JP2019064987A

JP2019064987A - MOLECULE PROBE FOR Bcr-Abl PROTEIN IMAGING

Info

Publication number: JP2019064987A
Application number: JP2017194585A
Authority: JP
Inventors: 英郎佐治; Hideo Saji; 木村　寛之; Hiroyuki Kimura; 寛之木村; 洋和松田; Hirokazu Matsuda; 佑佳相馬; Yusuke Soma; 修一中西; Shuichi Nakanishi
Original assignee: Arkray Inc; Kyoto University
Current assignee: Arkray Inc; Kyoto University
Priority date: 2017-10-04
Filing date: 2017-10-04
Publication date: 2019-04-25
Anticipated expiration: 2037-10-04
Also published as: JP6994715B2

Abstract

To provide a new compound that allows imaging of Bcr-Abl protein.SOLUTION: The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 5

Description

本開示は、Bcr-Ablタンパク質に結合可能な化合物及び該化合物を含むBcr-Ablタンパク質イメージング用分子プローブに関する。 The present disclosure relates to a compound capable of binding to Bcr-Abl protein and a molecular probe for imaging Bcr-Abl protein comprising the compound.

Bcr-Abl遺伝子及びそれから産生されるBcr-Ablタンパク質は、慢性骨髄性白血病（ＣＭＬ）の治療効果の評価や寛解の判断の指標の一つとされている（非特許文献１及び２）。なぜなら、ＣＭＬは、９番目の染色体と２２番目の染色体の相互転座が生じることによりフィラデルフィア染色体が形成され、その染色体上で形成されたBｃｒ−Ａｂｌ遺伝子産生するBcr-Ablタンパク質が白血球細胞の無制限な増殖を引き起こすことにより発症するとされているからである。 The Bcr-Abl gene and the Bcr-Abl protein produced therefrom are considered as one of the indices for evaluation of the therapeutic effect of chronic myelogenous leukemia (CML) and judgment of remission (Non-patent Documents 1 and 2). This is because CML forms a Philadelphia chromosome by the occurrence of reciprocal translocation between the 9th chromosome and the 22nd chromosome, and the Bcr-Abl protein produced by the Bcr-Abl gene formed on that chromosome is a leukocyte cell of It is believed to be caused by causing unlimited proliferation.

一方、イマチニブ等のチロシンキナーゼ阻害剤（Bcr-Abl TKI）はＣＭＬ治療においてもっとも有効性が高いとされているが、これらによる治療が有効ではない患者も中にはいる。このため、例えば、Bcr-Ablタンパク質の薬剤耐性変異によりBcr-Abl TKIによる治療が失敗する可能性を回避するために、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（非特許文献３及び４）。 On the other hand, tyrosine kinase inhibitors such as imatinib (Bcr-Abl TKI) are considered to be the most effective in CML treatment, but some patients for which these treatments are not effective. For this reason, for example, in order to avoid the possibility that treatment with Bcr-Abl TKI may fail due to drug resistance mutation of Bcr-Abl protein, studies of radioactive imaging probes for nuclear medicine diagnosis are being conducted (Non-patent Document 3). And 4).

造血器腫瘍診療ガイドライン 2013年版Hematologic malignancies medical treatment guideline 2013 version Michele Baccarani et al., European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013, BLOOD, 8 AUGUST 2013, VOLUME 122, NUMBER 6, 872-884Michele Baccarani et al., European Leukemia Net recommendations for the management of chronic myeloid leukemia: 2013, BLOOD, 8 AUGUST 2013, VOLUME 122, NUMBER 6, 872-884 Mikhail Doubrovin et al., 124I-Iodopyridopyrimidinone for PET of Abl Kinase−Expressing Tumors In Vivo, THE JOURNAL OF NUCLEAR MEDICINE, Vol. 51, No. 1, January 2010 121-129Mikhail Doubrovin et al., 124 I-Iodopyridopyrimidone for PET of Abl Kinase-Expressing Tumors in Vivo, THE JOURNAL OF NUCLEAR MEDICINE, Vol. 51, No. 1, January 2010 121-129 Athanasios P. Glekas, In Vivo Imaging of Bcr-Abl Overexpressing Tumors with a Radiolabeled Imatinib Analog as an Imaging Surrogate for Imatinib, THE JOURNAL OF NUCLEAR MEDICINE, Vol. 52, No. 8, August 2011 1301-1307Athanasios P. Glekas, In Vivo Imaging of Bcr-Abl Overexpressing Tumors with a Radiolabeled Imatinib Analog as an Imaging Surrogate for Imatinib, THE JOURNAL OF NUCLEAR MEDICINE, Vol. 52, No. 8, August 2011 1301-1307

しかしながら、Bcr-Ablタンパク質を検出する放射性化合物の検討は行われているが、Bcr-Abl TKIの感受性を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、Bcr-Ablタンパク質をイメージング可能かつBcr-Abl TKIの感受性を判別可能な新たな放射性化合物を提供する。 However, although studies have been conducted on radioactive compounds for detecting Bcr-Abl protein, a method capable of determining the sensitivity of Bcr-Abl TKI has not been developed yet. Thus, the present disclosure provides a novel radioactive compound capable of imaging Bcr-Abl protein and determining the sensitivity of Bcr-Abl TKI.

本開示は、一態様において、下記式（Ｉ）で表される化合物又はその製薬上許容される塩（以下、「本開示の放射性化合物」ともいう）に関する。
［式（Ｉ）中、
Ｘ¹は、
であって、Ｒ²は、放射性ハロゲン原子であり、
Ｒ¹は、
であって、
Ｒ³及びＲ⁵は、放射性ハロゲン原子であり、
Ｒ⁴は、水素原子又は−ＣＨ₂−Ｒ⁶であって、Ｒ⁶は、４−メチルピペラジン−１−イル基、４−エチルピペラジン−１−イル基、４−ｎ−プロピルピペラジン−１−イル基、１−ピロリジニル基、ピペリジノ基、モルホリノ基、ジメチルアミノ基又はジエチルアミノ基であり、
Ｒ²、Ｒ³、及びＲ⁵のいずれか一つは、放射性ハロゲン原子である。］ The present disclosure relates, in one aspect, to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as “a radioactive compound of the present disclosure”).
[In the formula (I),
X ¹ is
And R ² is a radioactive halogen atom,
R ¹ is
And
R ³ and R ⁵ are radioactive halogen atoms,
R ⁴ is a hydrogen atom or -CH ₂ -R ⁶ , and R ⁶ is 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-n-propylpiperazine-1- Yl, 1-pyrrolidinyl, piperidino, morpholino, dimethylamino or diethylamino;
Any one of R ² , R ³ and R ⁵ is a radioactive halogen atom. ]

本開示は、一態様において、下記式（ＩＩ）で表される化合物その製薬上許容される塩を含む、Bcr-Ablタンパク質イメージング用分子プローブに関する。
［式（ＩＩ）中、
Ｘ²は、
であって、Ｒ⁸は、トリアルキルスタニル基、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、ブロシレート基であり、
Ｒ⁷は、
であって、
Ｒ⁹及びＲ¹⁰は、トリアルキルスタニル基、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、
Ｒ⁴は、水素原子又は−ＣＨ₂−Ｒ⁶であって、Ｒ⁶は、４−メチルピペラジン−１−イル基、４−エチルピペラジン−１−イル基、４−ｎ−プロピルピペラジン−１−イル基、１−ピロリジニル基、ピペリジノ基、モルホリノ基、ジメチルアミノ基又はジエチルアミノ基であり、
Ｒ⁸、Ｒ⁹、及びＲ¹⁰のいずれか一つは、トリアルキルスタニル基、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 present disclosure relates, in one aspect, to a molecular probe for imaging Bcr-Abl protein, which comprises a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.
[In the formula (II),
X ² is
R ⁸ is a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group, a brosylate group,
R ⁷ is
And
R ⁹ and R ^{10 each} represent a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group, or a brosylate group;
R ⁴ is a hydrogen atom or -CH ₂ -R ⁶ , and R ⁶ is 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-n-propylpiperazine-1- Yl, 1-pyrrolidinyl, piperidino, morpholino, dimethylamino or diethylamino;
Any one of R ⁸ , R ⁹ and R ¹⁰ is a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group.

本開示は、一態様において、上記式（Ｉ）で表される化合物、その製薬上許容される塩又は上記分子プローブが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。 The present disclosure relates, in one aspect, to an imaging method comprising detecting a radioactive signal of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or a subject to which the above molecular probe is administered. About.

本開示は、一態様において、Bcr-Ablタンパク質をイメージング可能かつBcr-Abl TKIの感受性を判別可能な新たな放射性化合物を提供できる。 The present disclosure, in one aspect, can provide a new radioactive compound capable of imaging Bcr-Abl protein and determining the sensitivity of Bcr-Abl TKI.

図１は、[¹²⁵I]IMT-1、[¹²⁵I]IMT-2及び[¹²⁵I]IMT-3のK562細胞への取込の経時変化を示すグラフである。FIG. 1 is a graph showing the time course of the uptake of [ ¹²⁵ I] IMT-1, [ ¹²⁵ I] IMT-2 and [ ¹²⁵ I] IMT-3 into K562 cells. 図２は、K562担がんマウスにおける[¹²⁵I]IMT-1の腫瘍/臓器比の経時変化の一例を示すグラフであって、左から順に腫瘍／血液比、腫瘍／筋肉比及び腫瘍／骨比の経時変化を示すグラフである。FIG. 2 is a graph showing an example of the time course of the tumor / organ ratio of [ ¹²⁵ I] IMT-1 in K562 tumor-bearing mice, and the tumor / blood ratio, tumor / muscle ratio and tumor / bone in order from the left It is a graph which shows a time-dependent change of ratio. 図３は、K562担がんマウスにおける[¹²⁵I]IMT-5の腫瘍/臓器比の経時変化の一例を示すグラフであって、左から順に腫瘍／血液比、腫瘍／筋肉比及び腫瘍／骨比の経時変化を示すグラフである。FIG. 3 is a graph showing an example of the time course of the tumor / organ ratio of [ ¹²⁵ I] IMT-5 in K562 tumor-bearing mice, and the tumor / blood ratio, tumor / muscle ratio and tumor / bone in order from the left It is a graph which shows a time-dependent change of ratio. 図４は、K562担がんマウスにおける[¹²⁵I]IMT-5投与後６０分の各臓器への集積量を示すグラフである。FIG. 4 is a graph showing the accumulation amount in each organ for 60 minutes after [ ¹²⁵ I] IMT-5 administration in K562 tumor-bearing mice. 図５は、[¹²³I]IMT-5を投与したK562担がんマウスのＳＰＥＣＴ／ＣＴ撮像により得られた画像の一例である。FIG. 5 is an example of an image obtained by SPECT / CT imaging of a K562 tumor-bearing mouse to which [ ¹²³ I] IMT-5 has been administered.

本開示は、下記の放射性標識された化合物が、Bcr-Ablタンパク質に高い親和性を有し、かつ非特許文献４（THE JOURNAL OF NUCLEAR MEDICINE, Vol. 52, No. 8, August 2011 1301-1307）等に開示されたイマチニブを骨格とするイメージングプローブと比較して高い腫瘍／血液比及び腫瘍／筋肉比を示す、という知見に基づく。
According to the present disclosure, the following radiolabeled compound has high affinity to Bcr-Abl protein, and the non-patent document 4 (THE JOURNAL OF NUCLEAR MEDICINE, Vol. 52, No. 8, August 2011 1301-1307 And the like, based on the finding that they exhibit high tumor / blood ratio and tumor / muscle ratio as compared to the imatinib-based imaging probe disclosed in U.S. Pat.

本開示は、下記の放射性標識された化合物の薬剤耐性変異型Bcr-Ablタンパク質（中でもT315I変異型Bcr-Ablタンパク質）に対する親和性が、野生型Bcr-Ablタンパク質に対する親和性と比較して有意な差があり、前者は後者よりも低い、という知見に基づく。本開示は、下記の放射性標識された化合物の薬剤耐性変異型Bcr-Ablタンパク質の腫瘍／血液比及び腫瘍／筋肉比が、野生型Bcr-Ablタンパク質のそれと比較して有意な差があり、前者は、後者よりも低い、という知見に基づく。
The present disclosure shows that the affinity of the radiolabeled compound described below for the drug-resistant mutant Bcr-Abl protein (especially T315I mutant Bcr-Abl protein) is significant compared to the affinity for the wild-type Bcr-Abl protein. Based on the finding that there is a difference, the former is lower than the latter. The present disclosure shows that the tumor / blood ratio and the tumor / muscle ratio of the drug-resistant mutant Bcr-Abl protein of the radio-labeled compound described below have significant differences as compared to those of the wild-type Bcr-Abl protein, the former Is based on the finding that it is lower than the latter.

本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質に高い親和性を有し、かつ優れた腫瘍／血液比及び腫瘍／筋肉比を示すことができるという効果を奏しうる。このため、本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質の発現を非侵襲的に検出することができうるという効果を奏しうる。本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質が過剰に発現した腫瘍を非侵襲的に画像化、好ましくは定量できうるという効果を奏しうる。また、本開示の放射性化合物は、一又は複数の実施形態において、T315I変異型Bcr-Ablタンパク質に低い親和性を有し、かつ野生型における腫瘍／血液比及び腫瘍／筋肉比と比較して有意な差を示すことができるという効果を奏しうる。このため、本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質が過剰に発現した腫瘍に対するBcr-Abl TKIの感受性を非侵襲的に画像化、好ましくは定量できうるという効果を奏しうる。 The radioactive compound of the present disclosure can exhibit the effect of having high affinity to Bcr-Abl protein and capable of exhibiting excellent tumor / blood ratio and tumor / muscle ratio in one or more embodiments. For this reason, the radioactive compound of the present disclosure can exhibit an effect that the expression of Bcr-Abl protein can be detected noninvasively in one or more embodiments. The radioactive compound of the present disclosure can exhibit the effect of being able to noninvasively image, preferably quantify, a tumor in which Bcr-Abl protein is overexpressed, in one or more embodiments. In addition, the radioactive compounds of the present disclosure, in one or more embodiments, have a low affinity for the T315I mutant Bcr-Abl protein and are significant as compared to the tumor / blood ratio and the tumor / muscle ratio in wild type The effect of being able to show a difference can be produced. Therefore, in one or more embodiments, the radioactive compound of the present disclosure is capable of noninvasively imaging, preferably quantifying the sensitivity of Bcr-Abl TKI to a tumor in which Bcr-Abl protein is overexpressed. Can play.

本明細書における「Bcr-Abl TKIの感受性を判別可能」としては、一又は複数の実施形態において、野生型のBcr-Ablタンパク質と、T315I変異型Bcr-Ablタンパク質に対する効果を判別できることが挙げられる。 In the present specification, “capable of determining the sensitivity of Bcr-Abl TKI” includes, in one or more embodiments, the ability to determine the effect on a wild-type Bcr-Abl protein and a T315I mutant Bcr-Abl protein .

本開示において「Bcr-Ablタンパク質イメージング用分子プローブ」とは、可視化するための放射性同位元素を含み、標的となるBcr-Ablタンパク質を認識することができる分子をいう。イメージング用分子プローブは、一又は複数の実施形態において、陽電子断層撮影（ＰＥＴ）又は単光子断層撮影（ＳＰＥＣＴ）に用いることができる。 In the present disclosure, “a molecular probe for imaging Bcr-Abl protein” refers to a molecule that includes a radioactive isotope for visualization and can recognize a target Bcr-Abl protein. Molecular probes for imaging can be used in positron emission tomography (PET) or single photon emission tomography (SPECT) in one or more 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「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。 As used herein, the term "pharmaceutically acceptable salt" includes pharmacologically and / or pharmaceutically acceptable salts, such as inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acid or acid salts. Basic amino acid salts and the like can be mentioned. In the present disclosure, the “salt” may include a hydrate that can be formed by absorbing water when the compound is left in the air. In the present disclosure, the "salt of compound" may also include a solvate which may be formed by the compound absorbing some 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。 As used herein, the term "radioactive halogen atom" refers to a radioactive isotope of a halogen atom. The radioactive halogen atoms include ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br and ⁷⁷ Br. As used herein, the term "halogen atom" refers to non-radioactive isotopes of halogen atoms. As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom is mentioned.

［式（Ｉ）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（Ｉ）で表される化合物又はその製薬上許容される塩に関する。
[Compound represented by formula (I)]
The present disclosure relates, in one or more embodiments, to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

式（Ｉ）中、
Ｘ¹は、
であって、Ｒ²は、放射性ハロゲン原子である。
Ｒ¹は、
である。
Ｒ³及びＲ⁵は、放射性ハロゲン原子であり、Ｒ⁴は、水素原子又は−ＣＨ₂−Ｒ⁶であって、Ｒ⁶は、４−メチルピペラジン−１−イル基、４−エチルピペラジン−１−イル基、４−ｎ−プロピルピペラジン−１−イル基、１−ピロリジニル基、ピペリジノ基、モルホリノ基、ジメチルアミノ基又はジエチルアミノ基である。
式（Ｉ）において、Ｒ²、Ｒ³、及びＲ⁵のいずれか一つは、放射性ハロゲン原子である。
Ｘ¹及びＲ¹において、波線を付した結合手は、式（Ｉ）との結合部分を示す。 In formula (I),
X ¹ is
And R ² is a radioactive halogen atom.
R ¹ is
It is.
R ³ and R ⁵ are a radioactive halogen atom, R ⁴ is a hydrogen atom or -CH ₂ -R ^{^6,} R ⁶ is 4-methylpiperazin-1-yl group, 4-ethyl piperazine -1 -Yl, 4-n-propylpiperazin-1-yl, 1-pyrrolidinyl, piperidino, morpholino, dimethylamino or diethylamino.
In formula (I), any one of R ² , R ³ and R ⁵ is a radioactive halogen atom.
In X ¹ and R ¹ , the wavy bond represents a bonding portion with the formula (I).

式（Ｉ）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）から（５）のいずれかで表される化合物が挙げられる。
上記式においてＲ³、Ｒ⁵及びＲ²は、放射性ハロゲン原子である。 As a compound represented by Formula (I), the compound represented by either of following formula (1) to (5) in one or several embodiment is mentioned.
In the above formulae, R ³ , R ⁵ and R ² are radioactive halogen atoms.

本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質のイメージングに用いることができる。本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Abl陽性腫瘍のイメージングに用いることができる。イメージングとしては、一又は複数の実施形態において、ＰＥＴやＳＰＥＣＴ等のインビボ核医学イメージングが挙げられる。その他には、本開示の放射性化合物は、一又は複数の実施形態において、ＣＭＬと診断された被検体におけるBcr-Abl阻害作用を有するチロシンキナーゼ阻害剤による治療効果の有効性の評価を行うための情報を得ることを目的としたイメージングに用いることができる。よって本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Abl阻害作用を有するチロシンキナーゼ阻害剤のコンパニオン診断薬として使用することができる。さらにその他には、本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Abl TKIが標的とする又は結合するタンパク質のイメージングに用いることができる。 The radioactive compounds of the present disclosure can be used for imaging Bcr-Abl protein in one or more embodiments. The radioactive compounds of the present disclosure can be used to image Bcr-Abl positive tumors in one or more embodiments. Imaging, in one or more embodiments, includes in vivo nuclear medicine imaging such as PET or SPECT. In addition, the radioactive compound of the present disclosure, in one or more embodiments, is for evaluating the efficacy of a therapeutic effect of a tyrosine kinase inhibitor having Bcr-Abl inhibitory activity in a subject diagnosed with CML. It can be used for imaging for the purpose of obtaining information. Therefore, the radioactive compound of the present disclosure can be used as a companion diagnostic agent for a tyrosine kinase inhibitor having Bcr-Abl inhibitory activity in one or more embodiments. Still further, the radioactive compounds of the present disclosure can be used, in one or more embodiments, for imaging of proteins targeted or bound by Bcr-Abl TKI.

したがって、本開示は、一又は複数の実施形態において、本開示の放射性化合物を含む、Bcr-Ablタンパク質イメージング用分子プローブ又はイメージング用組成物に関する。本開示において、イメージング用分子プローブ及びイメージング用組成物の形態は、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。 Thus, the present disclosure relates, in one or more embodiments, to a molecular probe or composition for imaging Bcr-Abl protein, comprising a radioactive compound of the present disclosure. In the present disclosure, the forms of the imaging molecular probe and the imaging composition are not particularly limited, but in one or more embodiments, solutions or powders may be mentioned. These may contain pharmaceutical additives such as carriers.

［式（Ｉ）で表される化合物の製造方法］
本開示の放射性化合物は、一又は複数の実施形態において、下記式（ＩＩ）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（ＩＩ）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。
[Method for Producing Compound Represented by Formula (I)]
The radioactive compound of the present disclosure can be produced by radioactively labeling a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof in one or more embodiments. Thus, the present disclosure relates, in one or more embodiments, to a method of producing a radioactive compound comprising radiolabeling a compound of formula (II) or a pharmaceutically acceptable salt thereof.

式（ＩＩ）中、
Ｘ²は、
であり、Ｒ⁸は、トリアルキルスタニル基、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。
Ｒ⁷は、
であって、
Ｒ⁹及びＲ¹⁰は、トリアルキルスタニル基、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、
Ｒ⁴は、水素原子又は−ＣＨ₂−Ｒ⁶であって、Ｒ⁶は、４−メチルピペラジン−１−イル基、４−エチルピペラジン−１−イル基、４−ｎ−プロピルピペラジン−１−イル基、１−ピロリジニル基、ピペリジノ基、モルホリノ基、ジメチルアミノ基又はジエチルアミノ基で
ある。
式（ＩＩ）において、Ｒ⁸、Ｒ⁹、及びＲ¹⁰のいずれか一つは、トリアルキルスタニル基、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。
Ｘ²及びＲ⁷において、波線を付した結合手は、式（Ｉ）との結合部分を示す。 In formula (II),
X ² is
R ⁸ is a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group, or a brosylate group.
R ⁷ is
And
R ⁹ and R ^{10 each} represent a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group, or a brosylate group;
R ⁴ is a hydrogen atom or -CH ₂ -R ⁶ , and R ⁶ is 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-n-propylpiperazine-1- Yl, 1-pyrrolidinyl, piperidino, morpholino, dimethylamino or diethylamino.
In formula (II), any one of R ⁸ , R ⁹ and R ¹⁰ is a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group.
In X ² and R ⁷ , the wavy bond represents a bonding portion with the formula (I).

式（ＩＩ）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（６）から（１０）のいずれかで表される化合物が挙げられる。
上記式において、Ｒ⁹、Ｒ¹⁰は、及びＲ⁸は、ハロゲン原子、トリアルキルスタニル基、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。 As a compound represented by Formula (II), the compound represented by either of following formula (6) to (10) is mentioned in one or several embodiment.
In the above formulae, R ⁹ and R ¹⁰ and R ⁸ are a halogen atom, trialkylstannyl group, nitro group, tosylate group, mesylate group, triflate group, nosylate group or brosylate group.

本開示は、一又は複数の実施形態において、式（６）で表される化合物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。本開示は、一又は複数の実施形態において、式（７）で表される化合物を放射性標識することを含む、式（２）で表される化合物の製造方法に関する。式（８）で表される化合物を放射性標識することを含む、式（３）で表される化合物の製造方法に関する。本開示は、一又は複数の実施形態において、式（９）で表される化合物を放射性標識することを含む、式（４）で表される化合物の製造方法に関する。本開示は、一又は複数の実施形態において、式（１０）で表される化合物を放射性標識することを含む、式（５）で表される化合物の製造方法に関する。 The present disclosure relates, in one or more embodiments, to a method of producing a compound represented by Formula (1), which comprises radiolabeling a compound represented by Formula (6). The present disclosure relates, in one or more embodiments, to a method of producing a compound represented by Formula (2), which comprises radiolabeling a compound represented by Formula (7). The present invention relates to a method for producing a compound represented by the formula (3), which comprises radioactively labeling a compound represented by the formula (8). The present disclosure relates, in one or more embodiments, to a method of producing a compound represented by Formula (4), which comprises radiolabeling a compound represented by Formula (9). The present disclosure relates, in one or more embodiments, to a method of producing a compound represented by Formula (5), which comprises radiolabeling a compound represented by Formula (10).

放射性標識は、一又は複数の実施形態において、［^123/124/125Ｉ］ＮａＩ等を用いて直接標識法により行うことができる。 Radioactive labeling can be performed by direct labeling in one or more embodiments using [ ^123/124/125 I] NaI or the like.

式（ＩＩ）で表される化合物又はその製薬上許容される塩は、上述のとおり、標識前駆体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（ＩＩ）で表される化合物又はその製薬上許容される塩（以下、「本開示の標識前駆体化合物」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、本開示の放射性化合物を合成するための標識前駆体として使用する本開示の標識前駆体化合物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、本開示の標識前駆体化合物を含む本開示の放射性化合物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。 The compound represented by the formula (II) or a pharmaceutically acceptable salt thereof can be used as a labeled precursor as described above. Accordingly, the present disclosure relates, in one or more embodiments, to a compound represented by Formula (II) or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the labeled precursor compound of the present disclosure”). The present disclosure also relates, in one or more embodiments, to a composition comprising a labeled precursor compound of the present disclosure for use as a labeled precursor for synthesizing a radioactive compound of the present disclosure. The present disclosure also relates, in one or more embodiments, to a kit for preparing a radioactive compound of the present disclosure that includes a labeled precursor compound 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.

［イメージング方法］
本開示は、一態様において、本開示の放射性化合物又は本開示の分子プローブが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（以下、「本開示のイメージング方法」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、又はBcr-Ablが発現している可能性のある対象等が挙げられる。 [Imaging method]
In one aspect, the present disclosure provides an imaging method (hereinafter referred to as “the imaging method of the present disclosure”) which comprises detecting the radioactive signal of the compound from the subject to which the radioactive compound of the present disclosure or the molecular probe of the present disclosure has been administered. Say). The subject is not particularly limited, and in one or more embodiments, a human, a non-human mammal, a cultured cell, a subject in which Bcr-Abl may be expressed, and the like can be mentioned.

本開示のイメージング方法は、一又は複数の実施形態において、Bcr-Ablの発現レベルの測定、Bcr-Abl陽性腫瘍のイメージング、及びＣＭＬと診断された被検体におけるBcr-Abl阻害作用を有するチロシンキナーゼ阻害剤による治療効果の有効性の評価等の用途に用いることができる。 The imaging method of the present disclosure, in one or more embodiments, measures the expression level of Bcr-Abl, imaging Bcr-Abl positive tumors, and tyrosine kinases having Bcr-Abl inhibitory activity in a subject diagnosed with CML It can be used for applications such as evaluation of the efficacy of therapeutic effects by inhibitors.

シグナルの検出は、一又は複数の実施形態において、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。 The detection of the signal can be appropriately determined according to the type of radioactive isotope contained in the compound of the present disclosure to be used in one or more embodiments, and can be performed using, for example, PET and SPECT.

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。 The present disclosure will be further described by way of the following examples, which are illustrative, and the present disclosure should not be construed as being limited to the following examples.

［機器及び試薬］
¹H(400 MHz or 500 MHz) NMRスペクトルはLNM-AL 400又は500（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）とサーベイメーター NDW-351（日立アロカメディカル株式会社）を使用した。
逆相HPLC用カラムには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を使用した。TLCにはsilica gel 60 F₂₅₄（メルク株式会社）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。
[¹²⁵I]NaIは、PerkinElmer社より購入し、[¹²³I]NH₄Iは、日本メジフィジックス社より購入した。オートウェルガンマカウンターWallac 1480 WIARD 3（PerkinElmer社）を用いて測定した。
SPECT/CTによる画像収集は、GMI FX-3300 Pre-Clinical Imaging Systemを用い、データ解析には3D OSEMを使用した。 [Devices and Reagents]
¹ H (400 MHz or 500 MHz) NMR spectra were measured by LNM-AL 400 or 500 (JEOL Ltd.), and tetramethylsilane was used as an internal standard substance.
The reverse phase HPLC used LC-20AD (Shimadzu Corporation), and used SPD-20A UV (Shimadzu Corporation) and the survey meter NDW-351 (Hitachi Aloka Medical Co., Ltd.) as a detector.
Use of COSMOSIL C18-AR-II (10 x 250 mm) (Nacalai Tesque, Inc.) for reverse phase HPLC column and (A) 0.1% TFA aqueous solution and (B) 0.1% TFA acetonitrile solution for mobile phase did. For TLC, silica gel 60 F ₂₅₄ (Merck Corporation) was used.
For purification by column chromatography, medium pressure column W-Prep 2XY (Yamazen Co., Ltd.) was used, and for the silica gel, Hi Flash silica gel 40 mm, 60 Å (Yamazen Co., Ltd.) was used.
[ ¹²⁵ I] NaI was purchased from PerkinElmer, and [ ¹²³ I] NH ₄ I was purchased from Japan Medi-Physics. It measured using the autowell gamma counter Wallac 1480 WIARD 3 (PerkinElmer).
Image acquisition by SPECT / CT used GMI FX-3300 Pre-Clinical Imaging System and 3D OSEM for data analysis.

（製造例１）
下記スキームに従って下記式で表されるIMT-1を製造した。
3-Iodo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid ethyl ester (242.6 mg, 0.71 mmol)に水(0.17 mL)、濃塩酸(0.34 mL)加えた後、100℃で3 時間攪拌した。その後、溶媒を溜去しトルエンを加え共沸させた後、乾固した。次に、塩化チオニル(1.5 mL, 21.0 mmol)、DMF (3 drops)を加え室温にて22時間攪拌した。その後、溶液を濃縮し、乾固した。次にTHF (2.13 mL)を入れ2-(5-Amino-2-methylanilino)-4-(3-pyridyl)pyrimidine (169.2 mg, 0.61 mmol)、トリエチルアミン (360.3 μL, 2.44 mmol)を加え室温にて2時間攪拌した。攪拌停止後、水と酢酸エチルを加え、飽和NaHCO₃水溶液、水で洗浄後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 5 : 1) により精製し、IMT-1 (212.0 mg, 0.37 mmol, 60%, pale yellow solid)を得た。
¹H NMR (500 MHz, DMSO-d₆) δ10.26 (1H, s), 9.28 (1H, d, J=2.0Hz), 9.00 (1H, s), 8.69 (1H, dd, J=5.0, 1.5Hz), 8.52 (1H, d, J=5.0Hz), 8.48 (1H, ddd, J=8.0, 2.0, 1.5Hz), 8.40 (1H, d, J=2.0Hz), 8.06 (1H, d, J=2.0Hz), 7.94 (1H, dd, J=8.0, 2.0Hz), 7.53 (1H, dd, J=8.0, 5.0Hz), 7.52 (1H, d, J=8.0Hz), 7.47 (1H, dd, J=8.0, 2.0Hz), 7.44 (1H, d, J=5.0Hz), 7.22 (1H, d, J=8.0Hz), 3.52 (2H, s), 2.55-2.27 (8H, m), 2.23 (3H, s), 2.18 (3H, s). (Production Example 1)
IMT-1 represented by the following formula was produced according to the following scheme.
Water (0.17 mL) and concentrated hydrochloric acid (0.34 mL) were added to 3-Iodo-4- (4-methylpiperidin-1-ylmethyl) benzoic acid ethyl ester (242.6 mg, 0.71 mmol), and the mixture was stirred at 100 ° C. for 3 hours . After that, the solvent was distilled off, toluene was added, and the mixture was azeotroped and then dried. Next, thionyl chloride (1.5 mL, 21.0 mmol) and DMF (3 drops) were added, and the mixture was stirred at room temperature for 22 hours. The solution was then concentrated to dryness. Next, THF (2.13 mL) was added and 2- (5-Amino-2-methylanilino) -4- (3-pyridine) pyrimidine (169.2 mg, 0.61 mmol), triethylamine (360.3 μL, 2.44 mmol) were added, and the mixture was at room temperature. Stir for 2 hours. After stopping the stirring, water and ethyl acetate were added, and the mixture was washed with saturated aqueous NaHCO ₃ solution and water, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain IMT-1 (212.0 mg, 0.37 mmol, 60%, pale yellow solid).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.26 (1 H, s), 9.28 (1 H, d, J = 2.0 Hz), 9.00 (1 H, s), 8.69 (1 H, dd, J = 5.0, 1.5 Hz), 8.52 (1 H, d, J = 5.0 Hz), 8. 48 (1 H, ddd, J = 8.0, 2.0, 1.5 Hz), 8. 40 (1 H, d, J = 2.0 Hz), 8.06 (1 H, d, J = 2.0 Hz), 7.94 (1 H, dd, J = 8.0, 2.0 Hz), 7.53 (1 H, dd, J = 8.0, 5.0 Hz), 7.52 (1 H, d, J = 8.0 Hz), 7.54 (1 H, 1 H, dd, J = 8.0, 2.0 Hz), 7.44 (1 H, d, J = 5.0 Hz), 7.22 (1 H, d, J = 8.0 Hz), 3.52 (2 H, s), 2.55-2.27 (8 H, m), 2.23 (3H, s), 2.18 (3H, s).

（製造例２）
下記スキームに従って下記式で表されるIMT-3を製造した。
m-ヨード安息香酸 (248.0 mg, 1.0 mmol)に塩化チオニル(1.43 mL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶液を濃縮し乾固した。そこへTHF (6.20 mL)を入れ、2-(5-Amino-2-methylanilino)-4-(3-pyridyl)pyrimidine (A) (100.0 mg, 0.36 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (62.7 L, 0.43 mmol)を加え室温にて2.5時間攪拌した。水と酢酸エチルを加え、水で洗浄後、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(クロロホルム : メタノール = 20 : 1) により精製しIMT-3 (183.5 mg, 0.36 mmol, quant., white solid)を得た。
¹H NMR (500 MHz, DMSO-d₆) δ10.27 (1H, br), 9.27 (1H, d, J=2.0Hz), 8.98 (1H, br), 8.68 (1H, dd, J=4.5, 2.0Hz), 8.51 (1H, d, J=5.0Hz), 8.46 (1H, dt, J=8.0, 2.0Hz), 8.28 (1H, t, J=2.0Hz), 8.06 (1H, d, J=2.0Hz), 7.97-7.92 (2H, m), 7.51 (1H, dd, J=8.0, 4.5Hz) 7.46 (1H, dd, J=8.5, 2.0Hz), 7.43 (1H, d, J=5.0Hz), 7.33 (1H, t, J=8.0Hz), 7.20(1H, d, J=8.0Hz), 2.21 (3H, s). (Production Example 2)
IMT-3 represented by the following formula was produced according to the following scheme.
Thionyl chloride (1.43 mL) and DMF (3 drops) were added to m-iodobenzoic acid (248.0 mg, 1.0 mmol) and stirred at room temperature for 17 hours. The solution was then concentrated to dryness. The THF (6.20 mL) was put there, 2- (5-Amino-2-methylanilino) -4- (3-pyridyl) pyrimidine (A) (100.0 mg, 0.36 mmol), DMAP (1.2 mg, 0.01 mmol), N, N-Diisopropylethylamine (62.7 L, 0.43 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Water and ethyl acetate were added, and after washing with water, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain IMT-3 (183.5 mg, 0.36 mmol, quant., White solid).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.27 (1 H, br), 9.27 (1 H, d, J = 2.0 Hz), 8. 98 (1 H, br), 8. 68 ( ¹ H, dd, J = 4.5, 2.0 Hz), 8.51 (1 H, d, J = 5.0 Hz), 8. 46 (1 H, dt, J = 8.0, 2.0 Hz), 8. 28 (1 H, t, J = 2.0 Hz), 8.06 (1 H, d, J = 2.0 Hz), 7.97-7.92 (2 H, m), 7.51 (1 H, dd, J = 8.0, 4.5 Hz) 7.46 (1 H, dd, J = 8.5, 2.0 Hz), 7.43 (1 H, d, J = 5.0 Hz ), 7.33 (1 H, t, J = 8.0 Hz), 7.20 (1 H, d, J = 8.0 Hz), 2.21 (3 H, s).

（製造例３）
下記スキームに従って下記式で表されるIMT-4を製造した。
m-ヨードニコチン酸 (94.6 mg, 0.38 mmol)に塩化チオニル(0.53 mL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶液を濃縮し乾固した。そこへTHF (5.5 mL)を入れ、2-(5-Amino-2-methylanilino)-4-(3-pyridyl)pyrimidine (A) (70.2 mg, 0.32 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (66 L, 0.38 mmol)を加え室温にて2時間攪拌した。水と酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で洗浄後、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(クロロホルム : メタノール = 10 : 1) により精製しIMT-4 (111.2 mg, 0.22 mmol, 68%, pale yellow solid)を得た。
¹H NMR (500 MHz, DMSO-d₆) δ10.43 (1H, s), 9.27 (1H, d, J=2.0Hz), 9.04 (1H, d, J=2.0Hz), 8.98 (2H, m), 8.68 (1H, dd, J=4.0, 2.0Hz), 8.64 (1H, t, J=2.0Hz), 8.51 (1H, d, J=5.0Hz), 8.47 (1H, dt, J=8.0, 2.0Hz), 8.06 (1H, d, J=2.0Hz), 7.52 (1H, dd, J=8.0, 4.0Hz), 7.46 (1H, dd, J=8.0, 2.0), 7.43 (1H, d, J=5.0Hz), 7.2 (1H, d, J=8.0Hz), 2.22 (3H, s). (Production Example 3)
IMT-4 represented by the following formula was produced according to the following scheme.
Thionyl chloride (0.53 mL) and DMF (3 drops) were added to m-iodonicotinic acid (94.6 mg, 0.38 mmol), and the mixture was stirred at room temperature for 17 hours. The solution was then concentrated to dryness. The THF (5.5 mL) was put there, 2- (5-Amino-2-methylanilino) -4- (3-pyridyl) pyrimidine (A) (70.2 mg, 0.32 mmol), DMAP (1.2 mg, 0.01 mmol), N, N-Diisopropylethylamine (66 L, 0.38 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain IMT-4 (111.2 mg, 0.22 mmol, 68%, pale yellow solid).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.43 (1 H, s), 9.27 (1 H, d, J = 2.0 Hz), 9.04 (1 H, d, J = 2.0 Hz), 8.98 (2 H, m ), 8.68 (1H, dd, J = 4.0, 2.0 Hz), 8.64 (1 H, t, J = 2.0 Hz), 8.51 (1 H, d, J = 5.0 Hz), 8.47 (1 H, dt, J = 8.0, 2.0 Hz), 8.06 (1 H, d, J = 2.0 Hz), 7.52 (1 H, dd, J = 8.0, 4.0 Hz), 7.46 (1 H, dd, J = 8.0, 2.0), 7.43 (1 H, d, J = 5.0 Hz), 7.2 (1 H, d, J = 8.0 Hz), 2.22 (3 H, s).

（製造例４）
下記スキームに従って下記式で表されるIMT-5を製造した。
4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (107.2 mg, 0.35 mmol)に塩化チオニル(1.0 mL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶液を濃縮し、乾固した。その後、THF (5.0 mL)を入れ、3-Iodo-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (B) (96.0 mg, 0.29 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (60.6 μL, 0.35 mmol)を加え室温にて17時間攪拌した。水と酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で洗浄後、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(クロロホルム : メタノール = 5 : 1) により精製しIMT-5 (60.2 mg, 0.097 mmol, 33%, white solid)を得た。
¹H NMR (500 MHz, DMSO-d₆) δ10.23 (1H, s), 9.26 (1H, d, J=2.0Hz), 9.14 (1H, s), 8.68 (1H, d, J=5.0Hz), 8.53 (1H, d, J=5.0Hz), 8.43 (1H, d, J=8.0Hz), 8.33 (1H, d, J=2.0Hz), 8.25 (1H, s), 7.79 (1H, d, J=8.0Hz), 7.70 (1H, d, J=8.0Hz), 7.50 (1H, dd, J=8.0, 5.0Hz), 7.47 (1H, d, J=5.0Hz), 7.40 (1H, d, J=8.0Hz), 7.32 (1H, d, J=8.0Hz), 3.43 (2H, s), 2.55-2.36 (8H, m), 2.33 (3H, s), 2.24 (3H, s). (Production Example 4)
IMT-5 represented by the following formula was produced according to the following scheme.
Thionyl chloride (1.0 mL) and DMF (3 drops) are added to 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid (107.2 mg, 0.35 mmol), and it is 17 at room temperature. Stir for hours. The solution was then concentrated to dryness. After that, THF (5.0 mL) was added and 3-Iodo-4- (4-methyl-piperazin-1-ylmethyl) -phenylamine (B) (96.0 mg, 0.29 mmol), DMAP (1.2 mg, 0.01 mmol), N Then, N-Diisopropylethylamine (60.6 μL, 0.35 mmol) was added and the mixture was stirred at room temperature for 17 hours. Water and ethyl acetate were added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain IMT-5 (60.2 mg, 0.097 mmol, 33%, white solid).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.23 (1 H, s), 9.26 (1 H, d, J = 2.0 Hz), 9.14 (1 H, s), 8.68 (1 H, d, J = 5.0 Hz ), 8.53 (1H, d, J = 5.0 Hz), 8.43 (1H, d, J = 8.0 Hz), 8.33 (1H, d, J = 2.0 Hz), 8.25 (1H, s), 7.79 (1H, d) , J = 8.0 Hz), 7.70 (1 H, d, J = 8.0 Hz), 7. 50 (1 H, dd, J = 8.0, 5.0 Hz), 7. 47 (1 H, d, J = 5.0 Hz), 7. 40 (1 H, d) , J = 8.0 Hz), 7.32 (1 H, d, J = 8.0 Hz), 3.43 (2 H, s), 2.55-2.36 (8 H, m), 2.33 (3 H, s), 2.24 (3 H, s).

（製造例５）
下記スキームに従って下記式で表されるIMT-6を製造した。
化合物E (97.0 mg), N-ヨードスクシンイミド (91.5 mg), AgNO₃ (5.7 mg)をTHF(3 mL)に溶解させ、室温で撹拌させた。一晩撹拌後、1 M Na₂SO₃溶液と飽和炭酸水素ナトリウム水溶液加え、CHCl₃で3回抽出し、硫酸ナトリウムで脱水しろ過した。得られたろ液を減圧留去し、シリカゲルカラムクロマトグラフィー(ヘキサン: 酢酸エチル=1: 1→酢酸エチル) により精製し化合物 F(116.1 mg, 黄色固体)を得た。
¹H NMR (500 MHz, CDCl₃) δ9.30-9.20 (m, 1H), 8.73 (s, 1H), 8.56-8.50 (m, 1H), 8.43-8.25 (m, 2H), 7.50-7.41 (m, 1H), 7. 25-7.10 (m, 2H), 7.00-6.91 (s, 1H), 2.37 (s, 3H).
化合物F (77.0 mg), 化合物G (55.9 mg)をDMF(1 mL)に溶解させ、CuI (1.8 mg), Et₃N (53.1 uL)のTHF溶液 (1 mL)を加え室温で撹拌させた。一晩撹拌後、飽和炭酸水素ナトリウム水溶液加え、CHCl₃で3回抽出し、硫酸ナトリウムで脱水しろ過した。得られたろ液を減圧留去し、シリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 99: 1→95:5) により精製し IMT-6(61.4 mg, 淡黄色固体)を得た。
¹H NMR (500 MHz, CDCl₃) δ9.27 (s, 1H), 8.96 (s, 1H), 8.75-8.68 (m, 1H), 8.59-8.50 (m, 2H), 8.08 (d, J=8.5 Hz, 1H), 7.87 (s,1H), 7.78-7.73 (m, 1H), 7. 73-7.67 (m, 1H), 7.46 (dd, J=4.5, 8.0 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.21 (d, J=5.5 Hz, 1H), 7.08 (s, 1H), 3.77 (s, 2H), 2.70-2.39 (m, 11H), 2.33 (s, 3H). (Production Example 5)
IMT-6 represented by the following formula was produced according to the following scheme.
Compound E (97.0 mg), N-iodosuccinimide (91.5 mg), AgNO ₃ (5.7 mg) were dissolved in THF (3 mL) and stirred at room temperature. After stirring overnight, 1 M Na ₂ SO ₃ solution and saturated aqueous sodium hydrogen carbonate solution were added, extracted three times with CHCl ₃ , dried over sodium sulfate and filtered. The obtained filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to obtain Compound F (116.1 mg, yellow solid).
¹ H NMR (500 MHz, CDCl ₃ ) δ 9.30-9.20 (m, ¹ H), 8. 73 (s, 1 H), 8.56-8. 50 (m, 1 H), 8.43-8. 25 (m, 2 H), 7.50-7.41 ( m, 1 H), 7. 25-7. 10 (m, 2 H), 7.00-6. 91 (s, 1 H), 2. 37 (s, 3 H).
Compound F (77.0 mg) and Compound G (55.9 mg) were dissolved in DMF (1 mL), CuI (1.8 mg), Et ₃ N (53.1 uL) in THF (1 mL) was added, and the mixture was stirred at room temperature . After stirring overnight, saturated aqueous sodium hydrogen carbonate solution was added, extracted three times with CHCl ₃ , dried over sodium sulfate and filtered. The obtained filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1 → 95: 5) to obtain IMT-6 (61.4 mg, pale yellow solid).
¹ H NMR (500 MHz, CDCl ₃ ) δ 9.27 (s, ¹ H), 8. 96 (s, 1 H), 8. 75-8. 68 (m, 1 H), 8. 59-8. 50 (m, 2 H), 8.08 (d, J = 8.5 Hz, 1 H), 7. 87 (s, 1 H), 7. 78-7. 73 (m, 1 H), 7. 73-7. 67 (m, 1 H), 7.46 (dd, J = 4.5, 8.0 Hz, 1 H), 7. 36 (d , J = 7.5 Hz, 1 H), 7.21 (d, J = 5.5 Hz, 1 H), 7.08 (s, 1 H), 3.77 (s, 2 H), 2.70-2.39 (m, 11 H), 2.33 (s, 3 H) .

（製造例６）
下記スキームに従って下記式で表されるIMT-7を製造した。
IMT-6 (41.0 mg), AgF (36.6 mg), N,N,N',N'-テトラメチルエチレンジアミン (4.3 uL)をtoluene (0.58 mL)に溶解させ、120℃に加熱した。一晩撹拌後、飽和炭酸水素ナトリウム水溶液加え、CHCl₃で3回抽出し、硫酸ナトリウムで脱水しろ過した。得られたろ液を減圧留去し、シリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 99: 1→95:5) により精製し IMT-7 (18.1 mg, 淡黄色固体)を得た。
¹H NMR (500 MHz, CDCl₃) δ9.30 (d, J=2.0 Hz, 1H), 8.95 (s, 1H), 8.73 (dd, J=1.5, 4.5 Hz, 1H), 8.58-8.50 (m, 2H), 8.08 (d, J=8.0 Hz, 1H), 8.04 (s,1H), 7.93 (d, J=8.5 Hz, 1H), 7. 59 (d, J=8.5 Hz, 1H), 7.46 (dd, J=4.5, 8.0 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.23 (d, J=5.5 Hz, 1H), 7.10 (s, 1H), 3.75 (s, 2H), 2.78-2.38 (m, 11H), 2.33 (s, 3H). (Production Example 6)
IMT-7 represented by the following formula was manufactured according to the following scheme.
IMT-6 (41.0 mg), AgF (36.6 mg), N, N, N ', N'-tetramethylethylenediamine (4.3 uL) was dissolved in toluene (0.58 mL) and heated to 120 ° C. After stirring overnight, saturated aqueous sodium hydrogen carbonate solution was added, extracted three times with CHCl ₃ , dried over sodium sulfate and filtered. The obtained filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1 → 95: 5) to obtain IMT-7 (18.1 mg, pale yellow solid).
¹ H NMR (500 MHz, CDCl ₃ ) δ 9.30 (d, J = 2.0 Hz, 1 H), 8.95 (s, 1 H), 8.73 (dd, J = 1.5, 4.5 Hz, 1 H), 8.58-8.50 (m , 2H), 8.08 (d, J = 8.0 Hz, 1 H), 8.04 (s, 1 H), 7. 93 (d, J = 8.5 Hz, 1 H), 7. 59 (d, J = 8.5 Hz, 1 H), 7.46 (dd, J = 4.5, 8.0 Hz, 1 H), 7. 35 (d, J = 7.5 Hz, 1 H), 7.23 (d, J = 5.5 Hz, 1 H), 7. 10 (s, 1 H), 3. 75 (s, 2 H) , 2.78-2.38 (m, 11 H), 2.33 (s, 3 H).

［標識前駆体合成］
標識前駆体となるIMT-1 precursor、IMT-3 precursor、IMT-4 precursor及びIMT-5 precursorを合成した。 [Labeled precursor synthesis]
IMT-1 precursor, IMT-3 precursor, IMT-4 precursor and IMT-5 precursor, which are labeling precursors, were synthesized.

（製造例７）
下記スキームに従って下記式で表されるIMT-1 precursorを製造した。
3-Bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid ethyl ester (198.3 mg, 0.51 mmol)に水(0.12 mL)、濃塩酸(0.24 mL)を加え100℃で2 時間攪拌した。その後、溶媒を溜去しトルエンを加え共沸させた後、乾固した。次に、塩化チオニル(0.74 mL, 10.2 mmol)、DMF (3 drops)を加え室温にて22時間攪拌した。その後、溶液を濃縮し乾固した。乾固した中間体(122.0 mg, 0.44 mmol)をナスフラスコに入れ、THF (1.53 mL)を加え、2-(5-Amino-2-methylanilino)-4-(3-pyridyl)pyrimidine (A) (193.1 mg, 0.51 mmol)、トリエチルアミン (0.13 mL, 0.88 mmol)を加えて室温にて2時間攪拌した。反応終了後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 5 : 1) により精製しIMT-1 precursor (287.0 mg, 0.46 mmol, quant. pale yellow solid)を得た。
¹H NMR (500 MHz, DMSO-d₆) δ10.26 (1H, s), 9.26 (1H, d, J=2.5Hz), 8.98 (1H, s), 8.68 (1H, dd, J=5.0, 2.0Hz), 8.50 (1H, d, J=5.0Hz), 8.46 (1H, ddd, J=8.0, 2.5, 2.0Hz), 8.16 (1H, d, J=1.5Hz), 8.06 (1H, d, J=2.0Hz), 7.93 (1H, dd, J=8.0, 1.5Hz), 7.59 (1H, d, J=8.0Hz), 7.51 (1H, dd, J=8.0, 5.0Hz) 7.46 (1H, dd, J=8.0, 2.0Hz), 7.42 (1H, d, J=5.0Hz), 7.20(1H, d, J=8.0Hz), 3.58 (2H, s), 2.51-2.25 (8H, m), 2.21 (3H, s), 2.15 (3H, s). (Production Example 7)
An IMT-1 precursor represented by the following formula was produced according to the following scheme.
Water (0.12 mL) and concentrated hydrochloric acid (0.24 mL) were added to 3-Bromo-4- (4-methylpiperidin-1-ylmethyl) benzoic acid ethyl ester (198.3 mg, 0.51 mmol), and the mixture was stirred at 100 ° C. for 2 hours. After that, the solvent was distilled off, toluene was added, and the mixture was azeotroped and then dried. Next, thionyl chloride (0.74 mL, 10.2 mmol) and DMF (3 drops) were added, and the mixture was stirred at room temperature for 22 hours. The solution was then concentrated to dryness. The dried intermediate (122.0 mg, 0.44 mmol) is placed in an eggplant flask, THF (1.53 mL) is added, and 2- (5-Amino-2-methylanilino) -4- (3-pyridinyl) pyrimidine (A) ( 193.1 mg, 0.51 mmol) and triethylamine (0.13 mL, 0.88 mmol) were added and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain IMT-1 precursor (287.0 mg, 0.46 mmol, quant. Pale yellow solid).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.26 (1 H, s), 9.26 (1 H, d, J = 2.5 Hz), 8.98 (1 H, s), 8.68 (1 H, dd, J = 5.0, 2.0 Hz), 8.50 (1 H, d, J = 5.0 Hz), 8. 46 (1 H, ddd, J = 8.0, 2.5, 2.0 Hz), 8. 16 (1 H, d, J = 1.5 Hz), 8.06 (1 H, d, J = 2.0 Hz), 7.93 (1 H, dd, J = 8.0, 1.5 Hz), 7.59 (1 H, d, J = 8.0 Hz), 7.51 (1 H, dd, J = 8.0, 5.0 Hz) 7.46 (1 H, dd , J = 8.0, 2.0 Hz), 7.42 (1 H, d, J = 5.0 Hz), 7. 20 (1 H, d, J = 8.0 Hz), 3.58 (2 H, s), 2.51-2.25 (8 H, m), 2.21 (3H, s), 2.15 (3H, s).

（製造例８）
下記スキームに従って下記式で表されるIMT-3 precursorを製造した。
m-ブロモ安息香酸 (201.0 mg, 1.0 mmol)に塩化チオニル(1.43 mL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶液を濃縮し乾固した。乾固した中間体 (94.4 mg, 0.43 mmol)にTHF (6.20 mL)を入れ、2-(5-Amino-2-methylanilino)-4-(3-pyridyl)pyrimidine (A) (100.0 mg, 0.36 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (62.7 μL, 0.43 mmol)を加え室温にて2.5時間攪拌した。水と酢酸エチルを加え、水で洗浄後、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(クロロホルム : メタノール = 20 : 1) により精製しIMT-3 precursor (33.2 mg, 0.072 mmol, 20%, pale yellow solid)を得た。
¹H NMR (500 MHz, DMSO-d₆) δ10.30 (1H, s), 9.27 (1H, d, J=2.0Hz), 8.97 (1H, s), 8.68 (1H, dd, J=5.0, 1.5Hz), 8.51 (1H, d, J=5.0Hz), 8.46 (1H, dt, J=8.0, 2.0Hz), 8.13 (1H, t, J=2.0Hz), 8.07 (1H, d, J=2.0Hz), 7.94 (1H, d, J=8.0Hz), 7.78 (1H, d, J=8.0Hz), 7.51 (1H, dd, J=8.0, 5.0Hz) 7.49 (1H, t, J=8.0Hz), 7.46 (1H, dd, J=8.0, 2.0Hz), 7.43(1H, d, J=5.0Hz), 7.21(1H, d, J=8.0Hz), 2.22 (3H, s). Production Example 8
An IMT-3 precursor represented by the following formula was produced according to the following scheme.
Thionyl chloride (1.43 mL) and DMF (3 drops) were added to m-bromobenzoic acid (201.0 mg, 1.0 mmol) and stirred at room temperature for 17 hours. The solution was then concentrated to dryness. THF (6.20 mL) is added to the dried intermediate (94.4 mg, 0.43 mmol), and 2- (5-Amino-2-methylanilino) -4- (3-pyridinyl) pyrimidine (A) (100.0 mg, 0.36 mmol) ), DMAP (1.2 mg, 0.01 mmol) and N, N-diisopropylethylamine (62.7 μL, 0.43 mmol) were added and stirred at room temperature for 2.5 hours. Water and ethyl acetate were added, and after washing with water, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain IMT-3 precursor (33.2 mg, 0.072 mmol, 20%, pale yellow solid).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.30 (1 H, s), 9.27 (1 H, d, J = 2.0 Hz), 8.97 (1 H, s), 8.68 (1 H, dd, J = 5.0, 1.5 Hz), 8.51 (1 H, d, J = 5.0 Hz), 8. 46 (1 H, dt, J = 8.0, 2.0 Hz), 8.13 (1 H, t, J = 2.0 Hz), 8.07 (1 H, d, J = 2.0 Hz), 7.94 (1 H, d, J = 8.0 Hz), 7. 78 (1 H, d, J = 8.0 Hz), 7.51 (1 H, dd, J = 8.0, 5.0 Hz) 7.49 (1 H, t, J = 8.0) Hz), 7.46 (1 H, dd, J = 8.0, 2.0 Hz), 7.43 (1 H, d, J = 5.0 Hz), 7.21 (1 H, d, J = 8.0 Hz), 2.22 (3 H, s).

（製造例９）
下記スキームに従って下記式で表されるIMT-4 precursorを製造した。
m-ブロモニコチン酸 (202.0 mg, 1.0 mmol)に塩化チオニル(1.43 mL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶液を濃縮し乾固した。乾固した中間体(94.4 mg, 0.43 mmol)にTHF (6.20 mL)を入れ、2-(5-Amino-2-methylanilino)-4-(3-pyridyl)pyrimidine (A) (100.0 mg, 0.36 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (62.7 μL, 0.43 mmol)を加え室温にて2時間攪拌した。水と酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で洗浄後、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(クロロホルム : メタノール = 20 : 1) により精製しIMT-4 precursor (42.3 mg, 0.092 mmol, 26%, white solid)を得た。
¹H NMR (500 MHz, DMSO-d₆) δ10.46 (1H, s), 9.27 (1H, d, J=2.0Hz), 9.05 (1H, d, J=2.0Hz), 9.00 (1H, s), 8.89 (1H, d, J=2.0Hz), 8.68 (1H, dd, J=5.0, 2.0Hz), 8.53 (1H, t, J=2.0Hz), 8.51 (1H, d, J=5.0Hz), 8.47 (1H, dt, J=8.0, 2.0, Hz), 8.07 (1H, d, J=2.0Hz), 7.53 (1H, dd, J=8.0, 5.0Hz), 7.46 (1H, dd, J=8.0, 2.0Hz), 7.43 (1H, d, J=5.0Hz), 7.23(1H, d, J=8.0Hz), 2.22 (3H, s). Production Example 9
An IMT-4 precursor represented by the following formula was produced according to the following scheme.
Thionyl chloride (1.43 mL) and DMF (3 drops) were added to m-bromonicotinic acid (202.0 mg, 1.0 mmol) and stirred at room temperature for 17 hours. The solution was then concentrated to dryness. THF (6.20 mL) is added to the dried intermediate (94.4 mg, 0.43 mmol), and 2- (5-Amino-2-methylanilino) -4- (3-pyridine) pyrimidine (A) (100.0 mg, 0.36 mmol) ), DMAP (1.2 mg, 0.01 mmol) and N, N-diisopropylethylamine (62.7 μL, 0.43 mmol) were added and stirred at room temperature for 2 hours. Water and ethyl acetate were added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain IMT-4 precursor (42.3 mg, 0.092 mmol, 26%, white solid).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.46 (1 H, s), 9.27 (1 H, d, J = 2.0 Hz), 9.05 (1 H, d, J = 2.0 Hz), 9.00 (1 H, s ), 8.89 (1H, d, J = 2.0 Hz), 8.68 (1 H, dd, J = 5.0, 2.0 Hz), 8.53 (1 H, t, J = 2.0 Hz), 8.51 (1 H, d, J = 5.0 Hz) ), 8.47 (1 H, dt, J = 8.0, 2.0, Hz), 8.07 (1 H, d, J = 2.0 Hz), 7.53 (1 H, dd, J = 8.0, 5.0 Hz), 7.46 (1 H, dd, J = 8.0, 2.0 Hz), 7.43 (1 H, d, J = 5.0 Hz), 7.23 (1 H, d, J = 8.0 Hz), 2.22 (3 H, s).

（製造例１０）
下記スキームに従って下記式で表されるIMT-5 precursorを製造した。
4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (107.2 mg, 0.35 mmol)を入れ、塩化チオニル(0.50 mL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶液を濃縮乾固した。その後、THF (5.0 mL)を入れ、3-Bromo-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (C) (82.4 mg, 0.29 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (60.6 μL, 0.35 mmol)を加え室温にて2.5時間攪拌した。水と酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で洗浄後、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(クロロホルム : メタノール = 5 : 1) により精製しIMT-5 precursor (43.0 mg, 0.075 mmol, 25%, white solid)を得た。
¹H NMR (500 MHz, DMSO-d₆) δ10.33 (1H, s), 10.09 (1H, s), 9.30 (1H, d, J=2.0Hz), 8.76 (1H, d, J=5.0Hz), 8.74 (1H, dd, J=5.0, 1.5Hz), 8.51 (1H, ddd, J=8.5, 2.0, 1.5Hz), 8.09 (1H, d, J=2.0Hz), 8.02-7.98 (2H, m), 7.84 (1H, d, J=2.0Hz), 7.74 (1H, dd, J=8.5, 2.0Hz), 7.59-7.55 (2H, m), 7.39 (1H, d, J=8.0Hz), 3.47 (2H, s), 2.55-2.24 (8H, m), 2.16 (3H, s), 2.13 (3H, s). Production Example 10
An IMT-5 precursor represented by the following formula was produced according to the following scheme.
Add 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid (107.2 mg, 0.35 mmol), add thionyl chloride (0.50 mL), DMF (3 drops) and bring to room temperature The mixture was stirred for 17 hours. The solution was then concentrated to dryness. After that, THF (5.0 mL) was added, 3-Bromo-4- (4-methyl-piperazin-1-ylmethyl) -phenylamine (C) (82.4 mg, 0.29 mmol), DMAP (1.2 mg, 0.01 mmol), N , N-Diisopropylethylamine (60.6 μL, 0.35 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Water and ethyl acetate were added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain IMT-5 precursor (43.0 mg, 0.075 mmol, 25%, white solid).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.33 (1 H, s), 10.09 (1 H, s), 9.30 (1 H, d, J = 2.0 Hz), 8. 76 (1 H, d, J = 5.0 Hz ), 8.74 (1H, dd, J = 5.0, 1.5 Hz), 8.51 (1H, ddd, J = 8.5, 2.0, 1.5 Hz), 8.09 (1H, d, J = 2.0 Hz), 8.02-7.98 (2H, 2H, m), 7.84 (1 H, d, J = 2.0 Hz), 7.74 (1 H, dd, J = 8.5, 2.0 Hz), 7.59-7.55 (2 H, m), 7.39 (1 H, d, J = 8.0 Hz), 3.47 (2H, s), 2.55-2.24 (8H, m), 2.16 (3H, s), 2.13 (3H, s).

（製造例１１）
下記スキームに従って下記式で表されるIMT-5 precursor（スズ化合物）を製造した。
化合物C (235 mg)を1,4-ジオキサン溶液（8 mL）に溶解させ、(SnMe₃)₂ (523 uL)、Pd(PPh₃)₄ (4191.8 mg)を加えて、120℃で撹拌させた。一晩撹拌後、溶媒を減圧留去し、得られた残渣をクロロホルムに溶解させた。飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄後、硫酸ナトリウムで脱水しろ過した。得られたろ液を減圧留去し、シリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 95 : 5→9:1) により精製し化合物D (126.4 mg, 淡黄色固体)を得た。
¹H NMR (500 MHz, CDCl₃) δ 7.00 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2.5H), 6.57 (dd, J = 2.5, 8.0 Hz, 1H), 3.59 (s, 1H), 3.34 (s, 1H), 2.41 (brs, 6H), 2.28 (s, 3H), 1.62 (brs, 2H), 0.26 (s, 9H).
4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (16.6 mg)と化合物D (20 mg)をCH₂Cl₂ (0.5 mL)に溶解させ、N,N-ジイソプロピルアミン (14 uL)、N,N−ジメチル-4-アミノピリジン (3.3 mg)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩 (15.5 mg)を加え室温で撹拌させた。一晩撹拌後、飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、硫酸ナトリウムで脱水しろ過した。得られたろ液を減圧留去し、シリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 95 : 5→9:1) により精製し IMT-5 precursor（スズ化合物）(34.6 mg, 白色固体)を得た。
¹H NMR (500 MHz, CDCl₃) δ9.23 (s, 1H), 8.81 (s, 1H), 8.70 (d, J=4.5 Hz, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 7.93 (s,1H), 7.72-7.63 (m,1H), 7.63-7.58 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.40 (dd, J=4.5, 8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.30-7.18 (m, 2H), 7.11 (s, 1H), 3.44 (s, 2H), 2.45 (brs, 9H), 2.29 (s, 3H), 7.11 (s, 1H), 1.92 (brs, 2H), 0.30 (s, 9H). (Production Example 11)
An IMT-5 precursor (tin compound) represented by the following formula was produced according to the following scheme.
Compound C (235 mg) is dissolved in 1,4-dioxane solution (8 mL), (SnMe ₃ ) ₂ (523 uL), Pd (PPh ₃ ) ₄ (4191.8 mg) is added, and the mixture is stirred at 120 ° C. The After stirring overnight, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in chloroform. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate and filtered. The obtained filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5 → 9: 1) to obtain Compound D (126.4 mg, pale yellow solid).
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.00 (d, J = 8.0 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 2.5 H), 6.57 (dd, J = 2.5, 8.0 Hz, 1 H), 3.59 (s, 1 H), 3.34 (s, 1 H), 2.41 (brs, 6 H), 2. 28 (s, 3 H), 1.62 (brs, 2 H), 0.26 (s, 9 H).
Dissolve 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid (16.6 mg) and compound D (20 mg) in CH ₂ Cl ₂ (0.5 mL) Add N-diisopropylamine (14 uL), N, N-dimethyl-4-aminopyridine (3.3 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (15.5 mg) and stir at room temperature The After stirring overnight, it was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate and filtered. The obtained filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform: methanol = 95: 5 → 9: 1) to obtain IMT-5 precursor (tin compound) (34.6 mg, white solid).
¹ H NMR (500 MHz, CDCl ₃ ) δ 9.23 (s, 1 H), 8.81 (s, ¹ H), 8. 70 (d, J = 4.5 Hz, 1 H), 8.53 (d, J = 5.0 Hz, 1 H), 8.45 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 7.72-7.63 (m, 1 H), 7.63-7.58 (m, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.40 (dd, J = 4.5, 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.30-7.18 (m, 2 H), 7.11 (s, 1 H), 3.44 (s, 2 H), 2.45 ( brs, 9H), 2.29 (s, 3H), 7.11 (s, 1 H), 1. 92 (brs, 2 H), 0.30 (s, 9 H).

［放射化学合成］
放射性標識化合物である[^123/125I]IMT-1、[¹²⁵I]IMT-3、[¹²⁵I]IMT-4及び[^123/125I]IMT-5を合成した。 [Radiochemical synthesis]
^Radiolabeled compounds [ ¹²³ / ^125I ] IMT-1, [ ^125I ] IMT-3, [ ^125I ] IMT-4 and [ ¹²³ / ^125I ] IMT-5 were synthesized.

（製造例１２）
下記スキームに従って下記式で表される[¹²⁵I]IMT-1を製造した。
IMT-1 precursor (2.08 mg)、CuSO₄・5H₂O (6.75 mg)、(NH₄)₂SO₄ (5.00 mg)を反応バイアルへ入れ、MeOH (200 μL)、H₂O (200 μL)に懸濁させ、[¹²⁵I]NaI (232 μCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (200 μL)、MeOH (200 μL)、MeCN (200 μL)で反応物を洗浄した後、MeCN (200 μL)、H₂O (200 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 70% (A) and 30% (B), flow rate 1.0 mL/min, λ = 220, 254 nm, Rt = 22-23 min)にて精製し、[¹²⁵I]IMT-1を放射化学的収率72%、放射化学的純度>99%で得た。 Production Example 12
[ ^125I ] IMT-1 represented by the following formula was produced according to the following scheme.
IMT-1 precursor (2.08 mg) , CuSO 4 · 5H 2 O (6.75 mg), (NH 4) 2 SO 4 and (5.00 mg) were placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) And after adding [ ¹²⁵ I] NaI (232 μCi), heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction with MeCN (200 μL), MeOH (200 μL), MeCN (200 μL), MeCN (200 μL), H ₂ O (200 μL) is added and the solution is passed through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 70% (A) and 30% (B), flow rate 1.0 mL / min, λ = 220, 254 nm, Rt = 22-23 min) Purification gave [ ¹²⁵ I] IMT-1 in 72% radiochemical yield,> 99% radiochemical purity.

（製造例１３）
下記スキームに従って下記式で表される[¹²⁵I]IMT-3を製造した。
IMT-3 precursor (1.37 mg)、CuSO₄・5H₂O (4.28 mg)、(NH₄)₂SO₄ (4.48 mg)を反応バイアルへ入れ、MeOH (200 μL)、H₂O (200 μL)に懸濁させ、[¹²⁵I]NaI (212 μCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (200 μL)、MeCN (200 μL)、MeOH (200 μL)で反応物を洗浄した後、MeCN (200 μL)、H₂O (200 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 50% (A) and (B), flow rate 1.0 mL/min, λ = 220, 254 nm, Rt = 23.5-24.5 min)にて精製し、[¹²⁵I]IMT-3を放射化学的収率24%、放射化学的純度>99%で得た。 Production Example 13
[ ^125I ] IMT-3 represented by the following formula was produced according to the following scheme.
IMT-3 precursor (1.37 mg) , CuSO 4 · 5H 2 O (4.28 mg), (NH 4) 2 SO 4 and (4.48 mg) were placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) And after adding [ ¹²⁵ I] NaI (212 μCi), heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. Wash the reaction with MeCN (200 μL), MeCN (200 μL), MeOH (200 μL), add MeCN (200 μL), H ₂ O (200 μL), pass the solution through Cosmonicefilter S, reverse phase Purified by HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 50% (A) and (B), flow rate 1.0 mL / min, λ = 220, 254 nm, Rt = 23.5-24.5 min) , [ ¹²⁵ I] IMT-3 were obtained with a radiochemical yield of 24%, radiochemical purity> 99%.

（製造例１４）
下記スキームに従って下記式で表される[¹²⁵I]IMT-4を製造した。
IMT-4 precursor (1.84 mg)、CuSO₄・5H₂O (2.34 mg)、(NH₄)₂SO₄ (2.72 mg)を反応バイアルへ入れ、MeOH (200 μL)、H₂O (200 μL)に懸濁させ、[¹²⁵I]NaI (191 μCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeOH (200 μL)、MeCN (200 μL)で反応物を洗浄した後、MeCN (200 μL)、H₂O (200 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 60% (A) and 40% (B), flow rate 1.0 mL/min, λ = 220, 254 nm, Rt = 23.5-24.5 min)にて精製し、[¹²⁵I]IMT-4を放射化学的収率8%、放射化学的純度>99%で得た。 Production Example 14
According to the following scheme, [ ¹²⁵ I] IMT-4 represented by the following formula was produced.
IMT-4 precursor (1.84 mg) , CuSO 4 · 5H 2 O (2.34 mg), (NH 4) 2 SO 4 and (2.72 mg) were placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) The suspension was suspended in water, added with [ ¹²⁵ I] NaI (191 μCi), and heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction with MeOH (200 μL), MeCN (200 μL) MeCN (200 μL), H ₂ O (200 μL) is added and the solution is passed through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR -II, 10 x 250 mm, and purified by eluent 60% (A) and 40 % (B), flow rate 1.0 mL / min, λ = 220, 254 nm, Rt = 23.5-24.5 min), [125 I IMT-4 was obtained in radiochemical yield 8%, radiochemical purity> 99%.

（製造例１５）
下記スキームに従って下記式で表される[¹²⁵I]IMT-5を製造した。
IMT-5 precursor (1.63 mg)、CuSO₄・5H₂O (2.25 mg)、(NH₄)₂SO₄ (2.45 mg)を反応バイアルへ入れ、MeOH (200 μL)、H₂O (200 μL)に懸濁させ、[¹²⁵I]NaI (364 μCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (400 μL)、MeOH (400 μL)で反応物を洗浄した後、MeCN (200 μL)、H₂O (200 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 75% (A) and 25% (B), flow rate 1.5 mL/min, λ = 220, 254 nm, Rt = 21.0-22.5 min)にて精製し、[¹²⁵I]IMT-5を放射化学的収率52%、放射化学的純度>99%で得た。 Production Example 15
[ ^125I ] IMT-5 represented by the following formula was produced according to the following scheme.
IMT-5 precursor (1.63 mg) , CuSO 4 · 5H 2 O (2.25 mg), (NH 4) 2 SO 4 and (2.45 mg) were placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) And after adding [ ¹²⁵ I] NaI (364 μCi), heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction with MeCN (400 μL), MeOH (400 μL), MeCN (200 μL), H ₂ O (200 μL) is added and the solution is passed through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR -II, 10 x 250 mm, and purified by eluent 75% (A) and 25 % (B), flow rate 1.5 mL / min, λ = 220, 254 nm, Rt = 21.0-22.5 min), [125 I IMT-5 was obtained in radiochemical yield 52%, radiochemical purity> 99%.

（製造例１６）
下記スキームに従って下記式で表される[¹²³I]IMT-1を製造した。
IMT-1 precursor (2.51 mg)、CuSO₄・5H₂O (2.16 mg)、(NH₄)₂SO₄ (2.20 mg)を反応バイアルへ入れ、MeOH (200 μL)、H₂O (200 μL)に懸濁させ、[¹²³I]NH₄I (7.73 mCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (200 μL)、MeOH (200 μL)で反応物を洗浄した後、MeCN (200 μL)、H₂O (200 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 70% (A) and 30% (B), flow rate 1.0 mL/min, λ = 220, 254 nm, Rt = 22.75-23.5 min)にて精製し、[¹²³I]IMT-1を放射化学的収率41%、放射化学的純度>99%で得た。 Production Example 16
According to the following scheme, [ ¹²³ I] IMT-1 represented by the following formula was produced.
IMT-1 precursor (2.51 mg), CuSO ₄ • 5H ₂ O (2.16 mg), (NH ₄ ) ₂ SO ₄ (2.20 mg) were put into a reaction vial, MeOH (200 μL), H ₂ O (200 μL) The mixture was suspended in water, added with [ ¹²³ I] NH ₄ I (7.73 mCi), and then heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction with MeCN (200 μL), MeOH (200 μL), MeCN (200 μL), H ₂ O (200 μL) is added and the solution is passed through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR -II, 10 x 250 mm, eluent 70% (A) and 30% (B), flow rate 1.0 mL / min, λ = 220, 254 nm, Rt = 22.75-23.5 min), [ ¹²³ I IMT-1 was obtained in a radiochemical yield of 41%, radiochemical purity> 99%.

（製造例１７）
下記スキームに従って下記式で表される[¹²³I]IMT-5を製造した。
IMT-5 precursor (1.68 mg)、CuSO₄・5H₂O (3.33 mg)、(NH₄)₂SO₄ (3.58 mg)を反応バイアルへ入れ、MeOH (200 μL)、H₂O (200 μL)に懸濁させ、[¹²³I]NH₄I (24.5 mCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (400 μL)、MeOH (400 μL)で反応物を洗浄した後、MeCN (200 μL)、H₂O (200 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 ｘ 250 mm, eluent 75% (A) and 25% (B), flow rate 2.0 mL/min, λ = 220, 254 nm, Rt = 16.0-17.0 min)にて精製し、[¹²³I]IMT-5を放射化学的収率35%、放射化学的純度>99%で得た。 Production Example 17
According to the following scheme, [ ¹²³ I] IMT-5 represented by the following formula was produced.
IMT-5 precursor (1.68 mg) , CuSO 4 · 5H 2 O (3.33 mg), (NH 4) 2 SO 4 and (3.58 mg) were placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) The mixture was suspended in water, added with [ ¹²³ I] NH ₄ I (24.5 mCi), and then heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction with MeCN (400 μL), MeOH (400 μL), MeCN (200 μL), H ₂ O (200 μL) is added and the solution is passed through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR -II, 10 x 250 mm, eluent 75% (A) and 25% (B), flow rate 2.0 mL / min, λ = 220, 254 nm, Rt = 16.0-17.0 min), [ ¹²³ I IMT-5 was obtained in radiochemical yield 35%, radiochemical purity> 99%.

［細胞増殖抑制活性の測定］
96ウェルプレート上にK562細胞(3.0×10³ cells/well)またはBa/F3 Bcr-Abl^T315細胞(3.0×10³ cells/well)を播種し、10％ Fetal Bovine Serum含有RPMI1640培地中にて1晩培養した。各ウェルにIMT-1, -5, -6, -7を終濃度が0.3-10000 nMになるように添加し、CO₂インキュベーター中で７２時間インキュベートした。７２時間後、Cell Counting Kit-8（同仁科学株式会社）を用いて生存細胞数をカウントし、各濃度のカウント数から各化合物のIC50値を算出した。 [Measurement of cell growth inhibitory activity]
K562 cells (3.0 × 10 ³ cells / well) or Ba / F 3 Bcr-Abl ^T315 cells (3.0 × 10 ³ cells / well) are seeded on a 96-well plate, and 1 in RPMI 1640 medium containing 10% Fetal Bovine Serum. It was cultured overnight. To each well, IMT-1, -5, -6, -7 were added to a final concentration of 0.3-10000 nM and incubated in a CO ₂ incubator for 72 hours. After 72 hours, the number of viable cells was counted using Cell Counting Kit-8 (Dohito Science Co., Ltd.), and the IC50 value of each compound was calculated from the count number of each concentration.

表１に示すように、IMT-1, -5, -6, -7はBcr-Abl positive細胞であるK562細胞に対して結合親和性を示したが、Bcr-Abl変異細胞であるBa/F Bcr-AblT315Iに対して結合親和性を示さなかった。 As shown in Table 1, IMT-1, -5, -6, -7 showed binding affinity to K562 cells as Bcr-Abl positive cells, but Ba / F as Bcr-Abl mutant cells. It showed no binding affinity to Bcr-AblT315I.

［細胞取込実験］
24ウェルプレート上にてK562細胞(5.0×10⁵ cells/well)を10% Fetal Bovine Serum含有RPMI1640培地中にて1時間培養した。各ウェルに[¹²⁵I]IMT-1, -3, -4 HYPERLINK "ftp://FTP3(0.11" (3.7 KBq)を加えCO₂インキュベーター中で1, 2, 3時間インキュベートした。細胞を含む培地を回収し、2000 x gで5分間遠心後、上清を除去し、PBSで洗浄した。0.2 N NaOHで細胞を溶解させ、溶液の放射能をガンマカンターで計測した。その結果を図１に示す。図１に示すように、3時間インキュベート後において、[¹²⁵I]IMT-1は36.8 dose%、[¹²⁵I]IMT-3は4.5 dose%、[¹²⁵I]IMT -4は4.4 dose%であった。 [Cell uptake experiment]
K562 cells (5.0 × 10 ⁵ cells / well) were cultured in a 24-well plate for 1 hour in RPMI 1640 medium containing 10% Fetal Bovine Serum. [ ¹²⁵ I] IMT-1, -3, -4 HYPERLINK "ftp: // FTP3 (0.11" (3.7 KBq) was added to each well and incubated in a CO ₂ incubator for 1, 2 or 3 hours. Medium containing cells The supernatant was removed after centrifugation at 2000 xg for 5 minutes, washed with PBS, the cells were lysed with 0.2 N NaOH, and the radioactivity of the solution was counted with a gamma counter. As shown in FIG. 1, after incubation for 3 hours, [ ^125I ] IMT-1 is 36.8 dose%, [ ^125I ] IMT-3 is 4.5 dose%, and [ ^125I ] IMT-4 is 4.4 dose%. there were.

［K562担がんマウスを用いた[¹²⁵I]IMT-1体内動態評価］
Bcr-Abl positive細胞であるK562担がんマウスへ[¹²⁵I]IMT-1 (18.5 kBq/100 μL)をマウス尾静注より投与した。投与後60、120、180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果を図２に示す。図２は、左から順に腫瘍／血液比、腫瘍／筋肉比及び腫瘍／骨比の経時変化を示すグラフである。投与後60分において、腫瘍への集積は2.25 ID%/gであった。また、図２に示すように、画像化に重要な臓器比は腫瘍/血液比5.3、腫瘍/筋肉比6.1、腫瘍/骨比5.3と高い臓器比が得られた。 [ ¹²⁵ I] IMT-1 pharmacokinetics evaluation using K562 tumor-bearing mice]
[ ¹²⁵ I] IMT-1 (18.5 kBq / 100 μL) was administered from a mouse tail intravenous injection to K562 tumor-bearing mice that are Bcr-Abl positive cells. Each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed 60, 120, 180 minutes after administration. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. The results are shown in FIG. FIG. 2 is a graph showing the time course of the tumor / blood ratio, the tumor / muscle ratio and the tumor / bone ratio in order from the left. At 60 minutes post dose, tumor accumulation was 2.25 ID% / g. In addition, as shown in FIG. 2, organ ratios important for imaging were a tumor / blood ratio of 5.3, a tumor / muscle ratio of 6.1, and a tumor / bone ratio of 5.3, a high organ ratio.

［A431担がんマウスを用いた[¹²⁵I]IMT-1体内動態評価］
Bcr-Abl negative細胞であるA431担がんマウスへ[¹²⁵I]IMT-1 (18.5 kBq/100 μL)をマウス尾静注より投与した。投与後180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果、投与後180分において、腫瘍への集積は0.2 ID%/gであり、画像化に重要な臓器比は腫瘍/血液比0.5、腫瘍/筋肉比2.5、腫瘍/骨比1.21と低い臓器比が認められた。 [ ^125I ] IMT-1 pharmacokinetics evaluation using A431 tumor-bearing mice]
[ ¹²⁵ I] IMT-1 (18.5 kBq / 100 μL) was administered to A431 tumor-bearing mice, which are Bcr-Abl negative cells, by intravenous injection from the mouse tail. 180 minutes after administration, each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. As a result, at 180 minutes after administration, accumulation in the tumor is 0.2 ID% / g, organ ratios important for imaging are a low organ with a tumor / blood ratio of 0.5, a tumor / muscle ratio of 2.5, and a tumor / bone ratio of 1.21. A ratio was noted.

［K562担がんマウスを用いた[¹²⁵I]IMT-5体内動態評価］
Bcr-Abl positive細胞であるK562担がんマウスへ[¹²⁵I]IMT-5 (18.5 kBq/100 μL)をマウス尾静注より投与した。投与後60、120、180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果を図３及び４に示す。図３は、左から順に腫瘍／血液比、腫瘍／筋肉比及び腫瘍／骨比の経時変化を示すグラフである。図４は、投与後６０分の各臓器への集積量を示すグラフである。図５に示すように、投与後60分において、腫瘍への集積は2.5 ID%/gであった。また、図３に示すように、画像化に重要な臓器比は腫瘍/血液比8.4、腫瘍/筋肉比11.6、腫瘍/骨比8.4と高い臓器比が得られた。 [ ¹²⁵ I] IMT-5 pharmacokinetic evaluation using K562 tumor-bearing mice]
[ ¹²⁵ I] IMT-5 (18.5 kBq / 100 μL) was administered from a mouse tail intravenous injection to K562 tumor-bearing mice that are Bcr-Abl positive cells. Each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed 60, 120, 180 minutes after administration. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. The results are shown in FIGS. FIG. 3 is a graph showing the time course of the tumor / blood ratio, the tumor / muscle ratio and the tumor / bone ratio in order from the left. FIG. 4 is a graph showing the accumulation amount in each organ 60 minutes after administration. As shown in FIG. 5, at 60 minutes after administration, accumulation in the tumor was 2.5 ID% / g. In addition, as shown in FIG. 3, the organ ratio important for imaging was as high as 8.4 for tumor / blood, 11.6 for tumor / muscle, and 8.4 for tumor / bone.

［A431担がんマウスを用いた[¹²⁵I]IMT-5体内動態評価］
Bcr-Abl negative細胞であるA431担がんマウスへ[¹²⁵I]IMT-５ (18.5 kBq/100 μL)をマウス尾静注より投与した。投与後180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果、投与後180分において、腫瘍への集積は0.4 ID%/gであり、画像化に重要な臓器比は腫瘍/血液比1.5、腫瘍/筋肉比1.9、腫瘍/骨比1.2と低い臓器比が認められた。 [ ^125I ] IMT-5 pharmacokinetics evaluation using A431 tumor-bearing mice]
[ ^125I ] IMT-5 (18.5 kBq / 100 μL) was administered to A431 tumor-bearing mice, which are Bcr-Abl negative cells, by intravenous injection from the mouse tail. 180 minutes after administration, each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. As a result, at 180 minutes after administration, accumulation in the tumor is 0.4 ID% / g, and organ ratios important for imaging are a low organ with a tumor / blood ratio of 1.5, a tumor / muscle ratio of 1.9, and a tumor / bone ratio of 1.2. A ratio was noted.

［Ba/F Bcr-AblT315I担がんマウスを用いた[¹²⁵I]IMT-5体内動態評価］
Bcr-Abl変異細胞であるBa/F Bcr-AblT315I細胞であるA431担がんマウスへ[¹²⁵I]IMT-５ (18.5 kBq/100 μL)をマウス尾静注より投与した。投与後180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果、投与後180分において、腫瘍への集積は1.0 ID%/gであり、画像化に重要な臓器比は腫瘍/血液比4.0、腫瘍/筋肉比4.0、腫瘍/骨比1.7と低い臓器比が認められた。 [ ¹²⁵ I] IMT-5 pharmacokinetic evaluation using Ba / F Bcr-AblT 315I tumor-bearing mice.
[ ^125I ] IMT-5 (18.5 kBq / 100 μL) was administered to the A431 tumor-bearing mouse, which is a Bcr-Abl mutant cell, Ba / F Bcr-AblT315I cell, by intravenous injection of mouse tail. 180 minutes after administration, each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. As a result, at 180 minutes after administration, the accumulation in the tumor is 1.0 ID% / g, and the organ ratio important for imaging is a low organ with a tumor / blood ratio of 4.0, a tumor / muscle ratio of 4.0, and a tumor / bone ratio of 1.7. A ratio was noted.

［SPECT/CT撮像］
K562担がんマウスへ[¹²³I]IMT-5 (34.7 MBq/100 μL)をマウス尾静脈より投与した。投与後247分からイソフルラン(2.0%)吸引麻酔し投与後257分からSPECT/CT装置(FX-3300)を用いて48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。得られた画像を図５に示す。図５に示すように、移植したＫ５６２細胞をイメージングできた。撮像終了後、屠殺し各臓器を摘出し、各臓器の重量と放射能を測定し、単位重量あたりの放射能から集積量(%ID/g)を算出した。その結果、腫瘍/血液比5.6、腫瘍/筋肉比10.6、腫瘍/骨比5.9と高い近接臓器比が認められた。 [SPECT / CT imaging]
[ ¹²³ I] IMT-5 (34.7 MBq / 100 μL) was administered to K562 tumor-bearing mice from the tail vein of the mouse. After 247 minutes of administration, isoflurane (2.0%) suction anesthesia was performed, and after 257 minutes of administration, imaging was performed for 48 minutes using a SPECT / CT apparatus (FX-3300). Thereafter, CT imaging (60 kV, 320 μA) was performed. Image reconstruction was performed using 3D-OSEM. The obtained image is shown in FIG. As shown in FIG. 5, the transplanted K562 cells could be imaged. After the end of imaging, each animal was sacrificed, each organ was extracted, the weight and radioactivity of each organ were measured, and the accumulated amount (% ID / g) was calculated from the radioactivity per unit weight. As a result, a high adjacent organ ratio was recognized, which is a tumor / blood ratio of 5.6, a tumor / muscle ratio of 10.6, and a tumor / bone ratio of 5.9.

Claims

The compound represented by following formula (I), or its pharmaceutically acceptable salt.
[In the formula (I),
X ¹ is
And R ² is a radioactive halogen atom,
R ¹ is
And
R ³ is a radioactive halogen atom,
R ⁴ is a hydrogen atom or -CH ₂ -R ⁶ , and R ⁶ is 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-n-propylpiperazine-1- Yl, 1-pyrrolidinyl, piperidino, morpholino, dimethylamino or diethylamino;
R ⁵ is a radioactive halogen atom,
Any one of R ² , R ³ and R ⁵ is a radioactive halogen atom. ]

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) is a compound represented by any one of the following formulas (1) to (5).
[Equation (1), (2) and (4) in R ^3, R ² is a radioactive halogen atom of R ⁵ and in the formula (5) in equation (3). ]

The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the radioactive halogen atom is ¹²³¹ , ¹²⁴¹ or ^125I .

A molecular probe for imaging Bcr-Abl protein, comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

A precursor composition for radioactive labeling, which comprises a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.
[In the formula (II),
X ² is
R ⁸ is a halogen atom, a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group,
R ⁷ is
And
R ⁹ is a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group, or a brosylate group,
R ⁴ is a hydrogen atom or -CH ₂ -R ⁶ , and R ⁶ is 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-n-propylpiperazine-1- Yl, 1-pyrrolidinyl, piperidino, morpholino, dimethylamino or diethylamino;
R ¹⁰ is a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group, or a brosylate group,
Any one of R ⁸ , R ⁹ and R ¹⁰ is a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group. ]

The precursor composition for radiolabeling according to claim 5, wherein the compound represented by the formula (II) is a compound represented by any one of the following formulas (6) to (10).
Expression (6), R ⁹ in (7) and (9), R ⁸ of R ^10, and wherein (10) in equation (8) is a halogen atom, a trialkyl stannyl group, a nitro group, It is a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group. ]

A method of imaging comprising detecting a radioactive signal of the compound from a subject to which the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or the molecular probe according to claim 4 is administered.