様にして［１８Ｆ］ＦＢＭＢを得た。
(2-2d) Synthesis of [ 18 F] FBMB To the residue obtained in (2-1), N- {2-chloro-5-synthesized in (1-1d) above as a precursor of [ 18 F] FBMB (4-Trimethylammoniumphenylsulfonyl) phenyl} -3-bromo-5-chloro-2-methoxybenzamide trifluoromethanesulfonate 4 mg / DMSO 0.3 mL solution was added and acetonitrile / 0.1 M sodium acetate / [ 18 F] FBMB was obtained in the same manner as the synthesis of (2-2a) [ 18 F] FBHI except that acetic acid = 580/420/1 was used.
（２−３）化合物（Ｉ）の分析
得られた［１８Ｆ］ＦＢＨＩ、［１８Ｆ］ＦＢＨＢ、［１８Ｆ］ＦＢＭＩ及び［１８Ｆ］ＦＢＭＢを逆相ＨＰＬＣで定性分析を行った。定性分析は、カラムとしてＩｎｅｒｔｓｉｌ ＯＤＳ−３（カラム内径４．６ｍｍ、カラム長１５０ｍｍ、ＧＬサイエンス社）、移動相としてアセトニトリル／３０ｍＭ酢酸アンモニウム／酢酸＝５００／５００／２を用い、流速２ｍＬ／ｍｉｎ、検出波長２３０ｎｍの条件で行った。結果を表１に示す。
（実施例３）細胞増殖能の異なる癌細胞を移植したマウスを用いた実験
癌細胞にはヒト子宮頚癌細胞ＨｅＬａである、ｓｔｒａｉｎ：１５Ｓ３Ｄ（ＨｅＬａ−Ｋ）とＪＣＲＢ９００４（ＨｅＬａ−Ｂ）を用いた。ＨｅＬａ−Ｋは５×１０６個、ＨｅＬａ−Ｂは２×１０７個を、メスＢＡＬＢ／ｃＡ Ｊｃｌ−ｎｕヌードマウス（ＨｅＬａ−Ｋ：６週齢、ＨｅＬａ−Ｂ:４又は６週齢）の大腿皮下に移植した。ＨｅＬａ−Ｋ移植マウスは移植２週間後、ＨｅＬａ−Ｂ移植マウスは４週間又は２週間後に、それぞれ８週齢となったところで実験に用いた。
(Example 3) Experiment using mouse transplanted with cancer cells having different cell proliferation ability For cancer cells, human cervical cancer cells HeLa, strain: 15S3D (HeLa-K) and JCRB9004 (HeLa-B) are used. It was. 5 × 10 6 HeLa-K, 2 × 10 7 HeLa-B, female BALB / cA Jcl-nu nude mice (HeLa-K: 6 weeks old, HeLa-B: 4 or 6 weeks old) Transplanted subcutaneously into the thigh. HeLa-K transplanted mice were used for the experiments at the age of 8 weeks, 2 weeks after transplantation, and HeLa-B transplanted mice at 4 weeks or 2 weeks, respectively.
担癌マウスにおける化合物（Ｉ）の集積と腫瘍組織の増殖速度の関係を見るために、腫瘍の大きさを連日計測した。倍加時間（ｄｏｕｂｌｉｎｇ ｔｉｍｅ：ＤＴ）の計算は、Ｓｃｈｗａｒｔｚの提案した計算式：ＤＴ＝ｔ×ｌｏｇ２（Ｖ１／Ｖ０）にて算出した。なおｔは腫瘍体積がＶ０（ｍｍ３）からＶ１（ｍｍ３）になるまでの日数を示し、腫瘍体積（ｍｍ３）は、腫瘍の長径及び幅をもとに計算式：１／２×長径（ｍｍ）×（幅）２（ｍｍ２）で計算した。 In order to observe the relationship between the accumulation of compound (I) in tumor-bearing mice and the growth rate of tumor tissue, the size of the tumor was measured every day. The doubling time (DT) was calculated using the formula proposed by Schwartz: DT = t × log 2 (V1 / V0). Here, t represents the number of days until the tumor volume becomes V0 (mm 3 ) to V1 (mm 3 ), and the tumor volume (mm 3 ) is calculated based on the major axis and width of the tumor: 1/2 × major axis It calculated with (mm) x (width) 2 (mm 2 ).
［１８Ｆ］ＦＢＨＩ、［１８Ｆ］ＦＢＨＢ、［１８Ｆ］ＦＢＭＩ又は［１８Ｆ］ＦＢＭＢの生理食塩水溶液０．３ｍＬをマウスの尾静脈より投与し、６０分後にマウスを断頭屠殺し、血液、心臓、肺、肝臓、腎臓、脾臓、大腿骨、筋肉、腫瘍、小腸、消化管、膵臓、脳を採取した。臓器重量及び放射能を測定し、各化合物の集積量を求めた。 [18 F] FBHI, [18 F] FBHB, [18 F] FBMI or [18 F] FBMB saline solution 0.3mL was administered from the tail vein of mice, the mice were decapitated sacrificed after 60 minutes, blood, Heart, lung, liver, kidney, spleen, femur, muscle, tumor, small intestine, digestive tract, pancreas, and brain were collected. The organ weight and radioactivity were measured, and the accumulation amount of each compound was determined.
ＨｅＬａ−Ｋ及びＨｅＬａ−Ｂ腫瘍組織の体積の増加曲線を図１に示す。このように、同じＨｅＬａ細胞でも、継代条件により、その増殖に違いがあることが確認され、ＨｅＬａ−Ｋ腫瘍の方がＨｅＬａ−Ｂ腫瘍よりも増殖が早かった。ＨｅＬａ−Ｂ腫瘍組織のサイズがＨｅＬａ−Ｋの腫瘍組織のサイズとほぼ同じとなるＨｅＬａ−Ｂ移植後４週目と、移植後の日数をＨｅＬａ−Ｋと同一にしたＨｅＬａ−Ｂ移植後２週目の２つの条件で実験を行った。 The volume increase curves of HeLa-K and HeLa-B tumor tissues are shown in FIG. Thus, even in the same HeLa cells, it was confirmed that there was a difference in the growth depending on the passage conditions, and the growth of the HeLa-K tumor was faster than that of the HeLa-B tumor. 4 weeks after HeLa-B transplantation in which the size of the HeLa-B tumor tissue is almost the same as the size of the HeLa-K tumor tissue, and 2 weeks after HeLa-B transplantation in which the number of days after transplantation is the same as HeLa-K The experiment was conducted under the two conditions of the eye.
図２に、ＨｅＬａ−Ｋ腫瘍組織とＨｅＬａ−Ｂ腫瘍組織への［１８Ｆ］ＦＢＨＩ、［１８Ｆ］ＦＢＨＢ、［１８Ｆ］ＦＢＭＩ及び［１８Ｆ］ＦＢＭＢの単位体重あたりの投与量に対する集積量であるＳＵＶを示す。なお、ＳＵＶは以下の式により算出した。
ＳＵＶ＝（組織中の放射能（Ｂｑ）／組織重量（ｇ））／（トレーサーの投与量（Ｂｑ）／体重（ｇ））
ここで、ＨｅＬａ−Ｂ腫瘍組織のサイズがＨｅＬａ−Ｋの腫瘍組織のサイズとほぼ同じとなるＨｅＬａ−Ｂ移植後４週目と、移植後の日数をＨｅＬａ−Ｋと同一にしたＨｅＬａ−Ｂ移植後２週目の２つの条件の間で、ＨｅＬａ−Ｂ腫瘍組織におけるＳＵＶはデータに差がなかったため、図２には移植後２週目のデータのみ示した。
Figure 2, HeLa-K tumor tissue and HeLa-B to tumor tissue [18 F] FBHI, [18 F] FBHB, [18 F] FBMI and [18 F] integrated amount for dosage per unit body weight FBMB SUV is shown. SUV was calculated by the following formula.
SUV = (radioactivity in tissue (Bq) / tissue weight (g)) / (tracer dose (Bq) / body weight (g))
Here, the HeLa-B transplantation in which the size of the HeLa-B tumor tissue is approximately the same as the size of the HeLa-K tumor tissue is four weeks after the HeLa-B transplantation and the number of days after the transplantation is the same as the HeLa-K transplantation. Since there was no difference in the SUV data in the HeLa-B tumor tissue between the two conditions after 2 weeks, only the data for the 2nd week after transplantation are shown in FIG.
図３に、ＨｅＬａ−Ｋ移植マウスとＨｅＬａ−Ｂ移植マウスでの、［１８Ｆ］ＦＢＨＩ、［１８Ｆ］ＦＢＨＢ、［１８Ｆ］ＦＢＭＩ及び［１８Ｆ］ＦＢＭＢの血液への集積に対する腫瘍への集積の比（化合物（Ｉ）の腫瘍ＳＵＶ／化合物（Ｉ）の血液ＳＵＶ）を示す。ここで、ＨｅＬａ−Ｂ腫瘍組織のサイズがＨｅＬａ−Ｋの腫瘍組織のサイズとほぼ同じとなるＨｅＬａ−Ｂ移植後４週目と、移植後の日数をＨｅＬａ−Ｋと同一にしたＨｅＬａ−Ｂ移植後２週目の２つの条件の間で、ＨｅＬａ−Ｂ移植マウスにおける集積比はデータに差がなかったため、図３には移植後２週目のデータのみ示した。 FIG. 3 shows the tumor accumulation of [ 18 F] FBHI, [ 18 F] FBHB, [ 18 F] FBMI, and [ 18 F] FBMB in blood in HeLa-K and HeLa-B transplanted mice. The accumulation ratio (tumor SUV of compound (I) / blood SUV of compound (I)) is shown. Here, the HeLa-B transplantation in which the size of the HeLa-B tumor tissue is approximately the same as the size of the HeLa-K tumor tissue is four weeks after the HeLa-B transplantation and the number of days after the transplantation is the same as the HeLa-K transplantation. Since there was no difference in the accumulation ratio in the HeLa-B transplanted mice between the two conditions after the second week, only the data for the second week after the transplantation are shown in FIG.
図２及び図３で示すように、細胞増殖速度の速いＨｅＬａ−Ｋ腫瘍組織への化合物（Ｉ）の集積がＨｅＬａ−Ｂ腫瘍組織への化合物（Ｉ）の集積より低かった。特に［１８Ｆ］ＦＢＭＩ及び［１８Ｆ］ＦＢＭＢで、ＨｅＬａ−Ｋ腫瘍組織とＨｅＬａ−Ｂ腫瘍組織との差が大きかった。細胞増殖が遅いことはアポトーシスが積極的に生じていると考えられ、逆に細胞増殖が速いことはアポトーシスが生じている割合が低いと考えられる。ＨｅＬａ−Ｋ腫瘍組織よりもアポトーシスが積極的に生じていると考えられるＨｅＬａ−Ｂ腫瘍組織への化合物（Ｉ）の集積が高いことを示す結果となった。 As shown in FIGS. 2 and 3, the accumulation of compound (I) in HeLa-K tumor tissue having a high cell growth rate was lower than the accumulation of compound (I) in HeLa-B tumor tissue. In particular, [ 18 F] FBMI and [ 18 F] FBMB showed a large difference between the HeLa-K tumor tissue and the HeLa-B tumor tissue. Slow cell growth is considered to cause apoptosis actively, and conversely, fast cell growth is considered to have a low rate of apoptosis. The results showed that the accumulation of compound (I) in HeLa-B tumor tissue, which is considered to be more actively undergoing apoptosis than HeLa-K tumor tissue, was high.
（実施例４）抗癌剤投与マウスを用いた実験
ヒト子宮頚癌細胞ＨｅＬａ（ｓｔｒａｉｎ：１５Ｓ３Ｄ）細胞５×１０６個を、６週齢のメスＢＡＬＢ／ｃＡ Ｊｃｌ−ｎｕヌードマウスの大腿皮下に移植し担癌マウスを作製した。移植後２週間目に抗癌剤として、シスプラチン（ＣＤＤＰ）２ｍｇ／ｋｇ又はＣＤＤＰ６ｍｇ／ｋｇを含む生理食塩溶液を腹腔内に投与し、抗癌剤投与マウスを２群作製した。コントロールの担癌マウスには抗癌剤を含まない生理食塩溶液を腹腔内に投与した。
(Example 4) Experiment using anticancer drug-administered mice 5 × 10 6 human cervical cancer cells HeLa (strain: 15S3D) cells were transplanted subcutaneously into the thigh of 6-week-old female BALB / cA Jcl-nu nude mice. Tumor-bearing mice were prepared. Two weeks after transplantation, a physiological saline solution containing 2 mg / kg of cisplatin (CDDP) or 6 mg / kg of CDDP was administered intraperitoneally as an anticancer drug, and two groups of anticancer drug-administered mice were prepared. A physiological saline solution containing no anticancer agent was intraperitoneally administered to control cancer-bearing mice.
図４に抗癌剤を投与された担癌マウスの腫瘍体積（ｍｍ３）の変化を示す。癌を移植して２週間後にＣＤＤＰ投与を行い、さらに最初の投与から７日後に再度投与を行った。図４にはＣＤＤＰを最初に投与した日を第０日として示してある。ＣＤＤＰ２ｍｇ／ｋｇ投与群は、８匹中７匹が第４〜５日に死亡した。ＣＤＤＰ６ｍｇ／ｋｇ投与群は第４日まで腫瘍体積が減少し、その後再び増加し始めた。２回目の投与で再び減少したが、やはり２回目投与から４日（第１１日）の後に再び腫瘍体積の増加が見られた。ＣＤＤＰ２ｍｇ／ｋｇ投与群はコントロールに対して腫瘍体積の減少があまり見られなかった。 FIG. 4 shows changes in tumor volume (mm 3 ) of cancer-bearing mice administered with anticancer agents. Two weeks after the transplantation of the cancer, CDDP administration was carried out, and administration was carried out again 7 days after the first administration. FIG. 4 shows the day on which CDDP was first administered as day 0. In the CDDP 2 mg / kg administration group, 7 out of 8 animals died on the 4th to 5th days. In the CDDP 6 mg / kg group, the tumor volume decreased until day 4 and then began to increase again. Although it decreased again in the second administration, the increase in the tumor volume was again observed 4 days after the second administration (day 11). In the CDDP 2 mg / kg administration group, the tumor volume did not decrease much compared to the control.
第２日に上記担癌マウスをプラナーイメージング装置（ＰＰＩＳ）に固定し、［１８Ｆ］ＦＢＨＩ、［１８Ｆ］ＦＢＨＢ、［１８Ｆ］ＦＢＭＩ又は［１８Ｆ］ＦＢＭＢの生理食塩水溶液０．３ｍＬを尾静脈より投与し、プラナー画像を得た。化合物投与から６５分後にマウスを断頭屠殺し、血液、心臓、肺、肝臓、腎臓、脾臓、大腿骨、筋肉、腫瘍、小腸、消化管、膵臓、脳を採取した。臓器重量、及び放射能を測定し、各化合物の集積（ＳＵＶ）を求めた。 On the second day, the tumor-bearing mice were fixed to a planar imaging device (PPIS), and 0.3 mL of [ 18 F] FBHI, [ 18 F] FBHB, [ 18 F] FBMI or [ 18 F] FBMB in physiological saline was added. A planar image was obtained from the tail vein. 65 minutes after compound administration, the mice were decapitated and blood, heart, lung, liver, kidney, spleen, femur, muscle, tumor, small intestine, gastrointestinal tract, pancreas, and brain were collected. The organ weight and radioactivity were measured to determine the accumulation (SUV) of each compound.
図５は上記担癌マウスの腫瘍への［１８Ｆ］ＦＢＨＩ、［１８Ｆ］ＦＢＨＢ、［１８Ｆ］ＦＢＭＩ及び［１８Ｆ］ＦＢＭＢの集積（ＳＵＶ）を示している。［１８Ｆ］ＦＢＨＩは腫瘍への集積が低く、抗癌剤治療による集積の増加が見られなかった。［１８Ｆ］ＦＢＨＢも腫瘍への集積が低かったが、ＣＤＤＰ６ｍｇ／ｋｇ投与群では他の群より若干高かった。［１８Ｆ］ＦＢＭＩは、ＣＤＤＰ投与量と比例して腫瘍への集積が高くなる傾向にあった。［１８Ｆ］ＦＢＭＢはＣＤＤＰ投与で集積の増加が見られ、その増加の割合はＣＤＤＰ６ｍｇ／ｋｇ＞ＣＤＤＰ２ｍｇ／ｋｇであった。 FIG. 5 shows the accumulation (SUV) of [ 18 F] FBHI, [ 18 F] FBHB, [ 18 F] FBMI and [ 18 F] FBMB in the tumor of the tumor-bearing mouse. [ 18 F] FBHI had a low accumulation in the tumor, and no increase in accumulation due to anticancer drug treatment was observed. [ 18 F] FBHB was also less accumulated in the tumor, but was slightly higher in the CDDP 6 mg / kg administration group than in the other groups. [ 18 F] FBMI tended to increase in tumor accumulation in proportion to the CDDP dose. [ 18 F] FBMB increased with CDDP administration, and the rate of increase was CDDP 6 mg / kg> CDDP 2 mg / kg.
図６に上記担癌マウスの写真と、コントロール、ＣＤＤＰ２ｍｇ／ｋｇ群及びＣＤＤＰ６ｍｇ／ｋｇ群マウスの［１８Ｆ］ＦＢＭＢのプラナー画像写真を示す。マウス写真において右大腿部の丸く囲んだ部分が腫瘍部位である。プラナー画像においても腫瘍部位への［１８Ｆ］ＦＢＭＢの集積が見られた。 FIG. 6 shows photographs of the above tumor-bearing mice and planar image photographs of [ 18 F] FBMB of control, CDDP 2 mg / kg group mice and CDDP 6 mg / kg group mice. In the mouse photograph, the circled part of the right thigh is the tumor site. Also in the planar image, accumulation of [ 18 F] FBMB at the tumor site was observed.
（実施例５）脳虚血ラットを用いた実験
麻酔下のラットの中大脳動脈を露出させ、ローズベンガル試薬を投与し、光を血管外部より照射し、照射位置の血管内部に血栓を作った。こうして、脳虚血ラットを作製した。虚血から２４時間後に化合物（Ｉ）を投与した。化合物（Ｉ）の投与から３０分及び９０分後に断頭屠殺し、脳を取り出し、２ｍｍ厚の脳スライス片を作製した。脳スライス片を染色し、その後イメージングプレートを用いて脳スライス片の放射能分布を画像化した。また、関心領域における化合物（Ｉ）の集積を求めた。
(Example 5) Experiment using cerebral ischemic rat The middle cerebral artery of anesthetized rat was exposed, rose bengal reagent was administered, light was irradiated from outside the blood vessel, and a thrombus was formed inside the blood vessel at the irradiation position. . Thus, cerebral ischemic rats were prepared. Compound (I) was administered 24 hours after ischemia. Decapitation was performed 30 minutes and 90 minutes after administration of Compound (I), the brain was removed, and 2 mm thick brain slices were prepared. The brain slices were stained and then the radioactivity distribution of the brain slices was imaged using an imaging plate. In addition, accumulation of compound (I) in the region of interest was determined.
図７に脳虚血ラットの脳スライス片の染色写真及び［１８Ｆ］ＦＢＨＩの集積画像を示す。脳スライス片の染色写真で赤い部位は、細胞の活性があるために染色されている部位で、白い部分は虚血により細胞死を起こしたために染色されなかった部位（虚血部位）である。集積画像では、放射能量が高い部位から低い部位の色が、赤-オレンジ-黄-黄緑-緑-青-藍で表されている。脳スライス片の写真と集積画像を対応させると、［１８Ｆ］ＦＢＨＩの集積が高い部分（集積画像中、赤−オレンジの部分）が虚血部位周辺にあることがわかる。 FIG. 7 shows a stained photograph of a brain slice of a cerebral ischemic rat and an integrated image of [ 18 F] FBHI. In the stained photograph of a slice of brain, the red part is a part that is stained due to cell activity, and the white part is a part that is not stained because cell death is caused by ischemia (ischemic part). In the integrated image, the color from high to low radioactivity is represented by red-orange-yellow-yellow-green-green-blue-indigo. When the photograph of the brain slice piece is associated with the accumulated image, it can be seen that a portion where [ 18 F] FBHI is highly accumulated (the red-orange portion in the accumulated image) is around the ischemic site.
虚血部位及び虚血部位周辺部（虚血側）と、虚血を起こしていない反対側の脳の対応する部位（正常側）とを関心領域として設定し、化合物（Ｉ）の関心領域への集積比（虚血側への化合物（Ｉ）の集積（ＳＵＶ）／正常側への化合物（Ｉ）の集積（ＳＵＶ））を求めた。結果を図８に示す。いずれの化合物においても、アポトーシスが生じていることが予見される虚血側への集積が正常側への集積よりも高くなっていた。また、化合物（Ｉ）同士で比較すると、上記集積比は［１８Ｆ］ＦＢＨＩ及び［１８Ｆ］ＦＢＨＢが、［１８Ｆ］ＦＢＭＩ及び［１８Ｆ］ＦＢＭＢに対して高くなっていた。 An ischemic site and a peripheral part of the ischemic site (ischemic side) and a corresponding site (normal side) of the opposite brain not causing ischemia are set as a region of interest, and the region of interest of compound (I) The accumulation ratio of compound (I) on the ischemic side (SUV) / the accumulation of compound (I) on the normal side (SUV) was determined. The results are shown in FIG. In any of the compounds, the accumulation on the ischemic side, which is predicted to cause apoptosis, was higher than the accumulation on the normal side. Further, when compared between the compounds (I), the accumulation ratio of [ 18 F] FBHI and [ 18 F] FBHB was higher than that of [ 18 F] FBMI and [ 18 F] FBMB.
（実施例６）脳虚血サルを用いた実験
サルに塩酸ケタミン及び硫酸アトロピンを筋肉内投与して麻酔導入した。口腔内にリドカインを噴霧して局所表面麻酔を施し、気管内挿管し、Ｎ２Ｏ：Ｏ２＝０．７：０．３（Ｌ／ｍｉｎ）＋イソフルレン（０．８〜０．３％）又はＮ２Ｏ：Ｏ２＝１．４：０．６（Ｌ／ｍｉｎ）＋イソフルレン（０．８〜０．３％）で麻酔を開始した。筋弛緩剤である臭化パンクロニウムを、０．０５ｍｇ／ｋｇ／ｈ（静脈内投与）又は０．１ｍｇ／ｋｇ／２ｈ（筋肉内投与）を追加して麻酔を維持した。上記麻酔下で片側眼球を摘出し、硬膜を露出し、中大脳動脈を確保し、以下のようにして中大脳動脈の閉塞を行った。手術用実体顕微鏡下で中大脳動脈を露出し、２個の動脈瘤クリップを用いて、クリップ間に出来る限り多くの側枝が含まれる様に留意した。３時間閉塞を行った後、クリップを外して再潅流を行った。中大脳動脈を再灌流する際は、直視下又は手術用実体顕微鏡下でクリップを外した。こうして、大脳半球の片側が虚血側、その反対側が正常側の脳虚血サルモデルを作製した。
(Example 6) Experiment using cerebral ischemic monkeys Ketamine hydrochloride and atropine sulfate were intramuscularly administered to monkeys to induce anesthesia. Lidocaine is sprayed into the oral cavity to give local surface anesthesia, endotracheal intubation, N 2 O: O 2 = 0.7: 0.3 (L / min) + isoflurane (0.8 to 0.3%) Alternatively, anesthesia was started with N 2 O: O 2 = 1.4: 0.6 (L / min) + isoflurane (0.8 to 0.3%). Anesthesia was maintained by adding 0.05 mg / kg / h (intravenous administration) or 0.1 mg / kg / 2h (intramuscular administration) of pancuronium bromide, a muscle relaxant. Under the above anesthesia, the unilateral eyeball was removed, the dura mater was exposed, the middle cerebral artery was secured, and the middle cerebral artery was occluded as follows. The middle cerebral artery was exposed under a surgical stereomicroscope, and two aneurysm clips were used, taking care to include as many side branches as possible between the clips. After 3 hours of occlusion, the clip was removed and reperfusion was performed. To reperfuse the middle cerebral artery, the clip was removed under direct viewing or under a surgical stereo microscope. Thus, a cerebral ischemic monkey model was prepared in which one side of the cerebral hemisphere was ischemic and the other side was normal.
再潅流を開始した３時間後に[１８Ｆ]ＦＢＨＩ又は[１８Ｆ]ＦＤＧを投与してＰＥＴ計測を行った。[１８Ｆ]ＦＤＧは細胞の活性が高い部分に集積する化合物である。再潅流から３日後及び７日後に［１８Ｆ］ＦＤＧのＰＥＴ計測を行った。 Three hours after the start of reperfusion, [ 18 F] FBHI or [ 18 F] FDG was administered to perform PET measurement. [ 18 F] FDG is a compound that accumulates in a portion with high cell activity. PET measurement of [ 18 F] FDG was performed 3 days and 7 days after reperfusion.
図９に脳虚血サルの再潅流後の脳スライス片の［１８Ｆ］ＦＢＨＩ及び[１８Ｆ]ＦＤＧの集積画像を示す。再潅流から３時間後、[１８Ｆ]ＦＢＨＩでは虚血側に高い集積が観察された。一方［１８Ｆ］ＦＤＧでは再潅流から３時間後、虚血側と正常側で集積の差が観察されなかった。再潅流から３日後及び７日後、虚血側で［１８Ｆ］ＦＤＧの集積の低下が観察された。[１８Ｆ]ＦＢＨＩは、神経細胞の活性が数日後に低下する部位に高く集積した。この結果から、アポトーシスにより神経細胞の脱落が生じる部位を、[１８Ｆ]ＦＢＨＩを用いて検出できることが示唆された。 FIG. 9 shows an integrated image of [ 18 F] FBHI and [ 18 F] FDG of brain slices after reperfusion of cerebral ischemic monkeys. Three hours after reperfusion, [ 18 F] FBHI showed high accumulation on the ischemic side. On the other hand, with [ 18 F] FDG, 3 hours after reperfusion, no accumulation difference was observed between the ischemic side and the normal side. A decrease in [ 18 F] FDG accumulation was observed on the ischemic side 3 and 7 days after reperfusion. [ 18 F] FBHI was highly accumulated at sites where neuronal activity declined after several days. From this result, the site where neuronal loss occurs due apoptosis, suggesting that can be detected using [18 F] FBHI.
本発明の化合物（Ｉ）によれば、生体内で生じているアポトーシスを検出することが可能となる。また、［１８Ｆ］ＦＢＭＩ及び［１８Ｆ］ＦＢＭＢは腫瘍縮退におけるアポトーシスの検出に有効であると考えられ、抗癌剤の評価試薬として使用できる。一方、［１８Ｆ］ＦＢＨＩ及び［１８Ｆ］ＦＢＨＢは神経系のアポトーシス検出に有効であると考えられ、虚血性疾患におけるアポトーシス抑制剤の評価試薬として使用できる。 According to the compound (I) of the present invention, apoptosis occurring in the living body can be detected. [ 18 F] FBMI and [ 18 F] FBMB are considered to be effective in detecting apoptosis in tumor regression and can be used as evaluation reagents for anticancer agents. On the other hand, [ 18 F] FBHI and [ 18 F] FBHB are considered effective for detecting apoptosis of the nervous system, and can be used as evaluation reagents for apoptosis inhibitors in ischemic diseases.
Claims (5)
（式（Ｉ）中、Ｘはヨウ素原子又は臭素原子であり、Ｙは水酸基又はメトキシ基である。） The compound represented by the following general formula (I).
(In formula (I), X is an iodine atom or a bromine atom, and Y is a hydroxyl group or a methoxy group.)
（式（ＩＩ）中、Ｘはヨウ素原子又は臭素原子であり、Ｙは水酸基又はメトキシ基である。） The compound represented by the following general formula (II).
(In formula (II), X is an iodine atom or a bromine atom, and Y is a hydroxyl group or a methoxy group.)
A reagent for evaluating an apoptosis inhibitor, comprising the compound according to claim 1.
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