JP6739987B2 - Nuclear medicine diagnostic imaging agent - Google Patents
Nuclear medicine diagnostic imaging agent Download PDFInfo
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- JP6739987B2 JP6739987B2 JP2016088445A JP2016088445A JP6739987B2 JP 6739987 B2 JP6739987 B2 JP 6739987B2 JP 2016088445 A JP2016088445 A JP 2016088445A JP 2016088445 A JP2016088445 A JP 2016088445A JP 6739987 B2 JP6739987 B2 JP 6739987B2
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Description
本開示は、ピリド［３，４−ｄ］ピリミジン骨格を有する放射性標識化合物に関し、一態様において、上皮成長因子受容体（ＥＧＦＲ）の二次変異を判別するための情報を取得可能な放射性標識化合物に関する。 The present disclosure relates to a radiolabeled compound having a pyrido[3,4-d]pyrimidine skeleton, and in one aspect, a radiolabeled compound capable of obtaining information for discriminating a secondary mutation of epidermal growth factor receptor (EGFR). Regarding
肺癌は、世界における癌による死因第１位である。肺癌は、その組織型によって小細胞肺癌と非小細胞肺癌とに大別されるが、肺癌の８０％を占める非小細胞肺癌に罹患する患者の１０〜３０％において膜貫通型のチロシンキナーゼ受容体であるＥＧＦＲを構成するＥＧＦＲ遺伝子が変異していることが知られている。ＥＧＦＲは変異が生じると活性化され、この活性化が癌の増殖等に関与するとされている。また、ＥＧＦＲ遺伝子の変異が確認されると、一般的な抗がん剤よりも分子標的治療薬であるＥＧＦＲ−ＴＫＩ（上皮成長因子受容体チロシンキナーゼ阻害剤）が有効であると考えられている。このため、近年、肺癌と診断されると遺伝子検査によって患者の遺伝子の変異の有無の確認が行われている（例えば、非特許文献１）。これらの遺伝子検査は、生検によって採取された癌組織を用いて行われる場合が多い。しかしながら、癌患者に侵襲的な生検を試みるのは様々なリスクがあり、身体的な負担も大きい。このため、生検に伴う様々なリスクを回避しつつ、遺伝子検査にかわる新たな方法が求められている。その一つとして、癌におけるＥＧＦＲを検出可能な核医学診断用放射性イメージングプローブの検討が行われている(例えば、非特許文献２及び３)。 Lung cancer is the leading cause of cancer death in the world. Lung cancer is roughly classified into small cell lung cancer and non-small cell lung cancer according to its tissue type. Transmembrane tyrosine kinase receptor is accepted in 10 to 30% of patients suffering from non-small cell lung cancer, which accounts for 80% of lung cancer. It is known that the EGFR gene that constitutes the body's EGFR is mutated. It is said that EGFR is activated when a mutation occurs, and this activation is involved in cancer growth and the like. Moreover, when a mutation in the EGFR gene is confirmed, it is considered that EGFR-TKI (epithelial growth factor receptor tyrosine kinase inhibitor), which is a molecular targeted therapeutic agent, is more effective than general anticancer agents. .. Therefore, in recent years, when lung cancer is diagnosed, the presence or absence of gene mutations in patients has been confirmed by genetic testing (for example, Non-Patent Document 1). These genetic tests are often performed using cancer tissue collected by biopsy. However, attempting an invasive biopsy on a cancer patient poses various risks and imposes a heavy physical burden. Therefore, there is a need for new methods to replace genetic testing while avoiding various risks associated with biopsy. As one of them, studies have been conducted on radioactive imaging probes for nuclear medicine diagnosis that can detect EGFR in cancer (for example, Non-Patent Documents 2 and 3).
また、ＥＧＦＲ−ＴＫＩによって奏功しても、１年以内に耐性を獲得し、その結果、ＥＧＦＲ−ＴＫＩでは十分な治療効果が得られなくなる場合がある。耐性獲得の約半数に二次変異が関与していると考えられていることから、ＥＧＦＲ−ＴＫＩの治療開始後、再度遺伝子検査を行う必要がある。 In addition, even if successful with EGFR-TKI, resistance may be acquired within one year, and as a result, sufficient therapeutic effect may not be obtained with EGFR-TKI. Since it is considered that the secondary mutation is involved in about half of the acquired resistance, it is necessary to perform the genetic test again after starting the treatment of EGFR-TKI.
上記のとおり、ＥＧＦＲを検出するためのイメージングプローブの検討は行われているが、ＥＧＦＲの二次変異を非侵襲的に判別可能な方法は未だ開発されていない。そこで、本開示は、ＥＧＦＲの二次変異を判別可能な放射性標識化合物を提供する。 As described above, studies on imaging probes for detecting EGFR have been conducted, but a method capable of non-invasively discriminating the secondary mutation of EGFR has not yet been developed. Therefore, the present disclosure provides a radiolabeled compound capable of discriminating the secondary mutation of EGFR.
本開示は、一態様において、下記式（１）で表される化合物又は式（１）で表される化合物の製薬上許容される塩を含む核医学画像診断薬に関する。
Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基であり、
Ｒ1は、放射性ハロゲン原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、
Ｒ2は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、
Ｒ1及びＲ2の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ1基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、
Ｒ1又はＲ2は、放射性ハロゲン原子又は放射性炭素原子（11Ｃ）を含み、
Ｙは、−ＮＨ−又は−Ｏ−である。］
In one aspect, the present disclosure relates to a nuclear medicine diagnostic imaging agent containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1).
L 1 is an alkanediyl group having 1 to 5 carbon atoms, or an alkenediylcarbonyl group having 3 to 8 carbon atoms,
R 1 is a radioactive halogen atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent,
R 2 is a 6-8 membered aryl group having one substituent or a nitrogen-containing heteroaryl group,
The substituents of R 1 and R 2 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms or -(CH 2 ) 1 -(O- C 2 H 4 ) m —X 1 group, l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or -[ 11 C] CH 3 ,
R 1 or R 2 contains a radioactive halogen atom or a radioactive carbon atom ( 11 C),
Y is -NH- or -O-. ]
本開示は、一態様において、下記式（１）で表される化合物又は式（１）で表される化合物の製薬上許容される塩に関する。
Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基であり、
Ｒ1は、放射性ハロゲン原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、
Ｒ2は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、
Ｒ1及びＲ2の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ1基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、
Ｒ1又はＲ2は、放射性ハロゲン原子又は放射性炭素原子（11Ｃ）を含み、
Ｙは、−ＮＨ−又は−Ｏ−である。］
In one aspect, the present disclosure relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1).
L 1 is an alkanediyl group having 1 to 5 carbon atoms, or an alkenediylcarbonyl group having 3 to 8 carbon atoms,
R 1 is a radioactive halogen atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent,
R 2 is a 6-8 membered aryl group having one substituent or a nitrogen-containing heteroaryl group,
The substituents of R 1 and R 2 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms or -(CH 2 ) 1 -(O- C 2 H 4 ) m —X 1 group, l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or -[ 11 C] CH 3 ,
R 1 or R 2 contains a radioactive halogen atom or a radioactive carbon atom ( 11 C),
Y is -NH- or -O-. ]
本開示は、一態様において、下記式（２）で表される化合物又は式（２）で表される化合物の製薬上許容される塩を含む標識前駆体組成物に関する。
Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基であり、
Ｒ11は、塩素原子、臭素原子、ヨウ素原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、
Ｒ12は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、
Ｒ11及びＲ12の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ11基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ11は、塩素原子、臭素原子、ヨウ素原子、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基であり、
Ｙは、−ＮＨ−又は−Ｏ−である。］
In one aspect, the present disclosure relates to a labeling precursor composition containing a compound represented by the following formula (2) or a pharmaceutically acceptable salt of the compound represented by the formula (2).
L 1 is an alkanediyl group having 1 to 5 carbon atoms, or an alkenediylcarbonyl group having 3 to 8 carbon atoms,
R 11 is a chlorine atom, a bromine atom, an iodine atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent,
R 12 is a 6-8 membered aryl group having one substituent or a nitrogen-containing heteroaryl group,
The substituents of R 11 and R 12 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms, or —(CH 2 ) 1 —(O— a C 2 H 4) m -X 11 group, l is 0 to 5, m is 0 to 5 a number of repeating ethyleneoxy groups, X 11 is a chlorine atom, a bromine atom, An iodine atom, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group,
Y is -NH- or -O-. ]
本開示は、一態様において、上皮成長因子受容体チロシンキナーゼ阻害薬による非小細胞肺癌の治療が行われる被検体における上皮成長因子受容体チロシンキナーゼ阻害薬による治療の有効性を評価するための情報を得る方法であって、
本開示の核医学画像診断薬、又は本開示の式（１）で表される化合物若しくは式（１）で表される化合物の製薬上許容される塩が投与された被検体の肺癌腫瘍から前記核医学画像診断薬又は前記化合物の放射性シグナルを検出することを含む方法に関する。
The present disclosure provides, in one aspect, information for assessing the efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor in a subject undergoing treatment of non-small cell lung cancer with an epidermal growth factor receptor tyrosine kinase inhibitor. How to get
From the lung cancer tumor of a subject administered with the nuclear medicine diagnostic imaging agent of the present disclosure, or the compound represented by formula (1) or the pharmaceutically acceptable salt of the compound represented by formula (1) of the present disclosure, A nuclear medicine diagnostic imaging agent or a method comprising detecting a radioactive signal of said compound.
本開示は、一態様において、肺癌腫瘍における上皮成長因子受容体をコードする遺伝子におけるＴ７９０Ｍ変異の発生を評価する方法であって、
本開示の核医学画像診断薬、又は本開示の式（１）で表される化合物若しくは式（１）で表される化合物の製薬上許容される塩が投与された被検体の肺癌腫瘍から前記核医学画像診断薬又は前記化合物の放射性シグナルを検出すること、
前記被検体の肺癌腫瘍からの放射性シグナルの検出を上皮成長因子受容体チロシンキナーゼ阻害薬の治療期間中に繰り返し行うこと、
前記得られた情報又は検出された放射性シグナルを比較すること、及び
前記比較により情報又はシグナルの変動に基づき、肺癌腫瘍における上皮成長因子受容体をコードする遺伝子における、Ｔ７９０Ｍ変異の発生の有無を決定することを含む方法に関する。
The present disclosure, in one aspect, is a method of assessing the occurrence of a T790M mutation in a gene encoding an epidermal growth factor receptor in lung cancer tumors, comprising:
From the lung cancer tumor of a subject administered with the nuclear medicine diagnostic imaging agent of the present disclosure, or the compound represented by formula (1) or the pharmaceutically acceptable salt of the compound represented by formula (1) of the present disclosure, Detecting a radioactive signal of a nuclear medicine diagnostic imaging agent or said compound,
Repeating the detection of radioactive signals from the lung cancer tumor of the subject during the treatment period of the epidermal growth factor receptor tyrosine kinase inhibitor,
Comparing the obtained information or the detected radioactive signal, and determining the presence or absence of the T790M mutation in the gene encoding the epidermal growth factor receptor in lung cancer tumor based on the variation of the information or the signal by the comparison. To a method including doing.
本開示は、一態様において、上皮成長因子受容体チロシンキナーゼ阻害薬による非小細胞肺癌の治療が行われる被検体における上皮成長因子受容体チロシンキナーゼ阻害薬による治療の有効性を評価する方法であって、
上皮成長因子受容体チロシンキナーゼ阻害薬の投与開始前、投与開始後及び投与開始から一定期間経過後からなる群から選択される２以上のタイミングで本開示の情報を得る方法により得られた情報を比較することを含む方法に関する。
The present disclosure is, in one aspect, a method of assessing the efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor in a subject undergoing treatment of non-small cell lung cancer with an epidermal growth factor receptor tyrosine kinase inhibitor. hand,
The information obtained by the method of obtaining the information of the present disclosure at two or more timings selected from the group consisting of before administration of an epidermal growth factor receptor tyrosine kinase inhibitor, after administration, and after a certain period of time has elapsed from administration initiation, A method that includes comparing.
本開示は、一態様において、ＥＧＦＲの二次変異を判別可能な放射性標識化合物及びそれを用いたＥＧＦＲ−ＴＫＩの治療効果の有効性を評価する方法を提供できる。 The present disclosure can provide, in one aspect, a radiolabeled compound capable of discriminating a secondary mutation of EGFR and a method for evaluating the efficacy of therapeutic effect of EGFR-TKI using the same.
本開示は、一態様において、後述する実施例で合成した式Ｈ１〜Ｈ４（実施例表１）で表されるピリド［３，４−ｄ］ピリミジン骨格を有する化合物であれば、ＥＧＦＲ、中でもＬ８５８Ｒ変異型ＥＧＦＲに対する結合親和性と比較して、Ｌ８５８Ｒ／Ｔ７９０Ｍ変異型（二重変異体：ＤＭ）ＥＧＦＲに対して結合親和性が低い、との知見に基づく。
また、本開示は、一態様において、化合物［18Ｆ］Ｈ４（(E)-N-(4-((3-bromophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4-(4-(2-[18F]fluoroethyl)piperazin-1-yl)but-2-enamide）といったテトラヒドロピリドチエノ［２，３−ｄ］ピリミジン骨格を有する放射性ハロゲン標識化合物であれば、Ｌ８５８Ｒ変異型ＥＧＦＲを有するＨ３２５５担がんマウスのＰＥＴ撮像において高い近接臓器比を示し、かつＬ８５８Ｒ／Ｔ７９０Ｍ変異型ＥＧＦＲを有するＨ１９７５担がんマウスのＰＥＴ撮像においてＨ３２５５担がんマウスと比較して有意に低い近接臓器比を示す、との知見に基づく。
また、本開示は、一態様において、化合物Ｈ２（N4-(3-(2-fluoroethoxy)phenyl)-N6-(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-4, 6-diamine）（実施例表１）であれば、Ｌ８５８Ｒ変異型ＥＧＦＲに対する結合親和性が、野生型ＥＧＦＲに対する結合親和性及びＬ８５８Ｒ／Ｔ７９０Ｍ変異型ＥＧＦＲと比較して結合親和性が低い、との知見に基づく。
In one aspect, the present disclosure provides EGFR, particularly L858R, as long as it is a compound having a pyrido[3,4-d]pyrimidine skeleton represented by Formulas H1 to H4 (Example Table 1) synthesized in Examples described later. It is based on the finding that the binding affinity for L858R/T790M mutant (double mutant: DM) EGFR is lower than that for mutant EGFR.
The present disclosure also provides, in one aspect, the compound [ 18 F]H4((E)-N-(4-((3-bromophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4. If the compound is a radiohalogen-labeled compound having a tetrahydropyridothieno[2,3-d]pyrimidine skeleton such as -(4-(2-[18F]fluoroethyl)piperazin-1-yl)but-2-enamide), the L858R mutation In the PET imaging of the H3255 cancer-bearing mouse having the EGFR type, a high proximity organ ratio is shown, and in the PET imaging of the H1975 cancer-bearing mouse having the L858R/T790M mutant EGFR, it is significantly lower than that in the H3255 tumor-bearing mouse. Based on the finding that the ratio of adjacent organs is shown.
The present disclosure relates in one aspect, the compound H2 (N 4 - (3- ( 2-fluoroethoxy) phenyl) -N 6 - (2-morpholinoethyl) pyrido [3,4-d] pyrimidine-4, 6-diamine ) (Example Table 1), it is based on the finding that the binding affinity for the L858R mutant EGFR is lower than the binding affinity for the wild type EGFR and the L858R/T790M mutant EGFR. ..
上記式（１）で表される放射性標識化合物によれば、一又は複数の実施形態において、ＥＧＦＲ遺伝子においてＬ８５８Ｒ変異等のＥＧＦＲ−ＴＫＩの感受性を高める変異が発現した肺癌腫瘍において、二次変異であるＴ７９０Ｍ変異が発現しているか否かを非侵襲的に判別できるという効果を奏しうる。また、式（１）で表される放射性標識化合物によれば、一又は複数の実施形態において、Ｌ８５８Ｒ変異等のＥＧＦＲ−ＴＫＩの感受性を高める変異が発現した肺癌腫瘍において、ＥＧＦＲ−ＴＫＩ耐性を獲得したか否かの判定を非侵襲的に行うことができうるという効果を奏しうる。さらに、式（１）で表される放射性標識化合物によれば、一又は複数の実施形態において、ＥＧＦＲ遺伝子においてＬ８５８Ｒ変異等といったＥＧＦＲ−ＴＫＩの感受性を高める変異が発現した肺癌腫瘍を有する患者において、ＥＧＦＲ−ＴＫＩによる治療の有効性を評価することができるという効果を奏しうる。 According to the radio-labeled compound represented by the above formula (1), in one or a plurality of embodiments, in a lung cancer tumor in which a mutation that enhances EGFR-TKI sensitivity such as L858R mutation in the EGFR gene is expressed, a secondary mutation It is possible to exert an effect of non-invasively determining whether or not a certain T790M mutation is expressed. Further, according to the radiolabeled compound represented by the formula (1), in one or a plurality of embodiments, EGFR-TKI resistance is acquired in a lung cancer tumor expressing a mutation that enhances EGFR-TKI sensitivity such as L858R mutation. The effect that it can be determined non-invasively can be obtained. Furthermore, according to the radiolabeled compound represented by formula (1), in one or more embodiments, in a patient having a lung cancer tumor expressing a mutation that enhances EGFR-TKI sensitivity such as L858R mutation in the EGFR gene, The effect that the efficacy of the treatment with EGFR-TKI can be evaluated can be exerted.
化合物Ｈ２（N4-(3-(2-fluoroethoxy)phenyl)-N6-(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-4, 6-diamine）によれば、一又は複数の実施形態において、ＥＧＦＲ遺伝子においてＬ８５８Ｒ変異が発現しているか否かを非侵襲的に判別できるという効果を奏しうる。 According to the compound H2 (N 4 -(3-(2-fluoroethoxy)phenyl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-4, 6-diamine), one or more implementations In terms of morphology, it is possible to obtain the effect of noninvasively determining whether or not the L858R mutation is expressed in the EGFR gene.
本明細書における「ＥＧＦＲの二次変異を判別可能」としては、一又は複数の実施形態において、Ｌ８５８Ｒ変異（一次変異）が生じたＥＧＦＲと、Ｌ８５８Ｒ変異に加えてＴ７９０Ｍ変異（二次変異）が生じたＥＧＦＲとを判別できることが挙げられる。 In the present specification, "discriminating a secondary mutation of EGFR" means, in one or a plurality of embodiments, an EGFR having a L858R mutation (primary mutation) and a T790M mutation (secondary mutation) in addition to the L858R mutation. It is possible to distinguish the generated EGFR.
本明細書において「核医学画像診断薬」とは、放射性同位体（ＲＩ）を結合させた化合物を体内に投与し、体内から放出される放射線（放射性シグナル）を体外から計測・画像化し、臓器又は組織の生体機能の評価又は検査や、疾病の診断等を行うインビボ核医学検査に用いられる放射性標識化合物を含む薬剤、又は体内から採取した組織や血液等の試料と試験管内で反応させ、臓器又は組織の生体機能の評価又は検査や、疾病の診断等を行うインビトロ核医学検査に用いられる放射性標識化合物を含む薬剤をいう。インビボ核医学検査としては、一又は複数の実施形態において、ＳＰＥＣＴ（Single Photon Emission Computed Tomography）や、ＰＥＴ（Positron Emission Tomography）等といった核医学イメージングプローブを用いた方法が挙げられる。 In the present specification, the term “nuclear medicine diagnostic imaging agent” means that a compound bound with a radioisotope (RI) is administered into the body, and radiation (radioactive signal) emitted from the body is measured and imaged from outside the body to produce an organ. Or, a reaction or in vitro with a drug containing a radiolabeled compound used in in vivo nuclear medicine tests for evaluating or examining the biological function of tissues, diagnosing diseases, etc. Alternatively, it refers to a drug containing a radiolabeled compound which is used in in vitro nuclear medicine tests for evaluating or examining biological functions of tissues and diagnosing diseases. Examples of the in vivo nuclear medicine examination include a method using a nuclear medicine imaging probe such as SPECT (Single Photon Emission Computed Tomography) or PET (Positron Emission Tomography) in one or a plurality of embodiments.
本明細書において「製薬上許容される塩」とは、薬理上及び／又は医薬上許容される塩を含有し、例えば、無機酸塩、有機酸塩、無機塩基塩、有機塩基塩、酸性又は塩基性アミノ酸塩等が挙げられる。本開示において「化合物の塩」には、化合物が大気中に放置されることにより、水分を吸収して形成されうる水和物が包含され得る。また、本開示において「化合物の塩」には、化合物が他のある種の溶媒を吸収して形成されうる溶媒和物も包含され得る。 In the present specification, the “pharmaceutically acceptable salt” includes a pharmacologically and/or pharmaceutically acceptable salt, for example, an inorganic acid salt, an organic acid salt, an inorganic basic salt, an organic basic salt, an acidic or Basic amino acid salts and the like can be mentioned. In the present disclosure, “a salt of a compound” may include a hydrate that can be formed by absorbing water when the compound is left in the air. Further, in the present disclosure, “a salt of a compound” may also include a solvate which can be formed by the compound absorbing a certain other solvent.
本明細書において「放射性ハロゲン原子」とは、ハロゲン原子の放射性同位体をいう。放射性ハロゲン原子としては、18Ｆ、123Ｉ、124Ｉ、125Ｉ、131Ｉ、75Ｂｒ、76Ｂｒ、及び77Ｂｒが挙げられる。本明細書において「ハロゲン原子」とは、ハロゲン原子の非放射性同位体をいう。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子又はヨウ素原子が挙げられる。 The term “radioactive halogen atom” used herein refers to a radioactive isotope of a halogen atom. Examples of the radioactive halogen atom include 18 F, 123 I, 124 I, 125 I, 131 I, 75 Br, 76 Br, and 77 Br. The term “halogen atom” as used herein refers to a non-radioactive isotope of a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
本明細書において「炭素数１以上５以下のアルカンジイル基」とは、飽和脂肪族の分枝鎖又は直鎖を有し、かつ、直鎖又は分枝鎖の構造内に１個以上５個以下の炭素原子を有する二価の炭化水素基をいう。炭素数１以上５以下のアルカンジイル基としては、一又は複数の実施形態において、メタンジイル基、エタンジイル基、プロパンジイル基、ブタンジイル基又はペンタンジイル基等が挙げられる。 In the present specification, the "alkanediyl group having 1 to 5 carbon atoms" has a saturated aliphatic branched or straight chain, and 1 or more and 5 in a straight chain or branched chain structure. It refers to a divalent hydrocarbon group having the following carbon atoms. Examples of the alkanediyl group having 1 to 5 carbon atoms include, in one or a plurality of embodiments, a methanediyl group, an ethanediyl group, a propanediyl group, a butanediyl group, a pentanediyl group and the like.
本明細書において「炭素数３以上８以下のアルケンジイルカルボニル基」とは、少なくとも１個の炭素−炭素間の二重結合を有する不飽和脂肪族の分枝鎖又は直鎖と１個のカルボニル基とを有し、かつ、直鎖又は分枝鎖の構造内に２個以上７個以下の炭素原子を有する二価の炭化水素基をいう。炭素数３以上８以下のアルケンジイルカルボニル基としては、一又は複数の実施形態において、−（Ｃ＝Ｏ）−ＣＨ＝ＣＨ−、−（Ｃ＝Ｏ）−ＣＨ＝ＣＨ−ＣＨ2−、−（Ｃ＝Ｏ）−ＣＨ＝ＣＨ−Ｃ2Ｈ4−、又は−（Ｃ＝Ｏ）−ＣＨ＝ＣＨ−Ｃ3Ｈ6−等が挙げられる。 In the present specification, the term "alkenyldiylcarbonyl group having 3 to 8 carbon atoms" means an unsaturated aliphatic branched or straight chain having at least one carbon-carbon double bond and one carbonyl. Group and a divalent hydrocarbon group having 2 or more and 7 or less carbon atoms in the structure of a straight chain or a branched chain. The alkenediyl group having 3 to 8 carbon atoms, in one or more embodiments, - (C = O) -CH = CH -, - (C = O) -CH = CH-CH 2 -, - (C = O) -CH = CH -C 2 H 4 -, or - (C = O) -CH = CH-C 3 H 6 - , and the like.
本明細書において「５〜７員の単環式窒素含有ヘテロシクロアルキル基」とは、５個以上７個以下の環原子と、環原子を構成するヘテロ原子として１個又は２個以上の窒素原子と、必要に応じて１個又は２個以上の酸素原子とを含む、単環式の飽和ヘテロ環基をいう。５〜７員の単環式窒素含有ヘテロシクロアルキル基としては、一又は複数の実施形態において、モルホリニル基、ピペラジニル基、ピペリジニル基等が挙げられる。本明細書において、「１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキル基」とは、置換基を有さない５〜７員の単環式窒素含有ヘテロシクロアルキル基、又は、５〜７員の単環式窒素含有ヘテロシクロアルキル基の１個又は２個以上の炭素原子又はヘテロ原子が置換されたものをいう。 In the present specification, the "5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl group" means 5 or more and 7 or less ring atoms, and 1 or 2 or more nitrogen atoms as hetero atoms constituting the ring atoms. A monocyclic saturated heterocyclic group containing an atom and optionally one or more oxygen atoms. Examples of the 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl group include, in one or more embodiments, a morpholinyl group, a piperazinyl group, a piperidinyl group, and the like. In the present specification, the "5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl group which may have one substituent" means a 5- to 7-membered monocyclic group having no substituent. A nitrogen-containing heterocycloalkyl group or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl group in which one or more carbon atoms or heteroatoms are substituted.
本明細書において「６〜８員のアリール基」とは、６個以上８個以下の炭素原子を有する芳香族炭化水素の環炭素原子から１個の水素原子を除去することにより生成された基をいう。６〜８員のアリール基としては、一又は複数の実施形態において、フェニル基、ナフチル基等が挙げられる。本明細書において「６〜８員の窒素含有ヘテロアリール基」とは、６個以上８個以下の環原子と、環原子を構成するヘテロ原子として１個又は２個以上の窒素原子とを少なくとも含む不飽和の複素環式基をいう。６〜８員の窒素含有ヘテロアリール基としては、一又は複数の実施形態において、ピリジニル基、ピラジニル基等が挙げられる。本明細書において「１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基」とは、６〜８員のアリール又は６〜８員の窒素含有ヘテロアリール基の炭素原子又はヘテロ原子が、１個の置換基で置換されたものをいう。 In the present specification, the "6- to 8-membered aryl group" is a group formed by removing one hydrogen atom from a ring carbon atom of an aromatic hydrocarbon having 6 to 8 carbon atoms. Say. Examples of the 6- to 8-membered aryl group include a phenyl group and a naphthyl group in one or more embodiments. In the present specification, the “6- to 8-membered nitrogen-containing heteroaryl group” means at least 6 or more and 8 or less ring atoms and at least one or two or more nitrogen atoms as hetero atoms constituting the ring atoms. It includes unsaturated heterocyclic groups including. Examples of the 6- to 8-membered nitrogen-containing heteroaryl group include a pyridinyl group and a pyrazinyl group in one or a plurality of embodiments. In the present specification, the "6- to 8-membered aryl group or nitrogen-containing heteroaryl group having one substituent" means a carbon atom of a 6- to 8-membered aryl or a 6 to 8-membered nitrogen-containing heteroaryl group or A heteroatom is substituted with one substituent.
本明細書において「炭素数１以上５以下のアルキル基」とは、飽和脂肪族の分枝鎖又は直鎖を有し、かつ、直鎖又は分枝鎖の構造内に１個以上５個以下の炭素原子を有する一価の炭化水素基をいう。炭素数１以上５以下のアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基又はブチル基等が挙げられる。 In the present specification, the "alkyl group having 1 to 5 carbon atoms" has a saturated aliphatic branched or straight chain, and 1 or more and 5 or less in the structure of the straight chain or branched chain. A monovalent hydrocarbon group having carbon atoms of Examples of the alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group and butyl group.
本明細書において「炭素数１以上５以下のハロゲン化アルキル基」とは、ハロゲン置換された炭素数１以上５以下のアルキル基をいう。「ハロゲン置換された炭素数１以上５以下のアルキル基」とは、１又は２以上の水素原子がハロゲン原子によって置換されている炭素数１以上５以下のアルキル基をいう。ハロゲン置換された炭素数１以上５以下のアルキル基としては、モノフルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、トリフルオロエチル基、又はジフルオロメチレン基等が挙げられる。 In the present specification, the “halogenated alkyl group having 1 to 5 carbon atoms” means a halogen-substituted alkyl group having 1 to 5 carbon atoms. The “halogen-substituted alkyl group having 1 to 5 carbon atoms” refers to an alkyl group having 1 to 5 carbon atoms in which one or more hydrogen atoms are replaced by halogen atoms. Examples of the halogen-substituted alkyl group having 1 to 5 carbon atoms include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, and a difluoromethylene group.
［式（１）で表される化合物］
本開示は、一又は複数の実施形態において、下記式（１）で表される化合物又は式（１）で表される化合物の製薬上許容される塩（以下、「本開示の化合物（１）」という）に関する。本開示の化合物（１）は、一又は複数の実施形態において、Ｌ８５８Ｒ変異型ＥＧＦＲに対して比較的高い結合親和性を示すが、ＥＧＦＲの二次変異の一つであるＴ７９０Ｍ変異型ＥＧＦＲ及び二重変異体（ＤＭ）であるＬ８５８Ｒ／Ｔ７９０Ｍ変異型ＥＧＦＲに対して結合親和性を示さないという効果を奏しうる。
In one or a plurality of embodiments, the present disclosure provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1) (hereinafter, referred to as “compound (1) of the present disclosure”). ")) concerning. Compound (1) of the present disclosure, in one or more embodiments, exhibits a relatively high binding affinity for L858R mutant EGFR, but one of the secondary mutations of EGFR, T790M mutant EGFR and two mutants. It can exert the effect of not exhibiting binding affinity to the L858R/T790M mutant EGFR which is a heavy mutant (DM).
式（１）中、Ｙは、−ＮＨ−又は−Ｏ−である。 In formula (1), Y is -NH- or -O-.
式（１）中、Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基である。Ｌ1としては、一又は複数の実施形態において、−（ＣＨ2）2−又は−（Ｃ＝Ｏ）−ＣＨ＝ＣＨ−ＣＨ2−が挙げられる。 In formula (1), L 1 is an alkanediyl group having 1 to 5 carbon atoms or an alkenediylcarbonyl group having 3 to 8 carbon atoms. Examples of L 1 include —(CH 2 ) 2 — or —(C═O)—CH═CH—CH 2 — in one or more embodiments.
式（１）中、Ｒ1は、放射性ハロゲン原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、Ｒ2は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、Ｒ1及びＲ2の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ1基であって、Ｒ1又はＲ2は、放射性ハロゲン原子又は放射性炭素原子（11Ｃ）を含む。ここで、ｌは０、１、２、３、４、又は５であり、ｍはエチレンオキシ基の繰り返し数であって０、１、２、３、４又は５であり、Ｘ1は放射性ハロゲン原子又は−［11Ｃ］ＣＨ3である。 In the formula (1), R 1 is a radioactive halogen atom or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent, and R 2 is 1 A 6- to 8-membered aryl group having a substituent or a nitrogen-containing heteroaryl group, wherein the substituents of R 1 and R 2 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, and a carbon number. 1 to 5 halogenated alkyl group or - (CH 2) l - ( O-C 2 H 4) a m -X 1 group, R 1 or R 2 is a radioactive halogen atom or radioactive carbon atoms (11 Including C). Here, l is 0, 1, 2, 3, 4, or 5, m is the number of repeating ethyleneoxy groups and is 0, 1, 2, 3, 4 or 5, and X 1 is a radioactive halogen. atoms, or - [11 C] CH 3.
Ｒ1としては、一又は複数の実施形態において、放射性ハロゲン原子、
Ｒ2としては、一又は複数の実施形態において、
Ｒ1とＲ2との組み合わせとしては、一又は複数の実施形態において、下記表に示す組み合わせが挙げられる。
Ｒ1とＬ1とＲ2との組み合わせとしては、一又は複数の実施形態において、下記表に示す組み合わせが挙げられる。
式（１）で表される化合物としては、一又は複数の実施形態において、下記式（１−１）〜（１−４）で表される化合物又はそれらの化合物の製薬上許容される塩等が挙げられ、ＥＧＦＲの二次変異の判別を向上させる点から、好ましくはＬ８５８Ｒ変異型ＥＧＦＲに対する結合親和性が高くＬ８５８Ｒ／Ｔ７９０Ｍ変異型に対する結合親和性を低い化合物が得られる点から、式（１−１）又は（１−４）で表される化合物が好ましい。Ｌ８５８Ｒ変異型ＥＧＦＲに対して結合するが、Ｌ８５８Ｒ／Ｔ７９０Ｍ変異型ＥＧＦＲに対しては非常に低い結合親和性を示す化合物が得られる点からは、式（１−２）又は（１−３）で表される化合物が好ましい。野生型ＥＧＦＲに対して結合親和性が低い一方で、Ｌ８５８Ｒ変異型ＥＧＦＲに対して結合し、またＬ８５８Ｒ／Ｔ７９０Ｍ変異型ＥＧＦＲに対しては非常に低い結合親和性を示す化合物が得られる点からは、式（１−２）で表される化合物が好ましい。式（１−１）〜（１−４）において、Ｘ1は、放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、好ましくは［18Ｆ］フッ素原子である。Ｘ2は、ハロゲン原子であり、好ましくは臭素原子である。
本開示の化合物（１）は、一又は複数の実施形態において、Ｌ８５８Ｒ変異等のＥＧＦＲ−ＴＫＩの感受性を高める変異が発現した肺癌腫瘍又は該腫瘍を有する患者において、ＥＧＦＲの二次変異の発現を判別するためのイメージングプローブ、イメージング用組成物、核医学画像診断薬、ＥＧＦＲ−ＴＫＩ耐性獲得の評価用診断薬、又はＥＧＦＲ−ＴＫＩによる治療の有効性の評価用診断薬として用いることができる。したがって、本開示は、一又は複数の実施形態において、式（１）で表される化合物又は式（１）で表される化合物の製薬上許容される塩を含むイメージングプローブ、イメージング用組成物、核医学画像診断薬、ＥＧＦＲ−ＴＫＩ耐性獲得の評価用診断薬、又はＥＧＦＲ−ＴＫＩによる治療の有効性の評価用診断薬に関する。本開示は、一又は複数の実施形態において、有効成分として式（１）で表される化合物又は式（１）で表される化合物の製薬上許容される塩を含むイメージングプローブ、イメージング用組成物、核医学画像診断薬、ＥＧＦＲ−ＴＫＩ耐性獲得の評価用診断薬、又はＥＧＦＲ−ＴＫＩによる治療の有効性の評価用診断薬に関する。 In one or a plurality of embodiments, the compound (1) of the present disclosure shows the expression of a secondary mutation of EGFR in a lung cancer tumor or a patient having the tumor expressing a mutation that enhances the sensitivity of EGFR-TKI such as L858R mutation. It can be used as an imaging probe for discrimination, an imaging composition, a nuclear medicine image diagnostic agent, a diagnostic agent for evaluating the acquisition of EGFR-TKI resistance, or a diagnostic agent for evaluating the effectiveness of treatment with EGFR-TKI. Therefore, the present disclosure provides, in one or more embodiments, an imaging probe, a composition for imaging, comprising a compound represented by formula (1) or a pharmaceutically acceptable salt of the compound represented by formula (1), The present invention relates to a nuclear medicine image diagnostic agent, a diagnostic agent for evaluating the acquisition of EGFR-TKI resistance, or a diagnostic agent for evaluating the effectiveness of treatment with EGFR-TKI. In one or a plurality of embodiments of the present disclosure, an imaging probe, an imaging composition, which comprises, as an active ingredient, a compound represented by the formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1). , A nuclear medicine image diagnostic agent, a diagnostic agent for evaluating the acquisition of EGFR-TKI resistance, or a diagnostic agent for evaluating the effectiveness of treatment with EGFR-TKI.
本開示において、イメージング用組成物及び各種診断薬の形態は、特に限定されるものではないが、一又は複数の実施形態において、溶液又は粉末が挙げられる。これらは、担体等の医薬品添加物を含んでいてもよい。 In the present disclosure, the forms of the imaging composition and various diagnostic agents are not particularly limited, but in one or a plurality of embodiments, a solution or a powder is included. These may contain pharmaceutical additives such as carriers.
［式（１）で表される化合物の製造方法］
本開示の化合物（１）は、一又は複数の実施形態において、下記式（２）で表される化合物又はその製薬上許容される塩を放射性標識することにより製造できる。したがって、本開示は、一又は複数の実施形態において、式（２）で表される化合物又はその製薬上許容される塩を放射性標識することを含む、放射性化合物の製造方法に関する。また、本開示は、一又は複数の実施形態において、式（２）で表される化合物又はその製薬上許容される塩を放射性標識することを含む、式（１）で表される化合物の製造方法に関する。
The compound (1) of the present disclosure can be produced by radiolabeling the compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof in one or a plurality of embodiments. Accordingly, the present disclosure relates, in one or more embodiments, to a method for producing a radioactive compound, which comprises radiolabeling a compound represented by formula (2) or a pharmaceutically acceptable salt thereof. In addition, the present disclosure provides, in one or a plurality of embodiments, production of a compound represented by the formula (1), which comprises radiolabeling the compound represented by the formula (2) or a pharmaceutically acceptable salt thereof. Regarding the method.
式（２）中、Ｙは、−ＮＨ−又は−Ｏ−である。 In formula (2), Y is -NH- or -O-.
式（２）中、Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基である。Ｌ1としては、上記のものが挙げられる。 In the formula (2), L 1 is an alkanediyl group having 1 to 5 carbon atoms or an alkenediylcarbonyl group having 3 to 8 carbon atoms. Examples of L 1 include the above.
式（２）中、Ｒ11は、塩素原子、臭素原子、ヨウ素原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルである。 In the formula (2), R 11 is a chlorine atom, a bromine atom, an iodine atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent.
式（２）中、Ｒ12は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基である。 In formula (2), R 12 is a 6- to 8-membered aryl group having one substituent or a nitrogen-containing heteroaryl group.
Ｒ11及びＲ12の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ11基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ11は、塩素原子、臭素原子、ヨウ素原子、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基である。 The substituents of R 11 and R 12 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms, or —(CH 2 ) 1 —(O— a C 2 H 4) m -X 11 group, l is 0 to 5, m is 0 to 5 a number of repeating ethyleneoxy groups, X 11 is a chlorine atom, a bromine atom, It is an iodine atom, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group.
Ｒ11は、一又は複数の実施形態において、
Ｒ12は、一又は複数の実施形態において、
Ｒ11とＲ12との組み合わせとしては、一又は複数の実施形態において、下記表に示す組み合わせが挙げられる。
Ｒ11とＬ1とＲ12との組み合わせとしては、一又は複数の実施形態において、下記表に示す組み合わせが挙げられる。
式（２）で表される化合物としては、一又は複数の実施形態において、下記式（２−１）〜（２−５）で表される化合物又はそれらの化合物の製薬上許容される塩等が挙げられ、ＥＧＦＲの二次変異の判別を向上させる点から、好ましくはＬ８５８Ｒ変異型ＥＧＦＲに対する結合親和性が高くＬ８５８Ｒ／Ｔ７９０Ｍ変異型に対する結合親和性を低い化合物が得られる点から、式（２−１）、（２−４）又は（２−５）で表される化合物が好ましい。Ｌ８５８Ｒ変異型ＥＧＦＲに対して結合するが、Ｌ８５８Ｒ／Ｔ７９０Ｍ変異型ＥＧＦＲに対しては非常に低い結合親和性を示す化合物が得られる点からは、式（２−２）又は（２−３）で表される化合物が好ましい。式（２−１）〜（２−５）において、Ｘ11は、塩素原子、臭素原子、ヨウ素原子、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基である。Ｘ12は、ハロゲン原子であり、好ましくは臭素原子である。
式（２）で表される化合物の放射性標識を行う方法は、式（２）で表される化合物に応じて適宜決定できる。式（２）においてＸ11を含む場合、一又は複数の実施形態において、直接標識法を用いて標識することができる。式（２−４）のようにＲ11が
式（２）で表される化合物は、上述のとおり、標識前駆体（放射性標識化合物の製造に用いる非標識化合物）として使用することができる。したがって、本開示は、一又は複数の実施形態において、式（２）で表される化合物又は式（２）で表される化合物の製薬上許容される塩（以下、「本開示の化合物（２）」という）に関する。また、本開示は、一又は複数の実施形態において、本開示の化合物（１）を合成するための標識前駆体として使用する本開示の化合物（２）を含む組成物に関する。また、本開示は、一又は複数の実施形態において、本開示の化合物（２）を含む本開示の化合物（１）を調製するためのキットに関する。本開示のキットは、一又は複数の実施形態において、放射性ハロゲン原子を含む標識試薬をさらに含んでいてもよい。 As described above, the compound represented by the formula (2) can be used as a labeled precursor (unlabeled compound used for producing a radiolabeled compound). Therefore, in one or more embodiments, the present disclosure provides a compound represented by formula (2) or a pharmaceutically acceptable salt of the compound represented by formula (2) (hereinafter, referred to as “compound of the present disclosure (2 )”)). The present disclosure also relates, in one or more embodiments, to a composition comprising compound (2) of the present disclosure for use as a labeled precursor for synthesizing compound (1) of the present disclosure. The present disclosure also relates, in one or a plurality of embodiments, to a kit for preparing the compound (1) of the present disclosure including the compound (2) of the present disclosure. The kit of the present disclosure may further include a labeling reagent containing a radioactive halogen atom in one or more embodiments.
［ＥＧＦＲ−ＴＫＩによる治療の有効性評価のための情報を得る方法］
本開示は、一又は複数の実施形態において、ＥＧＦＲ−ＴＫＩによる非小細胞肺癌の治療が行われる被検体におけるＥＧＦＲ−ＴＫＩによる治療の有効性を評価するための情報を得る方法（以下、「本開示の情報を得る方法」ともいう）に関する。被検体は、特に限定されないが、一又は複数の実施形態において、ヒト、ヒト以外の哺乳類、培養細胞、及びＥＧＦＲが存在しうる対象から選択される。
[Method of Obtaining Information for Efficacy Evaluation of Treatment with EGFR-TKI]
The present disclosure, in one or more embodiments, is a method of obtaining information for assessing the efficacy of treatment with EGFR-TKI in a subject undergoing treatment of non-small cell lung cancer with EGFR-TKI (hereinafter " Also referred to as a "method of obtaining information for disclosure"). The subject is not particularly limited, but in one or more embodiments, it is selected from humans, non-human mammals, cultured cells, and subjects in which EGFR may be present.
本開示の情報を得る方法は、一又は複数の実施形態において、本開示の化合物（１）、又は本開示の化合物（１）を含む核医学画像診断薬が投与された被検体の肺癌腫瘍から本開示の化合物（１）又は前記核医学画像診断薬の放射性シグナルを検出することを含む。シグナルの検出は、使用する本開示の化合物に含まれる放射性同位元素の種類に応じて適宜決定でき、例えば、PET及びSPECT等を用いて行うことができる。情報としては、一又は複数の実施形態において、検出された放射性シグナル等が挙げられる。 The method for obtaining information of the present disclosure is, in one or more embodiments, from a lung cancer tumor of a subject to which a compound (1) of the present disclosure or a nuclear medicine diagnostic imaging agent containing the compound (1) of the present disclosure is administered. Detecting a radioactive signal of the compound (1) of the present disclosure or the nuclear medicine diagnostic imaging agent. The detection of the signal can be appropriately determined depending on the type of radioisotope contained in the compound of the present disclosure to be used, and can be performed using, for example, PET and SPECT. The information includes, in one or more embodiments, the detected radioactive signal and the like.
本開示の情報を得る方法は、一又は複数の実施形態において、前記被検体の肺癌腫瘍からの放射性シグナルの検出をＥＧＦＲ−ＴＫＩの治療期間中に繰り返し行うことを含む。 The method of obtaining the information of the present disclosure, in one or more embodiments, comprises repeatedly performing the detection of radioactive signals from the lung cancer tumor of the subject during the treatment period of EGFR-TKI.
治療に使用されるＥＧＦＲ−ＴＫＩとしては、一又は複数の実施形態において、可逆型ＥＧＦＲ−ＴＫＩが挙げられる。可逆型ＥＧＦＲ−ＴＫＩとしては、一又は複数の実施形態において、ゲフィチニブ又はエルロチニブ等が挙げられる。 EGFR-TKIs used for therapy include, in one or more embodiments, reversible EGFR-TKIs. Examples of the reversible EGFR-TKI include gefitinib and erlotinib in one or more embodiments.
［ＥＧＦＲ−ＴＫＩによる治療の有効性評価方法］
本開示は、一又は複数の実施形態において、ＥＧＦＲ−ＴＫＩによる非小細胞肺癌の治療が行われる被検体におけるＥＧＦＲ−ＴＫＩによる治療の有効性を評価する方法（以下、「本開示の評価方法」ともいう）に関する。
[Efficacy Evaluation Method of Treatment with EGFR-TKI]
In one or a plurality of embodiments, the present disclosure provides a method for evaluating the efficacy of treatment with EGFR-TKI in a subject treated with EGFR-TKI for non-small cell lung cancer (hereinafter, referred to as “evaluation method of the present disclosure”). Also called).
本開示の評価方法は、一又は複数の実施形態において、ＥＧＦＲ−ＴＫＩの投与開始前、投与開始後、及び投与開始から一定期間経過後からなる群から選択される２以上のタイミングで本開示の情報を得る方法により得られた情報を比較することを含む。 The evaluation method of the present disclosure, in one or a plurality of embodiments, is performed at two or more timings selected from the group consisting of before administration of EGFR-TKI, after administration, and after a certain period has elapsed from administration. Comparing the information obtained by the method of obtaining information.
本開示の評価方法は、一又は複数の実施形態において、前記比較によりシグナルの変動に基づき、肺癌腫瘍における上皮成長因子受容体をコードする遺伝子に、Ｔ７９０Ｍ変異が発現しているか否かを決定することを含んでいてもよい。また、本開示の評価方法の一又は複数の実施形態において、前記比較によりシグナルの減少が観察される場合は、ＥＧＦＲ−ＴＫＩによる治療の薬効の可能性が低下すると判断され、前記比較によりシグナルの減少が観察されない場合は、ＥＧＦＲ−ＴＫＩによる治療の薬理有効性の可能性があると判断されうる。また、本開示の評価方法の一又は複数の実施形態において、腫瘍の大きさが増加又は維持され、かつ前記シグナルの減少が観察される場合は、上皮成長因子受容体チロシンキナーゼ阻害薬による治療の薬理有効性の可能性が低下すると判断されうる。 In one or a plurality of embodiments, the evaluation method of the present disclosure determines whether or not a T790M mutation is expressed in a gene encoding an epidermal growth factor receptor in a lung cancer tumor based on the signal change by the comparison. May be included. Further, in one or more embodiments of the evaluation method of the present disclosure, when a decrease in signal is observed by the comparison, it is determined that the efficacy of the treatment with EGFR-TKI is decreased, and the signal by the comparison is determined. If no reduction is observed, it may be considered possible pharmacological efficacy of treatment with EGFR-TKI. Further, in one or more embodiments of the evaluation method of the present disclosure, if the tumor size is increased or maintained, and a decrease in the signal is observed, treatment with an epidermal growth factor receptor tyrosine kinase inhibitor is performed. It can be determined that the likelihood of pharmacological efficacy is reduced.
本開示の評価方法は、一又は複数の実施形態において、前記被検体のＣＴ又はＭＲＩを撮像すること、及び前記ＣＴ又はＭＲＩ画像と、前記検出した放射性シグナルから構築したイメージング画像とを融合又は比較することを含んでいてもよい。また、本開示の評価方法の一又は複数の実施形態において、前記融合又は比較に基づき、腫瘍の大きさが増加又は維持され、かつシグナルの減少が観察される場合は、ＥＧＦＲ−ＴＫＩによる治療の薬理有効性の可能性が低下すると判断されうる。 The evaluation method of the present disclosure, in one or more embodiments, images CT or MRI of the subject, and fuses or compares the CT or MRI image with an imaging image constructed from the detected radioactive signal. It may include doing. Further, in one or more embodiments of the evaluation method of the present disclosure, if tumor size is increased or maintained and a decrease in signal is observed based on the fusion or comparison, treatment with EGFR-TKI is performed. It can be determined that the likelihood of pharmacological efficacy is reduced.
［ＥＧＦＲ陽性肺癌腫瘍のイメージング方法］
本開示は、一又は複数の実施形態において、本開示の化合物（１）を投与された被検体から前記化合物の放射性シグナルを検出することを含むイメージング方法に関する。
[Method for imaging EGFR-positive lung cancer tumor]
The present disclosure, in one or more embodiments, relates to an imaging method including detecting a radioactive signal of the compound (1) of the present disclosure from a subject administered with the compound.
［式（３）で表される化合物］
本開示は、一又は複数の実施形態において、下記式（３−１）〜（３−５）で表される化合物又は式（３−１）〜（３−５）で表される化合物の製薬上許容される塩に関する。
In one or a plurality of embodiments, the present disclosure provides a compound represented by the following formulas (3-1) to (3-5) or a compound represented by the formulas (3-1) to (3-5). Regarding the acceptable salts above.
本開示は、以下の一又は複数の実施形態に関しうる。
〔１〕 下記式（１）で表される化合物又は式（１）で表される化合物の製薬上許容される塩を含む核医学画像診断薬。
Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基であり、
Ｒ1は、放射性ハロゲン原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、
Ｒ2は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、
Ｒ1及びＲ2の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ1基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、
Ｒ1又はＲ2は、放射性ハロゲン原子又は放射性炭素原子（11Ｃ）を含み、
Ｙは、−ＮＨ−又は−Ｏ−である。］
〔２〕 Ｌ1は、−（ＣＨ2）2−又は−（Ｃ＝Ｏ）−ＣＨ＝ＣＨ−ＣＨ2−である、〔１〕記載の核医学画像診断薬。
〔３〕 Ｒ1は、
ｌは０又は２であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は、放射性ハロゲン原子又は−［11Ｃ］ＣＨ3である、〔１〕又は〔２〕に記載の核医学画像診断薬。
〔４〕 Ｒ2は、
ｌは０又は２であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は、放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、Ｘ2は、ハロゲン原子である、〔１〕から〔３〕のいずれかに記載の核医学画像診断薬。
〔５〕 下記式（１）で表される化合物又は式（１）で表される化合物の製薬上許容される塩。
Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基であり、
Ｒ1は、放射性ハロゲン原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、
Ｒ2は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、
Ｒ1及びＲ2の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ1基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、
Ｒ1又はＲ2は、放射性ハロゲン原子又は放射性炭素原子（11Ｃ）を含み、
Ｙは、−ＮＨ−又は−Ｏ−である。］
〔６〕 下記式（２）で表される化合物又は式（２）で表される化合物の製薬上許容される塩を含む標識前駆体組成物。
Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基であり、
Ｒ11は、塩素原子、臭素原子、ヨウ素原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、
Ｒ12は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、
Ｒ11及びＲ12の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ11基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ11は、塩素原子、臭素原子、ヨウ素原子、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基であり、
Ｙは、−ＮＨ−又は−Ｏ−である。］
〔７〕 Ｌ1は、−（ＣＨ2）2−又は−（Ｃ＝Ｏ）−ＣＨ＝ＣＨ−ＣＨ2−である、〔６〕記載の組成物。
〔８〕 Ｒ11は、
ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ11は、塩素原子、臭素原子、ヨウ素原子、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基である、〔６〕又は〔７〕に記載の組成物。
〔９〕 Ｒ12は、
ｌは０又は２であり、ｍはエチレンオキシ基の繰り返し数であって１以上５以下であり、Ｘ11は、塩素原子、臭素原子、ヨウ素原子、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基であり、Ｘ12は、ハロゲン原子である、〔６〕から〔８〕のいずれかに記載の組成物。
〔１０〕 上皮成長因子受容体チロシンキナーゼ阻害薬による非小細胞肺癌の治療が行われる被検体における上皮成長因子受容体チロシンキナーゼ阻害薬による治療の有効性を評価するための情報を得る方法であって、
〔１〕から〔４〕のいずれかに記載の核医学画像診断薬又は〔５〕記載の化合物若しくはその製薬上許容される塩が投与された被検体の肺癌腫瘍から前記核医学画像診断薬又は前記化合物の放射性シグナルを検出することを含む、方法。
〔１１〕 前記被検体の肺癌腫瘍からの放射性シグナルの検出を上皮成長因子受容体チロシンキナーゼ阻害薬の治療期間中に繰り返し行うことを含む、〔１０〕記載の方法。
〔１２〕 肺癌腫瘍における上皮成長因子受容体をコードする遺伝子におけるＴ７９０Ｍ変異の発生を評価する方法であって、
〔１〕から〔４〕のいずれかに記載の核医学画像診断薬又は〔５〕記載の化合物若しくはその製薬上許容される塩が投与された被検体の肺癌腫瘍から前記核医学画像診断薬又は前記化合物の放射性シグナルを検出すること、
前記被検体の肺癌腫瘍からの放射性シグナルの検出を上皮成長因子受容体チロシンキナーゼ阻害薬の治療期間中に繰り返し行うこと、
前記得られた情報を比較すること、及び
前記比較によりシグナルの変動に基づき、肺癌腫瘍における上皮成長因子受容体をコードする遺伝子における、Ｔ７９０Ｍ変異の発生の有無を決定することを含む、方法。
〔１３〕 上皮成長因子受容体チロシンキナーゼ阻害薬による非小細胞肺癌の治療が行われる被検体における上皮成長因子受容体チロシンキナーゼ阻害薬による治療の有効性を評価する方法であって、
上皮成長因子受容体チロシンキナーゼ阻害薬の投与開始前、投与開始後及び投与開始から一定期間経過後からなる群から選択される２以上のタイミングで〔１０〕又は〔１１〕に記載の方法により得られた情報を比較することを含む、方法。
〔１４〕 前記比較によりシグナルの変動に基づき、肺癌腫瘍における上皮成長因子受容体をコードする遺伝子が、Ｔ７９０Ｍ変異を有している否かを決定することを含む、〔１３〕記載の方法。
〔１５〕 前記比較によりシグナルの減少が観察される場合は、上皮成長因子受容体チロシンキナーゼ阻害薬による治療の薬理有効性の可能性が低下すると判断され、前記比較によりシグナルの減少が観察されない場合は、上皮成長因子受容体チロシンキナーゼ阻害薬による治療の薬理有効性の可能性があると判断される、〔１３〕記載の方法。
〔１６〕 腫瘍の大きさが増加又は維持され、かつ前記シグナルの減少が観察される場合は、上皮成長因子受容体チロシンキナーゼ阻害薬による治療の薬理有効性の可能性が低下すると判断される、〔１３〕から〔１５〕のいずれかに記載の方法。
〔１７〕 前記被検体のＣＴ又はＭＲＩを撮像すること、及び
前記ＣＴ又はＭＲＩ画像と、前記検出した放射性シグナルから構築したイメージング画像とを融合又は比較することを含み、
前記融合又は比較に基づき、腫瘍の大きさが増加又は維持され、かつシグナルの減少が観察される場合は、上皮成長因子受容体チロシンキナーゼ阻害薬による治療の薬理有効性の可能性が低下すると判断される、〔１３〕から〔１６〕のいずれかに記載の方法。
The present disclosure may relate to one or more of the following embodiments.
[1] A nuclear medicine diagnostic imaging agent containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1).
L 1 is an alkanediyl group having 1 to 5 carbon atoms, or an alkenediylcarbonyl group having 3 to 8 carbon atoms,
R 1 is a radioactive halogen atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent,
R 2 is a 6-8 membered aryl group having one substituent or a nitrogen-containing heteroaryl group,
The substituents of R 1 and R 2 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms or -(CH 2 ) 1 -(O- C 2 H 4 ) m —X 1 group, 1 is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or -[ 11 C] CH 3 ,
R 1 or R 2 contains a radioactive halogen atom or a radioactive carbon atom ( 11 C),
Y is -NH- or -O-. ]
[2] The nuclear medicine diagnostic imaging agent according to [1], wherein L 1 is —(CH 2 ) 2 — or —(C═O)—CH═CH—CH 2 —.
[3] R 1 is
1 is 0 or 2, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or -[ 11 C]CH 3 , [1] or [2] ] The nuclear medicine image diagnostic agent according to [1].
[4] R 2 is
l is 0 or 2, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or —[ 11 C]CH 3 , and X 2 is a halogen atom. The nuclear medicine image diagnostic agent according to any one of [1] to [3].
[5] A compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1).
L 1 is an alkanediyl group having 1 to 5 carbon atoms, or an alkenediylcarbonyl group having 3 to 8 carbon atoms,
R 1 is a radioactive halogen atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent,
R 2 is a 6-8 membered aryl group having one substituent or a nitrogen-containing heteroaryl group,
The substituents of R 1 and R 2 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms or -(CH 2 ) 1 -(O- C 2 H 4 ) m —X 1 group, l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or -[ 11 C] CH 3 ,
R 1 or R 2 contains a radioactive halogen atom or a radioactive carbon atom ( 11 C),
Y is -NH- or -O-. ]
[6] A labeled precursor composition comprising a compound represented by the following formula (2) or a pharmaceutically acceptable salt of the compound represented by the formula (2).
L 1 is an alkanediyl group having 1 to 5 carbon atoms, or an alkenediylcarbonyl group having 3 to 8 carbon atoms,
R 11 is a chlorine atom, a bromine atom, an iodine atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent,
R 12 is a 6-8 membered aryl group having one substituent or a nitrogen-containing heteroaryl group,
The substituents of R 11 and R 12 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms, or —(CH 2 ) 1 —(O— a C 2 H 4) m -X 11 group, l is 0 to 5, m is 0 to 5 a number of repeating ethyleneoxy groups, X 11 is a chlorine atom, a bromine atom, An iodine atom, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group,
Y is -NH- or -O-. ]
[7] The composition according to [6], wherein L 1 is —(CH 2 ) 2 — or —(C═O)—CH═CH—CH 2 —.
[8] R 11 is
l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, and X 11 is chlorine atom, bromine atom, iodine atom, nitro group, tosylate group, mesylate group, triflate. The composition according to [6] or [7], which is a rate group, a nosylate group or a brosylate group.
[9] R 12 is
l is 0 or 2, m is the number of repeating ethyleneoxy groups and is 1 or more and 5 or less, and X 11 is chlorine atom, bromine atom, iodine atom, nitro group, tosylate group, mesylate group, triflate. The composition according to any one of [6] to [8], which is a group, a nosylate group or a brosylate group, and X 12 is a halogen atom.
[10] A method for obtaining information for evaluating the effectiveness of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor in a subject who is treated with epidermal growth factor receptor tyrosine kinase inhibitor for non-small cell lung cancer. hand,
The nuclear medicine image diagnostic agent from the lung cancer tumor of a subject to which the nuclear medicine image diagnostic agent according to any one of [1] to [4] or the compound according to [5] or a pharmaceutically acceptable salt thereof is administered, or A method comprising detecting a radioactive signal of said compound.
[11] The method according to [10], which comprises repeatedly detecting the radioactive signal from the lung cancer tumor of the subject during the treatment period of the epidermal growth factor receptor tyrosine kinase inhibitor.
[12] A method for evaluating the occurrence of a T790M mutation in a gene encoding an epidermal growth factor receptor in lung cancer tumor, the method comprising:
The nuclear medicine image diagnostic agent from the lung cancer tumor of a subject to which the nuclear medicine image diagnostic agent according to any one of [1] to [4] or the compound according to [5] or a pharmaceutically acceptable salt thereof is administered, or Detecting a radioactive signal of said compound,
Repeating the detection of radioactive signals from the lung cancer tumor of the subject during the treatment period of the epidermal growth factor receptor tyrosine kinase inhibitor,
Comparing the obtained information, and determining the presence or absence of the T790M mutation in the gene encoding the epidermal growth factor receptor in lung cancer tumors based on the change in the signal by the comparison.
[13] A method for evaluating the effectiveness of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor in a subject to be treated for non-small cell lung cancer with an epidermal growth factor receptor tyrosine kinase inhibitor,
Obtained by the method according to [10] or [11] at two or more timings selected from the group consisting of before administration of the epidermal growth factor receptor tyrosine kinase inhibitor, after administration, and after a lapse of a certain period from administration. A method comprising comparing the information provided.
[14] The method according to [13], which comprises determining whether or not the gene encoding the epidermal growth factor receptor in the lung cancer tumor has the T790M mutation based on the change in the signal by the comparison.
[15] When a decrease in signal is observed by the comparison, it is judged that the possibility of pharmacological efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor is decreased, and when a decrease in signal is not observed by the comparison The method according to [13], wherein is judged to be potentially pharmacologically effective for treatment with an epidermal growth factor receptor tyrosine kinase inhibitor.
[16] When the tumor size is increased or maintained and a decrease in the signal is observed, it is determined that the pharmacological efficacy of the treatment with an epidermal growth factor receptor tyrosine kinase inhibitor is decreased. The method according to any one of [13] to [15].
[17] including imaging CT or MRI of the subject, and fusing or comparing the CT or MRI image and an imaging image constructed from the detected radioactive signal,
Based on the fusion or comparison, if the tumor size is increased or maintained and a decrease in signal is observed, it is determined that the pharmacological efficacy of the treatment with the epidermal growth factor receptor tyrosine kinase inhibitor is reduced. The method according to any one of [13] to [16].
以下に、実施例を用いて本開示をさらに説明するが、これらは例示的なものであって、本開示は以下の実施例に限定して解釈されるものではない。 Hereinafter, the present disclosure will be further described with reference to Examples, but these are merely illustrative and the present disclosure should not be construed as being limited to the following Examples.
［機器及び試薬］
質量分析（ESI-MS）はLCMS-2010 EV（株式会社 島津製作所）にて測定した。
1H (400 MHz) NMRスペクトルはLNM-AL 400（日本電子株式会社）にて測定し、内部標準物質としてテトラメチルシランを用いた。
逆相HPLCはLC-20AD（株式会社 島津製作所）を用い、検出器としてSPD-20A UV（株式会社 島津製作所）を使用した。逆相HPLC用カラムにはCOSMOSIL C18-AR-II (4.6 x 250 mm)及びCOSMOSIL C18-AR-II (10 x 250 mm)（ナカライテスク株式会社）を用い、移動相には (A) 0.1% TFA水溶液及び (B) 0.1% TFAアセトニトリル溶液、(C) 0.01Mクエン酸緩衝液（pH 4.6）、(D) メタノールを使用した。TLCにはsilica gel 60 F254（メルク株式会社）を用いた。PTLCにはアミノシリカゲルpreparative TLCを用いた。
カラムクロマトグラフィーによる精製には中圧カラムW-Prep 2XY（株式会社 山善）を用い、シリカゲルはHi Flash silica gel 40 mm, 60Å（株式会社 山善）を使用した。
[18F]fluorideは京都大学医学部付属病院設置の[18O]H2O（太陽日酸株式会社）及び CYPRIS HM-18 サイクロトロン（住友重機械工業株式会社）を用いて製造した。
放射性化合物合成にはマイクロ波反応装置（サイダ社）を用いた。放射能はキュリーメーターIGC-7（ALOKA社）、オートウェルガンマカウンターWallac 1480 WIZARD 3（PerkinElmer社）を用いて測定した。
PET装置による画像収集は、GMI FX-3300 Pre-Clinical Imaging Systemを用いて行った。
[Devices and reagents]
Mass spectrometry (ESI-MS) was measured by LCMS-2010 EV (Shimadzu Corporation).
1 H (400 MHz) NMR spectrum was measured by LNM-AL 400 (JEOL Ltd.), and tetramethylsilane was used as an internal standard substance.
LC-20AD (Shimadzu Corporation) was used for the reverse phase HPLC, and SPD-20A UV (Shimadzu Corporation) was used as the detector. COSMOSIL C18-AR-II (4.6 x 250 mm) and COSMOSIL C18-AR-II (10 x 250 mm) (Nacalai Tesque, Inc.) were used for the reversed-phase HPLC column, and (A) 0.1% was used for the mobile phase. An aqueous TFA solution, (B) 0.1% TFA acetonitrile solution, (C) 0.01 M citrate buffer (pH 4.6), and (D) methanol were used. Silica gel 60 F 254 (Merck K.K.) was used for TLC. Amino silica gel preparative TLC was used for PTLC.
A medium pressure column W-Prep 2XY (Yamazen Co., Ltd.) was used for purification by column chromatography, and Hi Flash silica gel 40 mm, 60Å (Yamazen Co., Ltd.) was used as silica gel.
[ 18 F]fluoride was produced using [ 18 O]H 2 O (TAIYO NISSIN CO., LTD.) and CYPRIS HM-18 cyclotron (Sumitomo Heavy Industries, Ltd.) installed at Kyoto University Hospital.
A microwave reactor (Cida) was used for the synthesis of the radioactive compound. The radioactivity was measured using a Curie meter IGC-7 (ALOKA) and an Autowell gamma counter Wallac 1480 WIZARD 3 (PerkinElmer).
The image acquisition by the PET device was performed using GMI FX-3300 Pre-Clinical Imaging System.
［化合物の合成］
Ｈ１〜Ｈ４を合成した。なお、化合物１、６及び１０は、G. W. Rewcastle, D. K. Murray, W. L. Elliott, D. W. Fry, C. T. Howard, J. M. Nelson, B. J. Roberts, P. W. Vincent, H. D. H. Showalter, R. T. Winters, W. A. Denny, J. Med. Chem. 1998, 41, 742-751に準じて合成した。
[Synthesis of compound]
H1 to H4 were synthesized. Compounds 1, 6 and 10 are GW Rewcastle, DK Murray, WL Elliott, DW Fry, CT Howard, JM Nelson, BJ Roberts, PW Vincent, HDH Showalter, RT Winters, WA Denny, J. Med. Chem. 1998. , 41, 742-751.
（製造例１）
4-[(3-Bromophenyl)amino]-6-(2-fluoroethylamino)pyrido[3,4-d]pyrimidine (H1)の合成
下記スキームに従ってＨ１を合成した。
Synthesis of 4-[(3-Bromophenyl)amino]-6-(2-fluoroethylamino)pyrido[3,4-d]pyrimidine (H1) H1 was synthesized according to the following scheme.
（製造例２）
N 4 -(3-(2-fluoroethoxy)phenyl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-4, 6-diamine (H2)の合成
下記スキームに従ってＨ２を合成した。
Synthesis of N 4 -(3-(2-fluoroethoxy)phenyl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidine -4,6 -diamine (H2) H2 was synthesized according to the following scheme.
3-(2-fluoroethoxy)aniline (化合物5)
化合物4（1.375 mmol, 1.0 eq）をDMF（2.0 mL）に溶解し、K2CO3（2.749 mmol, 2.0 eq）及び2-fluoroethyl-4-toluene sulfonate（1.649 mmol, 1.2 eq）を加えて70℃で一晩加熱した。反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーにより精製し、化合物5を得た。
収量140.1 mg（65.7%）, 1H NMR (400 MHz, CDCl3) δ7.06 (1H, t, J = 8.0 Hz), 6.32 (2H, m), 6.27 (1H, t, J = 2.0 Hz), 6.27 (1H, t, J = 2.0 Hz), 4.73 (2H, dt, J = 47.6, 4.0 Hz), 4.17 (2H, dt, J = 28.0, 4.0 Hz), 3.67 (2H, br).
3-(2-fluoroethoxy)aniline (Compound 5)
Compound 4 (1.375 mmol, 1.0 eq) was dissolved in DMF (2.0 mL), K 2 CO 3 (2.749 mmol, 2.0 eq) and 2-fluoroethyl-4-toluene sulfonate (1.649 mmol, 1.2 eq) were added to add 70 Heated at °C overnight. The reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to give compound 5.
Yield 140.1 mg (65.7%), 1 H NMR (400 MHz, CDCl 3 ) δ7.06 (1H, t, J = 8.0 Hz), 6.32 (2H, m), 6.27 (1H, t, J = 2.0 Hz) , 6.27 (1H, t, J = 2.0 Hz), 4.73 (2H, dt, J = 47.6, 4.0 Hz), 4.17 (2H, dt, J = 28.0, 4.0 Hz), 3.67 (2H, br).
N-(3-(2-fluoroethoxy)phenyl)-6-fluoropyrido[3, 4-d]pyrimidin-4-amine (化合物7)
化合物6 (0.303 mmol, 1.0 eq) に化合物5（0.363 mmol, 1.2 eq）を加え2-propanol（2.0 mL）中105℃で2時間加熱還流した。反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーにより精製し、化合物7を得た。
収量 4.6 mg (5.0 %), 1H NMR (400 MHz, CD3OD) 8.87 (1H, s), 8.64 (1H, s), 8.03 (1H, br), 7.59 (1H, t, J = 2.0 Hz), 7.40 (1H, dd, J = 8.1 Hz), 7.33 (1H, t, J = 8.1 Hz), 6.82 (1H, dd, J = 8.1Hz), 4.81 (H, t, J = 3.8Hz), 4.69 (1H, t, J = 4.1Hz), 4.29 (1H, t, J = 4.1 Hz), 4.22 (1H, t, J = 4.1 Hz).
N-(3-(2-fluoroethoxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (Compound 7)
Compound 5 (0.363 mmol, 1.2 eq) was added to compound 6 (0.303 mmol, 1.0 eq), and the mixture was heated under reflux in 2-propanol (2.0 mL) at 105°C for 2 hours. The reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to give compound 7.
Yield 4.6 mg (5.0 %), 1 H NMR (400 MHz, CD 3 OD) 8.87 (1H, s), 8.64 (1H, s), 8.03 (1H, br), 7.59 (1H, t, J = 2.0 Hz ), 7.40 (1H, dd, J = 8.1 Hz), 7.33 (1H, t, J = 8.1 Hz), 6.82 (1H, dd, J = 8.1Hz), 4.81 (H, t, J = 3.8Hz), 4.69 (1H, t, J = 4.1Hz), 4.29 (1H, t, J = 4.1Hz), 4.22 (1H, t, J = 4.1Hz).
N 4 -(3-(2-fluoroethoxy)phenyl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-4,6-diamine (H2)
化合物7（4.1 mg, 0.014 mmol）をDMSO（900 μL）に溶解し、4-(2-amioethyl)morphorine（ALDRICH）（100 μL, 0.762 mmol）を加えて95℃で20hr加熱した。反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣を逆相HPLCにて精製し、H2を得た。MHz, CDCl3 8.93 (1H, s), 8.59 (1H, s), 7.64 (1H, s), 7.32 (1H, t, J = 8.4 Hz), 7.29 (1H, d, J = 7.6 Hz), 6.75 (1H, d, J = 7.6 Hz), 6.53 (1H, s), 4.79 (2H, dt, J = 47.2, 4.0 Hz), 4.28 (2H, dt, J = 28.0, 4.0 Hz), 3.78 (4H, t, J = 4.4 Hz), 3.48 (2H, t, J = 6.0 Hz), 2.77 (2H, t, J = 6.0 Hz), 2.60 (4H, t, J = 4.4 Hz).
N 4 -(3-(2-fluoroethoxy)phenyl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-4,6-diamine (H2)
Compound 7 (4.1 mg, 0.014 mmol) was dissolved in DMSO (900 μL), 4-(2-amioethyl)morphorine (ALDRICH) (100 μL, 0.762 mmol) was added, and the mixture was heated at 95° C. for 20 hr. The reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by reverse phase HPLC to give H2. MHz, CDCl 3 8.93 (1H, s), 8.59 (1H, s), 7.64 (1H, s), 7.32 (1H, t, J = 8.4 Hz), 7.29 (1H, d, J = 7.6 Hz), 6.75 (1H, d, J = 7.6 Hz), 6.53 (1H, s), 4.79 (2H, dt, J = 47.2, 4.0 Hz), 4.28 (2H, dt, J = 28.0, 4.0 Hz), 3.78 (4H, t, J = 4.4 Hz), 3.48 (2H, t, J = 6.0 Hz), 2.77 (2H, t, J = 6.0 Hz), 2.60 (4H, t, J = 4.4 Hz).
（製造例３）
N 4 -(6-fluoropyridin-3-yl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidin-4,6-diamine (H3)の合成
下記スキームに従ってＨ３を合成した。
Synthesis of N 4 -(6-fluoropyridin-3-yl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidin-4,6-diamine (H3) H3 was synthesized according to the following scheme.
N-(6-fluoropyridin-3-yl)-6-fluoropyrido[3, 4-d]pyrimidin-4-amine (化合物8)
化合物6（0.303 mmol）と5-Amino-2-fluoropyridine（ALDRICH）（0.363 mmol）を2-propanol（2.0 mL）溶媒中105℃で2 時間加熱還流した。反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーにより精製し、化合物8を得た。収量 20.0 mg (25.5 %), 1H NMR (400 MHz, CDCl3) 9.09 (1H, s), 8.81 (1H, s), 8.47 (1H, s), 8.44 (1H, dd, J = 8.8, 2.4 Hz), 7.41 (1H, s), 7.06 (1H, dd, J = 8.8, 3.2 Hz).
N-(6-fluoropyridin-3-yl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (Compound 8)
Compound 6 (0.303 mmol) and 5-Amino-2-fluoropyridine (ALDRICH) (0.363 mmol) were heated under reflux in a 2-propanol (2.0 mL) solvent at 105°C for 2 hours. The reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to give compound 8. Yield 20.0 mg (25.5 %), 1 H NMR (400 MHz, CDCl 3 ) 9.09 (1H, s), 8.81 (1H, s), 8.47 (1H, s), 8.44 (1H, dd, J = 8.8, 2.4 Hz), 7.41 (1H, s), 7.06 (1H, dd, J = 8.8, 3.2 Hz).
N 4 -(6-fluoropyridin-3-yl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidin-4,6-diamine (H3)
化合物8（20.0 mg, 0.077 mmol）をDMSO（900 μL）に溶解し、4-(2-amioethyl)morphorine（ALDRICH）（100μL, 0.762 mmol）を加えて95℃で20hr加熱した。反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣を逆相HPLCにて精製し、H3を得た。収量 14 mg (49.1 %), 1H NMR (400 MHz, CDCl3) 8.92 (1H,s), 8.61 (1H, s), 8.56 (1H, s), 8.47 (1H, m), 7.03 (1H, s), 6.99 (1H, dd, J = 8.8, 3.6 Hz), 3.94 (4H, t, J = 4.8 Hz), 3.74 (2H, t, J = 4.8 Hz), 3.10 (2H, t, J = 4.8 Hz), 3.01 (2H, m).
N 4 -(6-fluoropyridin-3-yl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidin-4,6-diamine (H3)
Compound 8 (20.0 mg, 0.077 mmol) was dissolved in DMSO (900 μL), 4-(2-amioethyl)morphorine (ALDRICH) (100 μL, 0.762 mmol) was added, and the mixture was heated at 95° C. for 20 hr. The reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by reverse phase HPLC to give H3. Yield 14 mg (49.1 %), 1 H NMR (400 MHz, CDCl 3 ) 8.92 (1H,s), 8.61 (1H, s), 8.56 (1H, s), 8.47 (1H, m), 7.03 (1H, s), 6.99 (1H, dd, J = 8.8, 3.6 Hz), 3.94 (4H, t, J = 4.8 Hz), 3.74 (2H, t, J = 4.8 Hz), 3.10 (2H, t, J = 4.8) Hz), 3.01 (2H, m).
（製造例４）
(E)-N-(4-((3-bromophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4-(4-(2-fluoroethyl)piperazin-1-yl)but-2-enamide (H4)の合成
下記スキームに従ってＨ４を合成した。
(E)-N-(4-((3-bromophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4-(4-(2-fluoroethyl)piperazin-1-yl)but- Synthesis of 2-enamide (H4) H4 was synthesized according to the following scheme.
(2Z)-N-[4-[(3-Bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-bromo-2-butenamide (化合物16)
4-Bromo-2-butenoic acid (33 mg, 0.20 mmol) をCH2Cl2 (0.5 mL)に溶解し、塩化オキザリル（40 mL, 0.457 mmol）とDMF（1滴）を加えて、室温下で1時間撹拌した。反応液を減圧濃縮後、残渣をTHF（0.3 mL）で溶解した後、化合物10（63.2 mg, 0.100 mmol）のTHF溶液（0.7 mL）及びN,N'-ジイソプロピルエチルアミンのTHF溶液（0.1 mL）を加え、室温下で一晩撹拌した。反応終了後、反応液を水に注ぎこみ、酢酸エチルで抽出した。得られた有機層をbrineで洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（CHCl3/MeOH = 20/1）及びpreparative TLC（CHCl3/MeOH = 10/1）にて精製した。収量 14.2 mg (15%), 1H NMR (400 MHz, DMSO-d6) δ11.08 (1H, br), 10.30 (1H, br), 9.01 (1H, d, J = 16.8 Hz), 8.66 (1H, s), 8.16 (1H, br), 7.89 (1H, d, J = 7.7 Hz), 7.39 (1H, d, J = 7.7 Hz), 7.34 (1H, dt, J = 8.0, 1.8 Hz), 6.98 (1H, dt, J = 15.0, 6.3 Hz), 6.68 (1H, d, J = 15.0 Hz), 4.66 (2H, dd, J = 6.3, 1.5 Hz).
(2Z)-N-[4-[(3-Bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-bromo-2-butenamide (Compound 16)
4-Bromo-2-butenoic acid (33 mg, 0.20 mmol) was dissolved in CH 2 Cl 2 (0.5 mL), oxalyl chloride (40 mL, 0.457 mmol) and DMF (1 drop) were added, and the mixture was stirred at room temperature. Stir for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in THF (0.3 mL), and then compound 10 (63.2 mg, 0.100 mmol) in THF (0.7 mL) and N,N'-diisopropylethylamine in THF (0.1 mL). Was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (CHCl 3 /MeOH = 20/1) and preparative TLC (CHCl 3 /MeOH = 10/1). Yield 14.2 mg (15%), 1 H NMR (400 MHz, DMSO-d 6 )δ 11.08 (1H, br), 10.30 (1H, br), 9.01 (1H, d, J = 16.8 Hz), 8.66 ( 1H, s), 8.16 (1H, br), 7.89 (1H, d, J = 7.7 Hz), 7.39 (1H, d, J = 7.7 Hz), 7.34 (1H, dt, J = 8.0, 1.8 Hz), 6.98 (1H, dt, J = 15.0, 6.3 Hz), 6.68 (1H, d, J = 15.0 Hz), 4.66 (2H, dd, J = 6.3, 1.5 Hz).
(2Z)-N-[4-[(3-Bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-[(4-tert-butoxycarbonyl)piperazin-1-yl]2-butenamide (化合物17)
N-Boc-piperazine（158 mg, 0.848 mmol）のTHF（2 mL）溶液に、化合物16（19.6 mg, 0.0423 mmol）のTHF-DMF混合溶液（2:1、1.5 mL）を加え、室温下で3.5時間撹拌した。反応終了後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎこみ、酢酸エチルで抽出した。得られた有機層を水、brineで順次洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルpreparative TLC（CHCl3/MeOH = 10/1）にて精製した。収量19.4 mg (81%), 1H NMR (400 MHz, DMSO-d6) δ10.91 (1H, s), 10.26 (1H, br), 9.02 (1H, s), 8.98 (1H, s), 8.64 (1H, s), 8.16 (1H, br s), 7.89 (1H, br d, J = 7.7 Hz), 7.39-7.32 (2H, m), 6.87 (1H, dt, J = 15.4, 5.8 Hz), 6.54 (1H, d, J = 15.4 Hz), 3.18 (2H, d, J = 5.8 Hz), 2.50 (4H, m), 2.37 (4H, br t, J = 4.8 Hz), 1.40 (9H, s).
(2Z)-N-[4-[(3-Bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-[(4-tert-butoxycarbonyl)piperazin-1-yl]2- butenamide (Compound 17)
To a THF (2 mL) solution of N-Boc-piperazine (158 mg, 0.848 mmol), a THF-DMF mixed solution of Compound 16 (19.6 mg, 0.0423 mmol) (2:1, 1.5 mL) was added, and the mixture was stirred at room temperature. Stir for 3.5 hours. After completion of the reaction, the reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was washed successively with water and brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel preparative TLC (CHCl 3 /MeOH=10/1). Yield 19.4 mg (81%), 1 H NMR (400 MHz, DMSO-d 6 )δ 10.91 (1H, s), 10.26 (1H, br), 9.02 (1H, s), 8.98 (1H, s), 8.64 (1H, s), 8.16 (1H, br s), 7.89 (1H, br d, J = 7.7 Hz), 7.39-7.32 (2H, m), 6.87 (1H, dt, J = 15.4, 5.8 Hz) , 6.54 (1H, d, J = 15.4 Hz), 3.18 (2H, d, J = 5.8 Hz), 2.50 (4H, m), 2.37 (4H, br t, J = 4.8 Hz), 1.40 (9H, s ).
(2Z)-N-[4-[(3-Bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-(piperazin-1-yl)2-butenamide (H4 precursor)
化合物17（19.4 mg, 0.0341 mmol）の塩化メチレン（1 mL）溶液に、TFA（500 mL）を加え、室温下で30分間撹拌した。反応終了後、反応液を飽和炭酸水素ナトリウム水溶液で中和し、クロロホルムで抽出した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をアミノシリカゲルpreparative TLC（CHCl3/MeOH = 20/1）にて精製した。収量12.1 mg (76%), 1H NMR (400 MHz, DMSO-d6) δ10.90 (1H, s), 10.28 (1H, br), 9.01 (1H, s), 8.98 (1H, s), 8.63 (1H, s), 8.15 (1H, s), 7.87 (1H, br d, J =7.4 Hz), 7.37 (1H, t, J = 8.1 Hz), 7.35-7.32 (1H, m), 6.87 (1H, dt, J = 15.4, 5.8 Hz), 6.53 (1H, d, J = 15.4 Hz), 3.12 (2H, br d, J = 5.8 Hz), 2.72 (4H, t, J = 4.8 Hz), 2.33 (4H, br).
得られた化合物(H4 precursor)は、標識前駆体として使用できる。
(2Z)-N-[4-[(3-Bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-(piperazin-1-yl)2-butenamide (H4 precursor)
TFA (500 mL) was added to a methylene chloride (1 mL) solution of compound 17 (19.4 mg, 0.0341 mmol), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The obtained organic layer was dried over sodium sulfate and the solvent was distilled off. The obtained residue was purified by amino silica gel preparative TLC (CHCl 3 /MeOH=20/1). Yield 12.1 mg (76%), 1 H NMR (400 MHz, DMSO-d 6 )δ 10.90 (1H, s), 10.28 (1H, br), 9.01 (1H, s), 8.98 (1H, s), 8.63 (1H, s), 8.15 (1H, s), 7.87 (1H, br d, J =7.4 Hz), 7.37 (1H, t, J = 8.1 Hz), 7.35-7.32 (1H, m), 6.87 ( 1H, dt, J = 15.4, 5.8 Hz), 6.53 (1H, d, J = 15.4 Hz), 3.12 (2H, br d, J = 5.8 Hz), 2.72 (4H, t, J = 4.8 Hz), 2.33 (4H, br).
The obtained compound (H4 precursor) can be used as a labeling precursor.
(E)-N-(4-((3-bromophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4-(4-(2-fluoroethyl)piperazin-1-yl)but-2-enamide (H4)
H4 precursor（17.5 mg, 0.0374 mmol）を無水DMF（0.75 mL）に溶解した後、Et3N（16μL, 0.115 mmol）と2-fluoroethyl 4-toluene sulfonate（16.8 mg, 0.0770 mmol）を加え、室温で5日間撹拌した。反応液を飽和炭酸水素ナトリウム水溶液に注ぎこみ、クロロホルムで抽出した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をアミノシリカゲルpreparative TLC（CHCl3/MeOH = 20/1）にて精製した。収量8.2 mg (42.7%), 1H NMR（400 MHz, DMSO-d6）10.91 (1H, s), 10.27 (1H, br s), 9.02 (1H, s), 8.99 (1H, s), 8.64 (1H, br s), 8.16 (1H, br s), 7.89 (1H, br d, J = 7.4 Hz), 7.34-7.37 (2H, m), 6.86 (1H, dt, J = 5.9, 15.4 Hz), 6.53 (1H, d, J = 15.4 Hz), 4.52 (2H, dt, J = 4.4, 48.0 Hz), 3.15 (2H, d, J = 5.9 Hz), 2.61 (2H, dt, J = 4.4, 28.6 Hz), 2.44 (8H, m); MS(EI+) m/z: 515 (M+2+, 5), 513 (M+, 5), 495 (3), 493 (3), 432 (15), 383 (100), 381 (96), 354 (40), 352 (38); HRMS (EI+) m/z: 513.1286 (Calcd for C23H25BrFN7O: 513.1288).
(E)-N-(4-((3-bromophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4-(4-(2-fluoroethyl)piperazin-1-yl)but- 2-enamide (H4)
After dissolving H4 precursor (17.5 mg, 0.0374 mmol) in anhydrous DMF (0.75 mL), Et 3 N (16 μL, 0.115 mmol) and 2-fluoroethyl 4-toluene sulfonate (16.8 mg, 0.0770 mmol) were added, and the mixture was stirred at room temperature. It was stirred for 5 days. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The obtained organic layer was dried over sodium sulfate and the solvent was distilled off. The obtained residue was purified by amino silica gel preparative TLC (CHCl 3 /MeOH=20/1). Yield 8.2 mg (42.7%), 1 H NMR (400 MHz, DMSO-d 6 ) 10.91 (1H, s), 10.27 (1H, br s), 9.02 (1H, s), 8.99 (1H, s), 8.64 (1H, br s), 8.16 (1H, br s), 7.89 (1H, br d, J = 7.4 Hz), 7.34-7.37 (2H, m), 6.86 (1H, dt, J = 5.9, 15.4 Hz) , 6.53 (1H, d, J = 15.4 Hz), 4.52 (2H, dt, J = 4.4, 48.0 Hz), 3.15 (2H, d, J = 5.9 Hz), 2.61 (2H, dt, J = 4.4, 28.6 Hz), 2.44 (8H, m); MS(EI + ) m/z: 515 (M + 2 + ,5), 513 (M + ,5), 495 (3), 493 (3), 432 (15 ), 383 (100), 381 (96), 354 (40), 352 (38); HRMS (EI + ) m/z: 513.1286 (Calcd for C 23 H 25 BrFN 7 O: 513.1288).
［標識前駆体合成］
標識前駆体となるＨ２ precursorを合成した。
[Synthesis of labeled precursor]
H2 precursor which is a labeling precursor was synthesized.
（製造例５）
2-(3-((6-((2-morpholinoethyl)amino)pyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)ethyl4-methylbenzenesulfonate (H2 precursor)の合成
下記スキームに従ってＨ２ precursorを合成した。
Synthesis of 2-(3-((6-((2-morpholinoethyl)amino)pyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)ethyl4-methylbenzenesulfonate (H2 precursor) Synthesized.
tert-butyldimethyl(2-(3-nitrophenoxy)ethoxy)silane (化合物12)
化合物11（600mg, 4.31 mmol）をDMF（8.0 mL）に溶解し、K2CO3（1192 mg, 8.62mmol）及び(2-bromoethoxy)(tert-butyl)dimethylsilane（1118 μL, 5.17 mmol）を加えて80℃で2.5時間加熱した。反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーにより精製し、化合物12を得た。収量1007.3 mg（78.5%）, 1H NMR (400 MHz, CDCl3) 7.81 (1H, d, J = 8.4 Hz), 7.75 (1H, s), 7.42 (1H, t, J = 8.4 Hz), 7.25 (1H, d, J = 8.4 Hz), 4.13 (2H, t, J = 4.8 Hz), 4.00 (2H, t, J = 4.8 Hz), 0.91 (9H, s).
tert-butyldimethyl(2-(3-nitrophenoxy)ethoxy)silane (Compound 12)
Compound 11 (600 mg, 4.31 mmol) was dissolved in DMF (8.0 mL), K 2 CO 3 (1192 mg, 8.62 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1118 μL, 5.17 mmol) were added. And heated at 80° C. for 2.5 hours. The reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to give compound 12. Yield 1007.3 mg (78.5%), 1H NMR (400 MHz, CDCl 3) 7.81 (1H, d, J = 8.4 Hz), 7.75 (1H, s), 7.42 (1H, t, J = 8.4 Hz), 7.25 ( 1H, d, J = 8.4 Hz), 4.13 (2H, t, J = 4.8 Hz), 4.00 (2H, t, J = 4.8 Hz), 0.91 (9H, s).
3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)aniline (化合物13)
化合物12（1007mg, 3.386 mmol）をMeOH（15 mL）に溶解し、Pd/C（150 mg）を加えてArガス下室温で12時間反応させた。その後Arガスを水素に置換し2時間撹拌した。Hyflo Super-Celでろ過後、溶媒を留去した。残渣をカラムクロマトグラフィーにより精製し、化合物13を得た。収量776.3 mg（85.7%）, 1H NMR (400 MHz, CDCl3) 6.94 (1H, t, J = 8.0 Hz), 6.22 (1H, d, J = 8.0 Hz), 6.18 (1H, d, J = 8.0Hz), 6.15 (1H, s), 3.88 (2H, d, J = 4.8 Hz), 3.85 (2H, d, J = 4.8 Hz), 3.54 (2H, br), 0.81 (9H, s).
3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)aniline (Compound 13)
Compound 12 (1007 mg, 3.386 mmol) was dissolved in MeOH (15 mL), Pd/C (150 mg) was added, and the mixture was reacted under Ar gas at room temperature for 12 hours. After that, Ar gas was replaced with hydrogen and the mixture was stirred for 2 hours. After filtering with Hyflo Super-Cel, the solvent was distilled off. The residue was purified by column chromatography to give compound 13. Yield 776.3 mg (85.7%), 1H NMR (400 MHz, CDCl 3 ) 6.94 (1H, t, J = 8.0 Hz), 6.22 (1H, d, J = 8.0 Hz), 6.18 (1H, d, J = 8.0 Hz), 6.15 (1H, s), 3.88 (2H, d, J = 4.8 Hz), 3.85 (2H, d, J = 4.8 Hz), 3.54 (2H, br), 0.81 (9H, s).
2-(3-((6-fluoropyrido[3, 4-d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (化合物14)
化合物6 (111mg, 0.606 mmol) に化合物13（243 mg, 0.908 mmol）を加え2-propanol（4.0 mL）中105℃で2時間加熱還流した。反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーにより精製し、化合物14を得た。収量 52.8 mg (29.0 %), 1H NMR (400 MHz, CD3OD) 8.86 (1H, s), 8.63 (1H, s), 8.02 (1H, s), 7.57 (1H, s), 7.39 (1H, d, J = 8.0 Hz), 7.31 (1H, t,J = 8.0 Hz), 6.83 (1H, d, J = 8.0 Hz), 4.10 (2H, t, J = 4.8Hz), 3.90 (2H, t, J = 4.8 Hz).
2-(3-((6-fluoropyrido[3, 4-d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (Compound 14)
Compound 13 (243 mg, 0.908 mmol) was added to compound 6 (111 mg, 0.606 mmol), and the mixture was heated under reflux in 2-propanol (4.0 mL) at 105°C for 2 hours. The reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to give compound 14. Yield 52.8 mg (29.0 %), 1H NMR (400 MHz, CD 3 OD) 8.86 (1H, s), 8.63 (1H, s), 8.02 (1H, s), 7.57 (1H, s), 7.39 (1H, d, J = 8.0 Hz), 7.31 (1H, t,J = 8.0 Hz), 6.83 (1H, d, J = 8.0 Hz), 4.10 (2H, t, J = 4.8Hz), 3.90 (2H, t, J = 4.8 Hz).
2-(3-((6-((2-morpholinoethyl)amino)pyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (化合物15)
化合物14（13 mg, 0.043 mmol）をDMSO（900 μL）に溶解し、4-(2-Aminoethyl)morpholine（100 μL, 0.762 mmol）を加えて95℃で20時間加熱した。反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーにより精製し、化合物15を得た。収量 7.6 mg (42.8 %), 1H NMR (400 MHz, CDCl3) 8.94 (1H, s), 8.59 (1H, s), 7.64 (1H, s), 7.31 (1H, t, J = 8.0 Hz), 7.23 (1H, d, J = 8.0 Hz), 6.75 (1H, d, J = 8.0 Hz), 6.43 (1H, s), 5.52 (1H, br), 4.15(2H, t, J = 4.0 Hz), 4.00 (2H, t, J = 4.0 Hz), 3.77 (4H, m), 3.44 (2H, t, J = 6.0 Hz), 2.74 (2H, t, J = 6.0 Hz), 2.56 (4H, m).
2-(3-((6-((2-morpholinoethyl)amino)pyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (Compound 15)
Compound 14 (13 mg, 0.043 mmol) was dissolved in DMSO (900 μL), 4-(2-Aminoethyl)morpholine (100 μL, 0.762 mmol) was added, and the mixture was heated at 95° C. for 20 hours. The reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to give compound 15. Yield 7.6 mg (42.8 %), 1H NMR (400 MHz, CDCl 3 ) 8.94 (1H, s), 8.59 (1H, s), 7.64 (1H, s), 7.31 (1H, t, J = 8.0 Hz), 7.23 (1H, d, J = 8.0 Hz), 6.75 (1H, d, J = 8.0 Hz), 6.43 (1H, s), 5.52 (1H, br), 4.15(2H, t, J = 4.0 Hz), 4.00 (2H, t, J = 4.0 Hz), 3.77 (4H, m), 3.44 (2H, t, J = 6.0 Hz), 2.74 (2H, t, J = 6.0 Hz), 2.56 (4H, m).
2-(3-((6-((2-morpholinoethyl)amino)pyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)ethyl4-methylbenzenesulfonate (H2 precursor)
化合物15 (17.8 mg, 0.043 mmol)をCH2Cl2 (2.0 mL)に溶解し、氷冷下Et3N (12.09 μL, 0.087 mmol)、4-toluenesulfonylchloride (9.09 mg, 0.048 mmol) 及びDMAP触媒量を加え、室温で一晩反応した反応終了後、反応液を酢酸エチルで抽出し、有機層を回収して硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーにより精製し、H2 precursorを得た。収量 2.3 mg (22.0 %), 1H NMR (400 MHz, CDCl3) 8.93 (1H, s), 8.58 (1H, s), 7.83 (2H, d, J = 8.4 Hz), 7.52 (1H, s), 7.35 (1H, d, J = 8.4 Hz), 7.32-7.26 (2H, m), 6.62 (1H, d, J = 6.4 Hz), 6.50 (1H, s), 5.54 (1H, br), 4.39 (2H, t, J = 4.0 Hz), 4.22 (2H, t, J = 4.0 Hz), 3.77 (4H, m), 3.47 (2H, t, J = 5.6 Hz), 2.76 (2H, t, J = 5.6 Hz), 2.59 (4H, m), 2.44 (3H, s).
2-(3-((6-((2-morpholinoethyl)amino)pyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)ethyl4-methylbenzenesulfonate (H2 precursor)
Compound 15 (17.8 mg, 0.043 mmol) was dissolved in CH 2 Cl 2 (2.0 mL), and ice-cooled Et 3 N (12.09 μL, 0.087 mmol), 4-toluenesulfonyl chloride (9.09 mg, 0.048 mmol) and DMAP catalytic amount. After completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic layer was collected and dried over sodium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography to obtain H2 precursor. Yield 2.3 mg (22.0%), 1H NMR (400 MHz, CDCl 3) 8.93 (1H, s), 8.58 (1H, s), 7.83 (2H, d, J = 8.4 Hz), 7.52 (1H, s), 7.35 (1H, d, J = 8.4 Hz), 7.32-7.26 (2H, m), 6.62 (1H, d, J = 6.4 Hz), 6.50 (1H, s), 5.54 (1H, br), 4.39 (2H , t, J = 4.0 Hz), 4.22 (2H, t, J = 4.0 Hz), 3.77 (4H, m), 3.47 (2H, t, J = 5.6 Hz), 2.76 (2H, t, J = 5.6 Hz ), 2.59 (4H, m), 2.44 (3H, s).
［放射化学合成］
放射性標識化合物である［18Ｆ］Ｈ２及び［18Ｆ］Ｈ４を合成した。
[Radiochemical synthesis]
Radiolabeled compounds [ 18 F]H2 and [ 18 F]H4 were synthesized.
（製造例６）
下記スキームに従って［18Ｆ］Ｈ２を合成した。
[ 18 F]H2 was synthesized according to the following scheme.
N 4 -(3-(2-[ 18 F]fluoroethoxy)phenyl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-4, 6-diamine ([ 18 F]H2)
[18F]fluoride溶液(3700 MBq)にKryptofix 2.2.2. (5.0 mg)及びMeCN(0.5 mL)を加え、N2気流下120℃で加熱し共沸脱水した。再度MeCNを加え、共沸脱水を繰り返し行った。これを無水MeCN (1.0 mL)に溶解し、H2 precursor (1.77 μmol, 1.0 mg)を加えマイクロウェーブを用いて120℃で1分間反応した。反応液を逆相HPLCにて分取精製した [COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 45% (C) and 55% (D), flow rate 5.0 mL/min, λ = 280 nm, Rt = 7.6 min]。得られた目的物のフラクションの溶媒を留去後、生理食塩水に溶解し、生物学的評価に用いた。放射化学的収率は50 %であり、放射化学的純度は>95 %であった。
N 4 -(3-(2-[ 18 F]fluoroethoxy)phenyl)-N 6 -(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-4, 6-diamine ([ 18 F]H2)
Kryptofix 2.2.2. (5.0 mg) and MeCN (0.5 mL) were added to the [ 18 F]fluoride solution (3700 MBq), and the mixture was heated at 120° C. under N 2 stream for azeotropic dehydration. MeCN was added again and azeotropic dehydration was repeated. This was dissolved in anhydrous MeCN (1.0 mL), H2 precursor (1.77 μmol, 1.0 mg) was added, and the mixture was reacted at 120° C. for 1 minute using a microwave. The reaction solution was purified by reverse phase HPLC [COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 45% (C) and 55% (D), flow rate 5.0 mL/min, λ = 280 nm, Rt = 7.6 min]. After distilling off the solvent of the obtained fraction of the desired product, it was dissolved in physiological saline and used for biological evaluation. The radiochemical yield was 50% and the radiochemical purity was >95%.
（製造例７）
下記スキームに従って［18Ｆ］Ｈ４を合成した。
[ 18 F]H4 was synthesized according to the following scheme.
2-[ 18 F]fluoroethyl-4-toluene sulfonate (化合物19)
[18F]fluoride溶液(3700 MBq)にKryptofix 2.2.2. (4.50 mg)及びMeCN (0.5 mL)を加え、N2気流下120℃で加熱し共沸脱水した。再度MeCNを加え、共沸脱水を繰り返し行った。これを無水MeCN (0.25 mL)に溶解し、ethylenglycol-1,2-ditosylate (18) (6.75 μmol, 2.50 mg)を加え90℃で5分間反応した。反応液に水(0.15 mL)を加え、逆相HPLCにて分取精製した [COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 50% (A) and (B), flow rate 4.0 mL/min, λ = 280 nm, Rt = 10-11 min]。得られた目的物のフラクションに水を加えて希釈し、Sep-Pak C18 Light Cartridge (日本ウォーターズ株式会社)にアプライ後、水を通してTFAを除去した。N2気流下カートリッジを乾燥し、DMFを通して目的物を溶出した。
2-[ 18 F]fluoroethyl-4-toluene sulfonate (Compound 19)
Kryptofix 2.2.2. (4.50 mg) and MeCN (0.5 mL) were added to the [ 18 F]fluoride solution (3700 MBq), and the mixture was heated at 120° C. under N 2 stream for azeotropic dehydration. MeCN was added again and azeotropic dehydration was repeated. This was dissolved in anhydrous MeCN (0.25 mL), ethylenglycol-1,2-ditosylate (18) (6.75 μmol, 2.50 mg) was added, and the mixture was reacted at 90° C. for 5 minutes. Water (0.15 mL) was added to the reaction mixture, and the mixture was purified by reverse phase HPLC [COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 50% (A) and (B), flow rate 4.0 mL/min. , λ = 280 nm, Rt = 10-11 min]. Water was added to the obtained fraction of the desired product to dilute it, and the fraction was applied to Sep-Pak C18 Light Cartridge (Japan Waters Co., Ltd.), and then TFA was removed by passing water. The target product was eluted through DMF by drying the cartridge under a stream of N 2 .
(E)-N-(4-((3-bromophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4-(4-(2-[ 18 F]fluoroethyl)piperazin-1-yl)but-2-enamide ([ 18 F]H4)
H4 precursor (1.07 μmol, 0.50 mg) を無水DMF (20 μL)に溶解し、化合物19のDMF溶液(100 μL)に加えた。さらにEt3N (1.45 μL)を加え、110℃で20分間反応した。反応液を逆相HPLCにて分取精製した [COSMOSIL 5C18-AR-II , 10 x 250 mm, gradient of 80:20(0 min)→60:40 (20 min) by (A) and (B), flow rate 5.0 mL/min, λ = 280 nm]。得られた目的物のフラクションに水を加えて希釈し、Sep-Pak C18 Light Cartridgeにアプライ後、水を通してTFAを除去した。溶媒を留去後、1% Tween生理食塩水に溶解し、生物学的評価に用いた。放射化学的収率は3.8 %であり、放射化学的純度は>95 %であった。
(E)-N-(4-((3-bromophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4-(4-(2-[ 18 F]fluoroethyl)piperazin-1- yl)but-2-enamide ([ 18 F]H4)
H4 precursor (1.07 μmol, 0.50 mg) was dissolved in anhydrous DMF (20 μL) and added to the DMF solution (100 μL) of compound 19. Et 3 N (1.45 μL) was further added, and the mixture was reacted at 110° C. for 20 minutes. The reaction solution was purified by reverse phase HPLC [COSMOSIL 5C18-AR-II, 10 x 250 mm, gradient of 80:20 (0 min) → 60:40 (20 min) by (A) and (B) , flow rate 5.0 mL/min, λ = 280 nm]. Water was added to the obtained fraction of the desired product to dilute it, and the mixture was applied to a Sep-Pak C18 Light Cartridge, and then TFA was removed by passing water. After evaporating the solvent, it was dissolved in 1% Tween physiological saline and used for biological evaluation. The radiochemical yield was 3.8% and the radiochemical purity was >95%.
［EGFRチロシンキナーゼ阻害活性の測定１］
各化合物（Ｈ１〜Ｈ４）及びゲフィチニブ（Gefitinib）のEGFRチロシンキナーゼに対する阻害活性をEGFR Kinase Enzyme System (Promega)及びADP-GloTM Kinase assay Kit (Promega, Catalog No. V9101)を用いて測定した。
EGFR Kinase Enzyme Systemは、EGFR Kinase Enzyme System(Catalog No. V3831)、EGFR (L858R) Kinase Enzyme System(Catalog No. V5322)、EGFR (T790M) Kinase Enzyme System(Catalog No. V4506)及びEGFR (T790M, L858R) Kinase Enzyme System(Catalog No. V5324)の４種類を用いて行った（いずれもPromega製）。
測定は、Promega protocol applications guideに準じて行った。すなわち、希釈溶液は、緩衝液（40 mM Tris-HCl, pH7.5, 20 mM MgCl2, 50 μM DTT and 0.1 mg/mL BSA）を使用した。化合物濃度は、100 μM（1% DMSOを含む最終濃度）を始めとし、緩衝液で5倍ずつ希釈し、10種類の濃度を調製した。PD158780のみ、初期濃度を10 μM（1% DMSOを含む最終濃度）とし、化合物群と同様に調製した。得られた各濃度の化合物を384ウェルプレートの各ウェルに2 μLずつ添加した。さらに、各EGFR Kinase Enzyme Systemに付属のEGFR Kinase Bufferを各ウェルに4 μL (20 ng)ずつ添加し、室温で10分インキュベートした。続いて、ATP (10 μM) と Poly(Glu, Tyr) (2 μg)基質の混合溶液を各ウェルに4 μLずつ添加し、室温で一時間インキュベートした。ADP-GloTM Reagent (ADP-GloTM Kinase Assay, Promega)を各ウェルに10 μLずつ添加し、室温で40分間反応した。さらに、Kinase Detection Reagent (ADP-GloTM Kinase Assay, Promega)を各ウェルに20 μLずつ添加し、室温で一時間反応した後、Luminescence Counter 1420 ARVOTM Light (株式会社 パーキンエルマー)を用いて発光量を測定した。得られたデータから、GraphPad Prism 5 (GraphPad Software, Inc.)を用いて、用量反応曲線及びIC50を算出した。その結果を下記表１に示す。下記表１において、WTはEGFR Kinase Enzyme Systemでの測定結果、L858RはEGFR (L858R) Kinase Enzyme Systemでの測定結果、T790MはEGFR (T790M) Kinase Enzyme Systemでの測定結果、及びDMはEGFR (T790M, L858R) Kinase Enzyme Systemでの測定結果を示す。
[Measurement of EGFR tyrosine kinase inhibitory activity 1]
The inhibitory activities of each compound (H1 to H4) and Gefitinib against EGFR tyrosine kinase were measured using EGFR Kinase Enzyme System (Promega) and ADP-Glo ™ Kinase assay Kit (Promega, Catalog No. V9101).
EGFR Kinase Enzyme System, EGFR Kinase Enzyme System (Catalog No. V3831), EGFR (L858R) Kinase Enzyme System (Catalog No. V5322), EGFR (T790M) Kinase Enzyme System (Catalog No. V4506) and EGFR (T790M, L858R) 4) Kinase Enzyme System (Catalog No. V5324) was used (all were manufactured by Promega).
The measurement was performed according to the Promega protocol applications guide. That is, a buffer solution (40 mM Tris-HCl, pH 7.5, 20 mM MgCl 2 , 50 μM DTT and 0.1 mg/mL BSA) was used as the diluted solution. The compound concentration was 100 μM (final concentration containing 1% DMSO) and was diluted 5-fold with a buffer solution to prepare 10 concentrations. PD158780 alone was prepared in the same manner as the compound group, with the initial concentration set to 10 μM (final concentration containing 1% DMSO). 2 μL of the obtained compound at each concentration was added to each well of a 384-well plate. Furthermore, 4 μL (20 ng) of EGFR Kinase Buffer attached to each EGFR Kinase Enzyme System was added to each well and incubated at room temperature for 10 minutes. Subsequently, 4 μL each of a mixed solution of ATP (10 μM) and Poly(Glu, Tyr) (2 μg) substrate was added to each well and incubated at room temperature for 1 hour. 10 μL of ADP-Glo ™ Reagent (ADP-Glo ™ Kinase Assay, Promega) was added to each well and reacted at room temperature for 40 minutes. Furthermore, the addition Kinase Detection Reagent (ADP-Glo TM Kinase Assay, Promega) to each 20 [mu] L to each well, after reacting at room temperature for one hour, the emission amount by using a Luminescence Counter 1420 ARVO TM Light (LTD PerkinElmer) Was measured. A dose-response curve and IC 50 were calculated from the obtained data using GraphPad Prism 5 (GraphPad Software, Inc.). The results are shown in Table 1 below. In Table 1 below, WT is the measurement result with the EGFR Kinase Enzyme System, L858R is the measurement result with the EGFR (L858R) Kinase Enzyme System, T790M is the measurement result with the EGFR (T790M) Kinase Enzyme System, and DM is the EGFR (T790M , L858R) shows the measurement results with Kinase Enzyme System.
表１に示すように、H1〜H4は、いずれも、L858R変異型EGFRに対して比較的高い結合親和性を示すが、L858R/T790M変異型EGFR（表１のDM）に対して結合親和性を示さなかった。また、H2はL858R変異型EGFRに対して比較的高い結合親和性を示すが、野生型EGFRに対する結合親和性が低く、またL858R/T790M変異型EGFRに対して結合親和性を示さなかった。 As shown in Table 1, all of H1 to H4 show relatively high binding affinity for L858R mutant EGFR, but binding affinity for L858R/T790M mutant EGFR (DM in Table 1). Was not shown. H2 showed a relatively high binding affinity for L858R mutant EGFR, but low binding affinity for wild type EGFR, and did not show binding affinity for L858R/T790M mutant EGFR.
［EGFRチロシンキナーゼ阻害活性の測定２］
化合物Ｈ４、エルロチニブ(Erlotinib)及びAZD9291を用い、ATP及びPoly(Glu, Tyr)基質添加後のインキュベートを２時間にした以外は、［EGFRチロシンキナーゼ阻害活性の測定１］と同様に行った。その結果を下記表２に示す。なお、AZD9291は、L858R変異型EGFR-TK及びL858R/T790M変異型EGFR-TKの両方の阻害作用するとされている化合物である。
Using Compound H4, Erlotinib and AZD9291, the same procedure as in [Measurement of EGFR tyrosine kinase inhibitory activity 1] was performed except that the incubation after addition of the ATP and Poly(Glu, Tyr) substrates was 2 hours. The results are shown in Table 2 below. AZD9291 is a compound that is said to have an inhibitory effect on both L858R mutant EGFR-TK and L858R/T790M mutant EGFR-TK.
表２に示すように、H4は、L858R変異型EGFRに対して比較的高い結合親和性を示した。H4のL858R変異型EGFRに対する結合親和性は、Erlotinib及びAZD9291と同程度であった。一方、H4のL858R/T790M変異型EGFRに対する結合親和性は、AZD9291よりも低く、Erlotinibよりも高かった。これにより、H4は、L858R変異型EGFRを特異的に結合すること示唆された。 As shown in Table 2, H4 showed a relatively high binding affinity for L858R mutant EGFR. The binding affinity of H4 for L858R mutant EGFR was similar to that of Erlotinib and AZD9291. On the other hand, the binding affinity of H4 for L858R/T790M mutant EGFR was lower than that of AZD9291 and higher than that of Erlotinib. This suggested that H4 specifically binds L858R mutant EGFR.
［細胞培養・モデルマウス］
2種類のEGFR変異陽性ヒト非小細胞肺癌細胞H3255（L858R変異）、H1975（L858R/T790M変異）をグルタミン、抗生物質（ペニシリン・ストレプトマイシン）とウシ胎児血清20%を含むDMEM/Ham's F-12培地（ナカライテスク）中で培養した。
オスのBALB/c nu/nu マウス5週齢（清水実験材料）の右肩にBD MatrigelTM Basement Membrane Matrixに懸濁させたH3255細胞を1×107 cells/mouse移植し、担がんマウスを作製した。腫瘍径は1cm以下で実験に使用した。
[Cell culture/Model mouse]
Human EGFR mutation positive human non-small cell lung cancer cells H3255 (L858R mutation), H1975 (L858R/T790M mutation) glutamine, antibiotics (penicillin streptomycin) and DMEM/Ham's F-12 medium containing fetal bovine serum 20% Cultured in (Nacalai Tesque).
Male BALB/c nu/nu mice 5 weeks old (Shimizu experimental material) were transplanted with 1 × 10 7 cells/mouse of H3255 cells suspended in BD Matrigel TM Basement Membrane Matrix on the right shoulder, and tumor-bearing mice were transplanted. It was made. The tumor diameter was 1 cm or less and used in the experiment.
［細胞取り込み阻害実験１］
H4の各変異型EGFR-TKに対する結合の特異性を、L858R変異細胞であるH3255細胞、及びL858R/T790M変異細胞であるH1975細胞を用いた細胞取り込み阻害実験にて評価した。12ウェルプレートにてH3255、H1975（4×105 cells/well）を48時間培養した。培地を除去後、各ウェルをPBS(-)で1回洗浄した。各ウェルに[18F]H4(0.15 MBq/mL)とgefitinib（0, 0.5, 1, 2.5μM）を加えたウシ胎児血清非含有のDMEM/Ham's F-12培地を加え、CO2インキュベーター中で2時間インキュベートした。各ウェルを0.1% Tween 80 / 1% DMSO / PBS(-)で3回洗浄し、0.2 N NaOHで細胞を溶解させた。溶液の放射能をガンマカンターで計測し、BCA Protein Assay Kit（Pierce, Rockford, IL）を用いてタンパク濃度を定量して、測定結果を解析した。その結果を図１に示す。
[Cell uptake inhibition experiment 1]
The specificity of the binding of H4 to each mutant EGFR-TK was evaluated in a cell uptake inhibition experiment using L858R mutant cells, H3255 cells, and L858R/T790M mutant cells, H1975 cells. H3255 and H1975 (4×10 5 cells/well) were cultured in a 12-well plate for 48 hours. After removing the medium, each well was washed once with PBS(-). [ 18 F]H4 (0.15 MBq/mL) and gefitinib (0, 0.5, 1, 2.5 μM) were added to each well and fetal calf serum-free DMEM/Ham's F-12 medium was added to each well in a CO 2 incubator. Incubated for 2 hours. Each well was washed 3 times with 0.1% Tween 80/1% DMSO/PBS(-), and the cells were lysed with 0.2 N NaOH. The radioactivity of the solution was measured with a gamma-canter, the protein concentration was quantified using the BCA Protein Assay Kit (Pierce, Rockford, IL), and the measurement results were analyzed. The result is shown in FIG.
図１に示すように、[18F]H4のH3255細胞への取り込みは、EGFR-TKIであるgefitinibにより阻害された。これに対し、[18F]H4のH1975細胞への取り込みは、gefitinibの添加の有無及びその添加濃度にかかわらず、50%ID/mg protein程度であった。これにより、[18F]H4によれば、一次変異であるL858R変異が導入されたL858R変異型EGFRと、一次変異に続いて出現した二次変異T790M変異が導入されたL858R/T790M変異型EGFRとを判別できる可能性が示唆された。 As shown in FIG. 1, [ 18 F]H4 uptake into H3255 cells was inhibited by EGFR-TKI gefitinib. On the other hand, uptake of [ 18 F]H4 into H1975 cells was about 50% ID/mg protein regardless of the presence or absence of addition of gefitinib and the concentration thereof. Thus, according to [ 18 F]H4, the L858R mutant EGFR introduced with the L858R mutation, which is the primary mutation, and the L858R/T790M mutant EGFR introduced with the secondary mutation T790M mutation, which appeared after the primary mutation, were introduced. The possibility of being able to discriminate between is suggested.
［細胞取り込み阻害実験２］
12ウェルプレートにてH3255、H1975（4×105 cells/well）を24時間培養した。培地を除去後、各ウェルをPBS(-)で1回洗浄した。各ウェルにAZD9291（0, 1, 5μM）を加えたウシ胎児血清非含有のDMEM/Ham's F-12培地を加え、5%CO2インキュベーター中で37℃で30分間インキュベートした。各ウェルに[18F]H4(148kBq/well)を加え、5%CO2インキュベーター中で37℃で2時間インキュベートした。各ウェルを0.1% Tween 80 / 1% DMSO / PBS(-)で3回洗浄し、0.2 N NaOHで細胞を溶解させた。溶液の放射能をガンマカンターで計測し、BCA Protein Assay Kit（Pierce, Rockford, IL）を用いてタンパク濃度を定量して、測定結果を解析した。その結果を図２に示す。
[Cell uptake inhibition experiment 2]
H3255 and H1975 (4×10 5 cells/well) were cultured in a 12-well plate for 24 hours. After removing the medium, each well was washed once with PBS(-). Fetal calf serum-free DMEM/Ham's F-12 medium containing AZD9291 (0, 1, 5 μM) was added to each well, and the mixture was incubated at 37° C. for 30 minutes in a 5% CO 2 incubator. [ 18 F]H4 (148 kBq/well) was added to each well and incubated at 37°C for 2 hours in a 5% CO 2 incubator. Each well was washed 3 times with 0.1% Tween 80/1% DMSO/PBS(-), and the cells were lysed with 0.2 N NaOH. The radioactivity of the solution was measured with a gamma-canter, the protein concentration was quantified using the BCA Protein Assay Kit (Pierce, Rockford, IL), and the measurement results were analyzed. The result is shown in FIG.
図２に示すように、[18F]H4のH3255細胞への取り込みは、EGFR-TKIであるAZD9291により阻害された。これに対し、[18F]H4のH1975細胞への取り込みは、AZD9291の添加の有無及びその添加濃度にかかわらず、50%ID/mg protein程度であった。これにより、[18F]H4は、L858R変異型EGFRに特異的に結合し、[18F]H4によれば、L858R変異型EGFRと、L858R/T790M変異型EGFRとを判別できる可能性が示唆された。 As shown in FIG. 2, uptake of [ 18 F]H4 into H3255 cells was inhibited by EGFR-TKI AZD9291. On the other hand, the uptake of [ 18 F]H4 into H1975 cells was about 50% ID/mg protein regardless of the presence or absence of AZD9291 addition and the concentration thereof. Thus, [ 18 F]H4 specifically binds to L858R mutant EGFR, and according to [ 18 F]H4, it is possible to distinguish L858R mutant EGFR and L858R/T790M mutant EGFR. Was done.
［体内分布実験］
[18F]H4を6μCi/100μLとなるように0.1% Tween 80生理食塩水に溶解させ、担がんマウスに100μLずつ尾静脈投与した。マウスは所定のタイムポイント（投与後30分、1時間、2時間、3時間）において断頭屠殺した。血液を回収及び組織を摘出して質量と集積した放射能を測定し、単位重量あたりの放射能から集積量（%dose/g）を算出して組織への集積を評価した。その結果を図３及び下記表３に示す。図３は、各臓器への[18F]H4の集積の経時変化の一例を示すグラフである。下記表３は、腫瘍／血液比（腫瘍の集積量／血液の集積量）及び腫瘍／筋肉比（腫瘍の集積量／筋肉の集積量）を示す。
[Distribution experiment]
[ 18 F]H4 was dissolved in 0.1% Tween 80 physiological saline at 6 μCi/100 μL, and 100 μL each was intravenously administered to tumor-bearing mice. Mice were killed by decapitation at predetermined time points (30 minutes, 1 hour, 2 hours, and 3 hours after administration). The blood was collected, the tissue was extracted, the mass and the accumulated radioactivity were measured, and the accumulated amount (% dose/g) was calculated from the radioactivity per unit weight to evaluate the accumulation in the tissue. The results are shown in FIG. 3 and Table 3 below. FIG. 3 is a graph showing an example of changes with time of accumulation of [ 18 F]H4 in each organ. Table 3 below shows the tumor/blood ratio (tumor accumulation amount/blood accumulation amount) and the tumor/muscle ratio (tumor accumulation amount/muscle accumulation amount).
各臓器における[18F]H4の集積を、投与後３０分から１８０分まで確認したところ、表３に示す通り、腫瘍／血液比は３前後、腫瘍／筋肉比はばらつきがあるものの５を超える値となっており、良好な結果が得られた。この結果より、[18F]H4を用いてL858R変異型EGFRをイメージングできる可能性が示唆された。また、肝臓から腸への速やかな移行が確認され、代謝及び***が速いことが分かった。 Accumulation of [ 18 F]H4 in each organ was confirmed from 30 minutes to 180 minutes after administration. As shown in Table 3, the tumor/blood ratio was around 3, and the tumor/muscle ratio varied, but exceeded 5. And good results were obtained. These results suggest that [ 18 F]H4 can be used to image L858R mutant EGFR. In addition, rapid transfer from the liver to the intestine was confirmed, and it was found that metabolism and excretion were fast.
［体内分布実験（ブロッキング実験）］
H3255担がんマウスへ[18F]H4（222kBq）及びAZD9291（17μg）をマウス尾静脈より投与した。投与後180分に屠殺してH3255腫瘍組織を摘出した。質量と集積した放射能を測定し、単位重量あたりの放射能から集積量（%dose/g）を算出した。また、AZD9291を投与しない以外は、上記と同様に行った。
また、H1975担がんマウスを使用した以外は、上記と同様に行った。
これらの結果を図４に示す。
[Distribution experiment (blocking experiment)]
[ 18 F]H4 (222 kBq) and AZD9291 (17 μg) were administered to H3255 tumor-bearing mice through the tail vein of the mice. 180 minutes after the administration, the mice were sacrificed and the H3255 tumor tissues were excised. The radioactivity accumulated with the mass was measured, and the accumulated amount (% dose/g) was calculated from the radioactivity per unit weight. Also, the same procedure as above was performed except that AZD9291 was not administered.
In addition, the same procedure as above was performed except that H1975 cancer-bearing mice were used.
The results are shown in FIG.
図４において左がH3255担がんマウスの結果、右がH1975担がんマウスの結果を示す。図４に示すように、H1975腫瘍（L858R/T790M変異）では、AZD9291の投与の有無にかかわらず[18F]H4の集積はほとんど変化しなかった。これに対し、H3255腫瘍（L858R変異）では、AZD9291を同時投与することにより、[18F]H4の集積が半分以上(54%)減少した。これにより、[18F]H4は、L858R変異型EGFRに特異的に結合し、[18F]H4によれば、L858R変異型EGFRと、L858R/T790M変異型EGFRとを判別できる可能性が示唆された。 In FIG. 4, the left shows the results of H3255 tumor-bearing mice, and the right shows the results of H1975 tumor-bearing mice. As shown in FIG. 4, in the H1975 tumor (L858R/T790M mutant), the accumulation of [ 18 F]H4 was hardly changed regardless of the administration of AZD9291. In contrast, in H3255 tumors (L858R mutation), co-administration of AZD9291 reduced [ 18 F]H4 accumulation by more than half (54%). Thus, [ 18 F]H4 specifically binds to L858R mutant EGFR, and according to [ 18 F]H4, it is possible to distinguish L858R mutant EGFR and L858R/T790M mutant EGFR. Was done.
［PET/CT撮像１］
H3255担がんマウスへ[18F]H4(9.8 MBq/150μL)をマウス尾静脈より投与した。投与後175分からイソフルラン(2.0%)吸引麻酔し投与後180分からPET/CT装置(FX-3300)を用いて20分間撮像した。その後、CT撮像(60 kV, 320 μA)を行った。画像再構成は、3D-OSEMを用いて行った。
＜撮像条件＞
Animal : Balb/c nu/nu mouse, 10 w, male, 22.2 g
Cell : H3255 (1×107 cells / 100 μL)
Injection dose : 264 μCi / 150 μL
PET/CT : FX-3300 (GMI)
Image acquisition : 180 - 200 min after administration
Reconstruction : 3D-OSEM
Condition of CT : 60kV, 320 μA
[PET/CT imaging 1]
[ 18 F]H4 (9.8 MBq/150 μL) was administered to H3255 tumor-bearing mice through the tail vein of the mice. Isoflurane (2.0%) was anesthetized by suction from 175 minutes after administration, and imaging was performed for 20 minutes using the PET/CT apparatus (FX-3300) from 180 minutes after administration. After that, CT imaging (60 kV, 320 μA) was performed. Image reconstruction was performed using 3D-OSEM.
<Imaging conditions>
Animal :Balb/c nu/nu mouse, 10 w, male, 22.2 g
Cell : H3255 (1 × 10 7 cells / 100 μL)
Injection dose : 264 μCi / 150 μL
PET/CT : FX-3300 (GMI)
Image acquisition : 180-200 min after administration
Reconstruction : 3D-OSEM
Condition of CT : 60kV, 320 μA
撮像により得られた画像を図５に示す。図５における左図が冠状断像（coronal view）であり、右図が横断像（transverse view）である。図５において丸で囲った部分が、H3255が移植された部分である。図５に示すように、[18F]H4はH3255が移植された部分に特異的に集積し、[18F]H4によってL858R変異EGFRをイメージングすることができた。 The image obtained by imaging is shown in FIG. The left view in FIG. 5 is a coronal view (coronal view), and the right view is a transverse view (transverse view). The part surrounded by a circle in FIG. 5 is the part where H3255 was transplanted. As shown in FIG. 5, [ 18 F]H4 was specifically accumulated in the region where H3255 was transplanted, and L858R mutant EGFR could be imaged by [ 18 F]H4.
［PET/CT撮像２］
Ｈ1975担がんマウスを使用し、下記撮像条件とした以外は、［PET/CT撮像１］と同様に行った。
＜撮像条件＞
Animal : Balb/c nu/nu mouse, 9 w, male, 20.9 g
Cell : H1975 (3×106 cells)
Injection dose : 486 μCi / 150 μL
PET/CT : FX-3300 (GMI)
Image acquisition : 180 - 200 min after administration
Reconstruction : 3D-OSEM
Condition of CT : 60 kV, 320 μA
[PET/CT imaging 2]
The same procedure as in [PET/CT imaging 1] was performed except that H1975 cancer-bearing mice were used and the following imaging conditions were used.
<Imaging conditions>
Animal : Balb/c nu/nu mouse, 9 w, male, 20.9 g
Cell : H1975 (3 × 10 6 cells)
Injection dose : 486 μCi / 150 μL
PET/CT : FX-3300 (GMI)
Image acquisition : 180-200 min after administration
Reconstruction : 3D-OSEM
Condition of CT : 60 kV, 320 μA
撮像により得られた画像を図６に示す。図６における左図が冠状断像（coronal view）であり、右図が横断像（transverse view）である。図６において丸で囲った部分が、H1975が移植された部分である。図６に示すように、H1975が移植された部分には、[18F]H4の特異的な集積を確認することができなかった。 The image obtained by imaging is shown in FIG. The left diagram in FIG. 6 is a coronal view, and the right diagram is a transverse view. The circled area in FIG. 6 is the area where H1975 was transplanted. As shown in FIG. 6, no specific accumulation of [ 18 F]H4 could be confirmed in the area where H1975 was transplanted.
以上のPET/CT撮像の結果により、[18F]H4を用いたイメージングによってがん組織（腫瘍）におけるEGFR遺伝子がL858R変異型かL858R/T790M変異型かを確認できることが示された。これにより、イメージングによって、二次変異の発現の有無や、EGFR-TKI耐性を有するか否かを確認することができた。 The results of the above PET/CT imaging showed that it was possible to confirm whether the EGFR gene in the cancer tissue (tumor) was the L858R mutant type or the L858R/T790M mutant type by imaging using [ 18 F]H4. As a result, it was possible to confirm the presence or absence of the expression of the secondary mutation and whether or not it had EGFR-TKI resistance by imaging.
Claims (13)
Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基であり、
Ｒ1は、放射性ハロゲン原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、
Ｒ2は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、
Ｒ1及びＲ2の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ1基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、
Ｒ1又はＲ2は、放射性ハロゲン原子又は放射性炭素原子（11Ｃ）を含み、
Ｙは、−ＮＨ−又は−Ｏ−である。］ A nuclear medicine diagnostic imaging agent comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1).
L 1 is an alkanediyl group having 1 to 5 carbon atoms, or an alkenediylcarbonyl group having 3 to 8 carbon atoms,
R 1 is a radioactive halogen atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent,
R 2 is a 6-8 membered aryl group having one substituent or a nitrogen-containing heteroaryl group,
The substituents of R 1 and R 2 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms or -(CH 2 ) 1 -(O- C 2 H 4 ) m —X 1 group, l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or -[ 11 C] CH 3 ,
R 1 or R 2 contains a radioactive halogen atom or a radioactive carbon atom ( 11 C),
Y is -NH- or -O-. ]
ｌは０又は２であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は、放射性ハロゲン原子又は−［11Ｃ］ＣＨ3である、請求項１又は２に記載の核医学画像診断薬。 R 1 is
l is 0 or 2, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, and X 1 is a radioactive halogen atom or -[ 11 C]CH 3; The described nuclear medicine diagnostic imaging agent.
ｌは０又は２であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は、放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、Ｘ2は、ハロゲン原子である、
請求項１から３のいずれかに記載の核医学画像診断薬。 R 2 is
l is 0 or 2, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or —[ 11 C]CH 3 , and X 2 is a halogen atom. Is
The nuclear medicine image diagnostic agent according to any one of claims 1 to 3.
Ｌ1は、炭素数１以上５以下のアルカンジイル基、又は炭素数３以上８以下のアルケンジイルカルボニル基であり、
Ｒ1は、放射性ハロゲン原子、又は１個の置換基を有していてもよい５〜７員の単環式窒素含有ヘテロシクロアルキルであり、
Ｒ2は、１個の置換基を有する６〜８員のアリール基又は窒素含有ヘテロアリール基であり、
Ｒ1及びＲ2の置換基は、それぞれ独立して、ハロゲン原子、炭素数１以上５以下のアルキル基、炭素数１以上５以下のハロゲン化アルキル基又は−（ＣＨ2）l−（Ｏ−Ｃ2Ｈ4）m−Ｘ1基であり、ｌは０以上５以下であり、ｍはエチレンオキシ基の繰り返し数であって０以上５以下であり、Ｘ1は放射性ハロゲン原子又は−［11Ｃ］ＣＨ3であり、
Ｒ1又はＲ2は、放射性ハロゲン原子又は放射性炭素原子（11Ｃ）を含み、
Ｙは、−ＮＨ−又は−Ｏ−である。］ A compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1).
L 1 is an alkanediyl group having 1 to 5 carbon atoms, or an alkenediylcarbonyl group having 3 to 8 carbon atoms,
R 1 is a radioactive halogen atom, or a 5- to 7-membered monocyclic nitrogen-containing heterocycloalkyl which may have one substituent,
R 2 is a 6-8 membered aryl group having one substituent or a nitrogen-containing heteroaryl group,
The substituents of R 1 and R 2 are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms or -(CH 2 ) 1 -(O- C 2 H 4 ) m —X 1 group, l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups and is 0 or more and 5 or less, X 1 is a radioactive halogen atom or -[ 11 C] CH 3 ,
R 1 or R 2 contains a radioactive halogen atom or a radioactive carbon atom ( 11 C),
Y is -NH- or -O-. ]
請求項１から４のいずれかに記載の核医学画像診断薬又は請求項５記載の化合物若しくはその製薬上許容される塩が投与された被検体の肺癌腫瘍から前記核医学画像診断薬又は前記化合物の放射性シグナルを検出することを含む、方法。 A method for obtaining information for evaluating the efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor in a subject undergoing treatment of non-small cell lung cancer with an epidermal growth factor receptor tyrosine kinase inhibitor,
The nuclear medicine image diagnostic agent or the compound from a lung cancer tumor of a subject to which the nuclear medicine image diagnostic agent according to any one of claims 1 to 4 or the compound according to claim 5 or a pharmaceutically acceptable salt thereof is administered. Detecting the radioactive signal of the.
請求項１から４のいずれかに記載の核医学画像診断薬又は請求項５記載の化合物若しくはその製薬上許容される塩が投与された被検体の肺癌腫瘍から前記核医学画像診断薬又は前記化合物の放射性シグナルを検出すること、
前記被検体の肺癌腫瘍からの放射性シグナルの検出を上皮成長因子受容体チロシンキナーゼ阻害薬の治療期間中に繰り返し行うこと、
前記検出された放射性シグナルを比較すること、及び
前記比較によりシグナルの変動に基づき、肺癌腫瘍における上皮成長因子受容体をコードする遺伝子におけるＴ７９０Ｍ変異の発生の有無を決定することを含む、方法。 A method for evaluating the occurrence of a T790M mutation in a gene encoding an epidermal growth factor receptor in lung cancer tumor, comprising:
The nuclear medicine image diagnostic agent or the compound from a lung cancer tumor of a subject to which the nuclear medicine image diagnostic agent according to any one of claims 1 to 4 or the compound according to claim 5 or a pharmaceutically acceptable salt thereof is administered. Detecting the radioactive signal of
Repeating the detection of radioactive signals from the lung cancer tumor of the subject during the treatment period of the epidermal growth factor receptor tyrosine kinase inhibitor,
Comparing the detected radioactive signals, and determining the presence or absence of the T790M mutation in the gene encoding the epidermal growth factor receptor in lung cancer tumors based on the variation of the signals by the comparison.
上皮成長因子受容体チロシンキナーゼ阻害薬の投与開始前、投与開始後及び投与開始から一定期間経過後からなる群から選択される２以上のタイミングで請求項７又は８に記載の方法により得られた情報を比較することを含む、方法。 A method for evaluating the efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor in a subject undergoing treatment for non-small cell lung cancer with an epidermal growth factor receptor tyrosine kinase inhibitor, comprising:
It was obtained by the method according to claim 7 or 8 at two or more timings selected from the group consisting of before administration of the epidermal growth factor receptor tyrosine kinase inhibitor, after administration, and after a certain period of time has elapsed from administration. A method comprising comparing information.
前記ＣＴ又はＭＲＩ画像と、前記検出した放射性シグナルから構築したイメージング画像とを融合又は比較することを含み、
前記融合又は比較に基づき、腫瘍の大きさが増加又は維持され、かつシグナルの減少が観察される場合は、上皮成長因子受容体チロシンキナーゼ阻害薬による治療の薬理有効性の可能性が低下すると判断される、請求項９から１２のいずれかに記載の方法。 Imaging CT or MRI of the subject, and fusing or comparing the CT or MRI image with an imaging image constructed from the detected radioactive signal,
Based on the fusion or comparison, if the tumor size is increased or maintained and a decrease in signal is observed, it is determined that the pharmacological efficacy of the treatment with the epidermal growth factor receptor tyrosine kinase inhibitor is reduced. It is the method of any of claims 9-12.
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