JP6709552B2 - Nuclear medicine diagnostic imaging agent - Google Patents

Description

The present disclosure relates to a radiolabeled compound having a tetrahydropyridothieno[2,3-d]pyrimidine skeleton, and in one embodiment, information for discriminating a secondary mutation of epidermal growth factor receptor (EGFR) can be obtained. It relates to radiolabeled compounds.

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 constituting the body EGFR is mutated. EGFR is activated when a mutation occurs, and this activation is said to be involved in cancer growth and the like. Further, 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. .. For this reason, 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 tests 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).

Further, even if the EGFR-TKI is successful, resistance may be acquired within one year, and as a result, the EGFR-TKI may not be able to obtain a sufficient therapeutic effect. 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.

Guideline for EGFR Mutation Testing in Lung Cancer Patients Version 2.1 (2014) Japanese Society of Lung Cancer M. A. Pantaleo et al., Annals of Oncology 2009; 20: 213-226 Emily B. Corcoran et al., Medicinal Research Reviews 2014; 34: 596-643

As described above, studies have been conducted on imaging probes for detecting EGFR, 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.

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).
[In Formula (1),
R ₁ is a group represented by the following formula (a), (b) or (c),
R ₂ is a group represented by the following formula (d) or (e),
Y is -NH- or -O-,
In formulas (a) and (b), L ₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less,
In the formulas (b) and (c), n is an integer of 1 or more and 3 or less,
In formulas (a), (b) and (c), X ₁ is a radioactive halogen atom or —[ ¹¹ C]CH ₃ ,
In formula (d), R ₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (d) and (e), R ₄ is a hydrogen atom or a halogen atom. ]

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).
[In Formula (1),
R ₁ is a group represented by the following formula (a), (b) or (c),
R ₂ is a group represented by the following formula (d) or (e),
Y is -NH- or -O-,
In formulas (a) and (b), L ₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less,
In the formulas (b) and (c), n is an integer of 1 or more and 3 or less,
In formulas (a), (b) and (c), X ₁ is a radioactive halogen atom or —[ ¹¹ C]CH ₃ ,
In formula (d), R ₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (d) and (e), R ₄ is a hydrogen atom or a halogen atom. ]

In one aspect, the present disclosure relates to a compound represented by the following formula (2) or a pharmaceutically acceptable salt of the compound represented by the formula (2).
[In the formula (2),
R ₁₁ is a group represented by the following formula (f) or (g),
R ₁₂ is a group represented by the following formula (h) or (i),
Y is -NH- or -O-,
In formulas (f) and (g), R ₁₅ is a hydrogen atom or —L ₁₁ —X ₁₁ , and L ₁₁ is an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less, and X ₁₁ is a chlorine atom, a bromine atom, or an iodine atom. , A nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group, and in the formula (g), n is an integer of 1 or more and 3 or less,
In formula (h), R ₁₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (h) and (i), R ₁₄ is a hydrogen atom or a halogen atom. ]

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
The present invention relates to a method, which comprises detecting a radioactive signal of the nuclear medicine image diagnostic agent from a lung cancer tumor of a subject administered with the nuclear medicine image diagnostic agent.

The present disclosure provides, in one aspect, a method of assessing the occurrence of a T790M mutation in a gene encoding an epidermal growth factor receptor in a lung cancer tumor, comprising:
Detecting a radioactive signal of the nuclear medicine image diagnostic agent from a lung cancer tumor of a subject to which the nuclear medicine image diagnostic agent of the present disclosure has been administered,
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 tumors based on the change in the signal by the comparison. Regarding the method including.

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,
Comparing the information obtained by the above method 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. Regarding the method.

In one aspect, the present disclosure relates to a compound represented by the following formula (3) or a pharmaceutically acceptable salt of the compound represented by the formula (3).
[In Formula (3),
R ₂₁ is a group represented by the following formula (j), (k) or (l),
R ₂₂ is a group represented by the following formula (m) or (n),
Y is -NH- or -O-,
In formulas (j) and (k), L ₂₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less,
In formulas (k) and (l), n is an integer of 1 or more and 3 or less,
In formulas (j), (k) and (l), X ₂₁ is a halogen atom,
In formula (m), R ₂₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (m) and (n), R ₂₄ is a hydrogen atom or a halogen atom. ]

In one aspect, the present disclosure can provide 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.

FIG. 1 is a graph showing an example of the result of the cell uptake experiment. FIG. 2 is an image showing an example of the result of PET/CT imaging, FIG. 2A is an image showing an example of the result of imaging using H3255 (L858R mutant) tumor-bearing mouse, and FIG. 2B is an image showing H1975( (L858R/T790M mutation) Fig. 6 is an image showing an example of the result of imaging using a cancer-bearing mouse.

In one aspect, the present disclosure provides an EGFR if it is a compound having a tetrahydropyridothieno[2,3-d]pyrimidine skeleton represented by Formulas P1 to P10 synthesized in Examples described later (Example Table 1). In particular, it is based on the finding that it exhibits a relatively high binding affinity for the L858R mutant EGFR, but does not exhibit a binding affinity for the L858R/T790M mutant EGFR. Further, in one aspect, the present disclosure provides an L858R mutant EGFR in the case of a radiohalogen-labeled compound having a tetrahydropyridothieno[2,3-d]pyrimidine skeleton such as compound [ ¹⁸ F]P2 synthesized in the following Examples. In PET imaging of H1975 cancer-bearing mice showing a high proximal organ ratio (for example, tumor/muscle ratio or tumor/blood ratio) in H3255 tumor-bearing mice having L858R/T790M mutant EGFR. Based on the finding that it shows a significantly lower proximal organ ratio (eg, tumor/muscle ratio, or tumor/blood ratio) compared to H3255 cancer-bearing mice.

According to the radiolabeled compound represented by the above formula (1), in one or a plurality of embodiments, a secondary mutation is caused in a lung cancer tumor in which a mutation that enhances EGFR-TKI sensitivity such as L858R mutation in the EGFR gene is expressed. 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. Further, according to the radio-labeled compound represented by the 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 of being able to evaluate the efficacy of treatment with EGFR-TKI can be exerted.

In the present specification, “discriminating a secondary mutation of EGFR” includes, 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 can be mentioned that the generated EGFR can be distinguished.

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, and organs are measured. Or, the reaction or in vitro with a drug containing a radiolabeled compound used in in vivo nuclear medicine tests for evaluation or examination of biological functions of tissues, diagnosis of diseases, etc., or in vitro with samples such as tissues or blood collected from the body, Alternatively, it refers to a drug containing a radiolabeled compound which is used for 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.

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 Examples thereof include basic amino acid salts. 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 may be formed by absorbing a certain other solvent by the compound.

In the present specification, the “radioactive halogen atom” refers to a radioactive isotope of a halogen atom. The radioactive halogen atom includes ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹⁸ F, ⁷⁵ Br, ⁷⁶ Br, and ⁷⁷ Br.

In the present specification, the “alkanediyl group having 1 to 10 carbon atoms” has a saturated aliphatic branched or straight chain, and 1 to 10 in the structure of the straight chain or branched chain. It refers to a divalent hydrocarbon group having the following carbon atoms. Examples of the alkanediyl group having 1 to 10 carbon atoms include methanediyl group, ethanediyl group, propanediyl group, butanediyl group, pentanediyl group, hexanediyl group, heptanediyl group, octanediyl group, nonanediyl group, decandiyl group and the like. ..

In the present specification, the "halogen-substituted alkyl group having 1 to 4 carbon atoms" may be an alkyl group having 1 to 4 carbon atoms or a halogen-substituted alkyl group having 1 to 4 carbon atoms. .. The "alkyl group having 1 to 4 carbon atoms" has a saturated aliphatic branched or straight chain, and has 1 to 4 carbon atoms in the structure of the straight chain or branched chain. A monovalent hydrocarbon group having. Examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, propyl group and isopropyl group. The “halogen-substituted alkyl group having 1 to 4 carbon atoms” refers to an alkyl group having 1 to 4 carbon atoms in which one or more hydrogen atoms are replaced by halogen atoms. Examples of the halogen-substituted alkyl group having 1 to 4 carbon atoms include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, and a difluoromethylene group.

In the present specification, the “hydroxyalkyl group having 1 to 4 carbon atoms” refers to one in which one or two or more alkyl groups having 1 to 4 carbon atoms are substituted with a hydroxyl group. Examples of the hydroxyalkyl group having 1 to 4 carbon atoms include hydroxymethyl group, hydroxyethyl group, and hydroxypropyl group.

In the present specification, the "alkoxyalkyl group having 1 to 4 carbon atoms" has 1 to 4 carbon atoms in which one or two or more linear or branched alkyl groups are substituted with an alkoxy group. A group having an atom. Examples of the alkoxyalkyl group having 1 to 4 carbon atoms include methoxymethyl group, ethoxymethyl group, and methoxyethyl group.

[Compound Represented by Formula (1)]
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 an effect of not showing binding affinity to L858R/T790M mutant EGFR which is a heavy mutant (DM).

In the formula (1), R ₁ is a group represented by the following formula (a), (b) or (c).

In formulas (a) and (b), L ₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
(1 is 0 or more and 5 or less, and m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and is 1 or more and 5 or less). L ₁ is, in one or more embodiments, an ethanediyl group, a propanediyl group, a butanediyl group, a pentanediyl group, a hexanediyl group, a methyleneoxyethylene group, an ethyleneoxyethylene group, an ethylenetrioxyethylene group, or an ethylenetetraoxy group. Ethylene groups and the like, from the viewpoint of improving the discrimination of the secondary mutation of EGFR, preferably from the viewpoint of obtaining a compound having a high binding affinity to the L858R mutant EGFR and a low binding affinity to the L858R/T790M mutant, ethanediyl group, ethylene oxyethylene group _{(-C 2 H 4 -O-C} 2 H 4 - group) or ethylene tri oxyethylene group _{(-C 2 H 4 - (O} -C 2 H 4) 3 - group) include Be done.

In the formulas (b) and (c), n is an integer of 1 or more and 3 or less, and from the viewpoint of improving the discrimination of the secondary mutation of EGFR, it preferably has a high binding affinity for the L858R mutant EGFR and the L858R/T790M mutation. 2 is preferable because a compound having a low binding affinity for the mold can be obtained.

In formulas (a), (b) and (c), X ₁ is a radioactive halogen atom or -[ ¹¹ C]CH ₃ , which can be used as a PET preparation, has a suitable half-life, and is an atom. ¹⁸ F is preferred in one or more embodiments due to its relatively small size.

R ₁ is preferably a Michael acceptor from the viewpoint of improving the discrimination of the secondary mutation of EGFR, and from the viewpoint of obtaining a compound having a high binding affinity to the L858R mutant EGFR and a low binding affinity to the L858R/T790M mutant. A group having a group and represented by the formula (a) is preferable, and a group represented by the following formula (a1) is more preferable.
In formula (a1), l is 0 or more and 5 or less, and is 1 or 2 or 3 in one or some embodiment. m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and is 1 or more and 5 or less, and in one or more embodiments, 1, 2, 3, 4 or 5.

In the formula (1), R ₂ is a group represented by the following formula (d) or (e).
In formula (d), R ₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. .. Examples of R ₃ include a methyl group, a trifluoromethyl group, a hydroxymethyl group, a methoxymethyl group, and the like in one or more embodiments, and from the viewpoint of improving the discrimination of the secondary mutation of EGFR, preferably the L858R mutation A methyl group, a hydroxymethyl group or a methoxymethyl group is preferable from the viewpoint that a compound having a high binding affinity for the type EGFR and a low binding affinity for the L858R/T790M mutant type can be obtained.
In formulas (d) and (e), R ₄ is a hydrogen atom or a halogen atom, and in one or a plurality of embodiments, a hydrogen atom or a bromine atom can be mentioned.

From the viewpoint of improving the discrimination of the secondary mutation of EGFR, R ₂ is preferably a compound having a high binding affinity for the L858R mutant EGFR and a low binding affinity for the L858R/T790M mutant, and therefore is represented by the formula (d Group represented by the formula (4) is preferable, and a group represented by the following formula (d1), (d2) or (d3) is more preferable.

In formula (1), Y is -NH- or -O-.

In one or a plurality of embodiments, the compound represented by the formula (1) preferably has a high binding affinity to the L858R mutant EGFR and has a high binding affinity to the L858R/T790M mutant in order to improve the discrimination of the secondary mutation of the EGFR. The compound represented by the following formula (1a) or (1b) is preferable from the standpoint of a compound having a low binding affinity to R, and more preferably R ₂ in the formula (1a) or (1b) is a substituent R ₇ A compound having a phenylmethylene group (a compound represented by the following formula (1c) or (1d)).
In formulas (1a) to (1d), X ₁ and Y are as described above. In formulas (1a) and (1b), R ₂ is as described above. In formulas (1b) and (1d), l and m are as described above.
In formulas (1a) and (1c), n is 1 or more and 10 or less. In formulas (1c) and (1d), R ₇ is a methyl group, a hydroxymethyl group or a methoxymethyl group.

As the compound represented by the formula (1), in one or a plurality of embodiments, the compounds represented by the following formulas (1-1) to (1-10), pharmaceutically acceptable salts of these compounds, and the like. From the viewpoint of improving the discrimination of the secondary mutation of EGFR, preferably the compound having a high binding affinity for the L858R mutant EGFR and a low binding affinity for the L858R/T790M mutant, Compounds represented by 2), (1-5), (1-7), (1-9) or (1-10) are preferable. In formulas (1-1) to (1-10), X ₁ is a radioactive halogen atom or —[ ¹¹ C]CH ₃ , preferably a [ ¹⁸ F]fluorine atom.

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 EGFR-TKI sensitivity 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. Accordingly, the present disclosure provides, in one or a plurality of 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 and an imaging composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1) as an active ingredient. , A nuclear medicine imaging 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 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 can be mentioned. These may contain pharmaceutical additives such as carriers.

[Method for producing compound represented by formula (1)]
The compound (1) of the present disclosure can be produced, in one or a plurality of embodiments, by radioactively labeling the compound represented by the following formula (2). Accordingly, the present disclosure relates, in one or more embodiments, to a method for producing a radioactive compound, which comprises radioactively labeling the compound represented by formula (2) or a pharmaceutically acceptable salt thereof. Moreover, this indication is related with the manufacturing method of the compound represented by Formula (1) including radiolabeling the compound represented by Formula (2) in one or some embodiment.

In the formula (2), R ₁₁ is a group represented by the following formula (f) or (g).

In formulas (f) and (g), R ₁₅ is a hydrogen atom or —L ₁₁ —X ₁₁ . L ₁₁ is an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, and m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and is 1 or more and 5 or less. Examples of L ₁₁ include the same as L ₁ in formula (1).
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.

In the formula (g), n is an integer of 1 or more and 3 or less, and preferably has a high binding affinity for the L858R mutant EGFR and a high binding affinity for the L858R/T790M mutant from the viewpoint of improving the discrimination of the secondary mutation of EGFR. 2 is preferable from the viewpoint that a compound having low property is obtained.

R ₁₁ is preferably a labeled compound having a high binding affinity for the L858R mutant EGFR and a low binding affinity for the L858R/T790M mutant because it provides a labeled compound with improved discrimination of the secondary mutation of EGFR. From this viewpoint, the group represented by the formula (f) is preferable, and the group represented by the following formula (f1) or (f2) is more preferable.
In formula (f2), l is 0 or more and 5 or less, and is 1 or 2 or 3 in one or some embodiment. m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and is 1 or more and 5 or less, and in one or more embodiments, 1, 2, 3, 4 or 5.

In the formula (2), R ₁₂ is a group represented by the following formula (h) or (i).
In formula (h), R ₁₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. .. Examples of R ₁₃ include the same as R ₃ of the formula (1).
In formulas (h) and (i), R ₁₄ is a hydrogen atom or a halogen atom. Examples of R ₁₄ include the same as R ₄ in formula (1).
R ₁₂ is preferably the same as R ₂ in formula (1).

In formula (2), Y is -NH- or -O-.

The compound represented by the formula (2) preferably has a binding affinity to the L858R mutant EGFR from the viewpoint of obtaining a labeled compound with improved discrimination of the secondary mutation of EGFR in one or more embodiments. A compound represented by the following formula (2-1) or (2-2) is preferable, and a compound represented by formula (2-1) is more preferable, since a labeled compound having a high binding affinity to the L858R/T790M mutant is obtained. Alternatively, R ₁₂ in (2-2) is a compound (a compound represented by the following formula (2-3) or (2-4)) which is a phenylmethylene group having a substituent R ₁₇ .
In formulas (2-3) and (2-4), R ₁₇ is a methyl group, a hydroxymethyl group or a methoxymethyl group. In formulas (2-1) to (2-4), Y and R ₁₂ are as described above. In formulas (2-2) and (2-4), 1 and m are as described above.

The method of radioactively labeling the compound represented by formula (2) can be appropriately determined according to the structure of the compound represented by formula (2). When R ₁₅ is —L ₁₁ —X ₁₁ in formula (2), in one or more embodiments, it can be labeled using a direct labeling method. In the formula (2), when R ₁₅ is a hydrogen atom, it can be labeled by an indirect labeling method using X ₁ -L ₁₁ -X _{11 and the} like. X ₁ and X ₁₁ are as described above.

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. Moreover, this indication is related with the kit for preparing the compound (1) of this indication containing the compound (2) of this indication in one or some embodiment. The kit of the present disclosure may further include a labeling reagent containing a radioactive halogen atom in one or more embodiments.

[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 for obtaining disclosed information"). The subject is not particularly limited, but in one or more embodiments, is selected from humans, non-human mammals, cultured cells, and subjects in which EGFR may be present.

The method for obtaining the information of the present disclosure is, in one or more embodiments, a compound (1) of the present disclosure, or a lung cancer tumor of a subject to which a nuclear medicine diagnostic imaging agent containing the compound (1) of the present disclosure is administered. The method includes 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.

The method of obtaining 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 a treatment period of EGFR-TKI.

EGFR-TKIs used for treatment include, in one or more embodiments, reversible EGFR-TKIs. Examples of the reversible EGFR-TKI include gefitinib and erlotinib in one or more embodiments.

[Method for evaluating secondary mutation occurrence in EGFR]
The disclosure relates, in one or more embodiments, to a method of assessing the occurrence of a T790M mutation in a gene encoding an epidermal growth factor receptor in lung cancer tumors. The evaluation method of the present disclosure, in one or more embodiments, detecting a radioactive signal of the nuclear medicine image diagnostic agent from a lung cancer tumor of the subject administered with the nuclear medicine image diagnostic agent of the present disclosure, the subject Detection of radioactive signals from the lung cancer tumor of the above is repeated during the treatment period of the epidermal growth factor receptor tyrosine kinase inhibitor, the obtained information is compared, and the lung cancer tumor is detected based on the fluctuation of the signal by the comparison. Determining the occurrence of the T790M mutation in the gene encoding the epidermal growth factor receptor in.

[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 EGFR-TKI treatment in a subject who is treated with EGFR-TKI for non-small cell lung cancer (hereinafter referred to as “evaluation method of the present disclosure”). Also referred to as).

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 of time has elapsed from administration. Comparing the information obtained by the method of obtaining information.

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 evaluated that the drug efficacy of treatment with EGFR-TKI is decreased, and by the comparison, If no reduction is observed, it may be assessed as 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 may be assessed as having a reduced potential for pharmacological efficacy.

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. In addition, 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 may be assessed as having a reduced potential for pharmacological efficacy.

[Method for imaging EGFR-positive lung cancer tumor]
The present disclosure, in one or more embodiments, relates to an imaging method comprising detecting a radioactive signal of the compound (1) of the present disclosure from a subject administered with the compound.

[Compound represented by Formula (3)]
In one or a plurality of embodiments, the present disclosure relates to a compound represented by the following formula (3) or a pharmaceutically acceptable salt of the compound represented by the formula (3).
In the formula (3), R ₂₁ is a group represented by the following formula (j), (k) or (l),
R ₂₂ is a group represented by the following formula (m) or (n),
Y is -NH- or -O-,
In formulas (j) and (k), L ₂₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 0 or more and 5 or less,
In formulas (k) and (l), n is an integer of 1 or more and 3 or less,
In formulas (j), (k) and (l), X ₂₁ is a halogen atom,
In formula (m), R ₂₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (m) and (n), R ₂₄ is a hydrogen atom or a halogen atom.

The compound represented by the formula (3) has a relatively high binding affinity to the L858R mutant EGFR in one or more embodiments, but is one of the secondary mutations of the EGFR, the T790M mutant EGFR. And an effect of not exhibiting binding affinity to L858R/T790M mutant EGFR which is a double mutant (DM). L ₂₁ , R ₂₂ and n are the same as L ₁ , R ₂ and n in the formula (1), respectively.

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).
[In Formula (1),
R ₁ is a group represented by the following formula (a), (b) or (c),
R ₂ is a group represented by the following formula (d) or (e),
Y is -NH- or -O-,
In formulas (a) and (b), L ₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less,
In formulas (b) and (c), n is an integer of 1 or more and 3 or less,
In formulas (a), (b) and (c), X ₁ is a radioactive halogen atom or —[ ¹¹ C]CH ₃ ,
In formula (d), R ₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (d) and (e), R ₄ is a hydrogen atom or a halogen atom. ]
[2] The nuclear medicine diagnostic imaging agent according to [1], wherein L ₁ is an ethanediyl group, an ethyleneoxyethylene group, or an ethylenetrioxyethylene group.
[3] The nuclear medicine diagnostic imaging agent according to [1] or [2], wherein R ₃ is a methyl group, a trifluoromethyl group, a hydroxymethyl group or a methoxymethyl group.
[4] The nuclear medicine image diagnostic agent according to any one of [1] to [3], wherein R ₄ is a hydrogen atom or a bromine atom.
[5] A compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1).
[In Formula (1),
R ₁ is a group represented by the following formula (a), (b) or (c),
R ₂ is a group represented by the following formula (d) or (e),
Y is -NH- or -O-,
In formulas (a) and (b), L ₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less,
In formulas (b) and (c), n is an integer of 1 or more and 3 or less,
In formulas (a), (b) and (c), X ₁ is a radioactive halogen atom or —[ ¹¹ C]CH ₃ ,
In formula (d), R ₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (d) and (e), R ₄ is a hydrogen atom or a halogen atom. ]
[6] A compound represented by the formula (2) or a pharmaceutically acceptable salt of the compound represented by the formula (2).
[In the formula (2),
R ₁₁ is a group represented by the following formula (f) or (g),
R ₁₂ is a group represented by the following formula (h) or (i),
Y is -NH- or -O-,
In formulas (f) and (g), R ₁₅ is a hydrogen atom or —L ₁₁ —X ₁₁ , and L ₁₁ is an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less, and X ₁₁ is a chlorine atom, a bromine atom, or an iodine atom. , A nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group, and in the formula (g), n is an integer of 1 or more and 3 or less,
In formula (h), R ₁₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (h) and (i), R ₁₄ is a hydrogen atom or a halogen atom. ]
[7] The compound according to [6], wherein R ₁₅ is a hydrogen atom.
[8] A composition containing the compound according to [6] or [7], which is used as a labeling precursor for synthesizing the nuclear medicine diagnostic imaging agent according to any one of [1] to [4].
[9] A method for obtaining information for evaluating the efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor in a subject treated with epidermal growth factor receptor tyrosine kinase inhibitor for non-small cell lung cancer. hand,
A method comprising detecting a radioactive signal of the nuclear medicine image diagnostic agent from a lung cancer tumor of a subject administered with the nuclear medicine image diagnostic agent according to any one of [1] to [4].
[10] The method according to [9], 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.
[11] A method for evaluating the occurrence of a T790M mutation in a gene encoding an epidermal growth factor receptor in lung cancer tumor, comprising:
Detecting a radioactive signal of the nuclear medicine image diagnostic agent from a lung cancer tumor of a subject administered with the nuclear medicine image diagnostic agent according to any one of [1] to [4],
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 tumor based on the change in the signal by the comparison.
[12] A method for evaluating the efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor in a subject in which non-small cell lung cancer is treated with an epidermal growth factor receptor tyrosine kinase inhibitor,
Obtained by the method according to [9] or [10] at two or more timings selected from the group consisting of before the start of administration of the epidermal growth factor receptor tyrosine kinase inhibitor, after the start of administration, and after a certain period has elapsed from the start of administration. A method comprising comparing the information provided.
[13] The method according to [12], 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 signal change by the comparison.
[14] When a decrease in the signal is observed by the comparison, it is evaluated that the efficacy of the treatment with the epidermal growth factor receptor tyrosine kinase inhibitor is decreased, and when a decrease in the signal is not observed by the comparison, The method according to [12] or [13], which evaluates the potential therapeutic effect of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor.
[15] If the tumor size is increased or maintained and a decrease in the signal is observed, it is evaluated that the efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor is decreased, [12] Alternatively, the method according to [13].
[16] imaging a 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 evaluated that the efficacy of treatment with an epidermal growth factor receptor tyrosine kinase inhibitor is decreased. The method according to any one of [12] to [15].
[17] A compound represented by the following formula (3) or a pharmaceutically acceptable salt of the compound represented by the formula (3).
[In Formula (3),
R ₂₁ is a group represented by the following formula (j), (k) or (l),
R ₂₂ is a group represented by the following formula (m) or (n),
Y is -NH- or -O-,
In formulas (j) and (k), L ₂₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less,
In formulas (k) and (l), n is an integer of 1 or more and 3 or less,
In formulas (j), (k) and (l), X ₂₁ is a halogen atom,
In formula (m), R ₂₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (m) and (n), R ₂₄ is a hydrogen atom or a halogen atom. ]
[18] A kit for preparing the compound according to [5], which comprises the compound according to [6] or [7] or the composition according to [8].

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.

[Devices and reagents]
Mass spectrometry (ESI-MS) was measured by LCMS-2010 EV (Shimadzu Corporation).
¹ H (400 MHz or 500 MHz) NMR spectrum was measured by LNM-AL 400 or 500 (JEOL Ltd.), and tetramethylsilane was used as an internal standard substance.
Reverse-phase HPLC used LC-20AD (Shimadzu Corporation), SPD-20A UV (Shimadzu Corporation) and survey meter NDW-351 (Hitachi Aloka Medical Co., Ltd.) as detectors. 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 as the mobile phase. An aqueous TFA solution and (B) a 0.1% TFA acetonitrile solution were used. Silica gel 60 F ₂₅₄ (Merck Co., Ltd.) was used for TLC.
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.
Radioactivity was measured using a Curie meter IGC-7 (ALOKA) and an Autowell gamma counter Wallac 1480 WIARD 3 (PerkinElmer).
The image acquisition by the PET device was performed using GMI FX-3300 Pre-Clinical Imaging System.

[Synthesis of compound]
(Process A)
Tetrahydropyridothieno-[2,3-d]pyrimidine skeleton (Compound 4) was synthesized by the method reported by Hsien et al. (Wu, CH bbet al., Design and Synthesis of Tetrahydropyridothieno[2,3-d]pyrimidine Scaffold Based Growth Factor Receptor (EGFR) Kinase Inhibitors: The Role of Side Chain and Michael Acceptor Group for Maximal Potency. J. Med. Chem. 2010, 53, 7316-7326.) (Scheme 1).

(Process B)
Synthesis of Compound 8-13 (P 2-7) Compound 8-13 (P 2-7) was synthesized according to Scheme 2.

Various side chains were introduced into the chloro group of compound 4 to give compounds 5a-c (Scheme 2). Compound 5d was obtained by methylating the side chain hydroxyl group of compound 5a.

Synthesis of Compounds 5a-c Compound 4 (1.77 mmol) was heated to reflux in alcohol (40 mL) at 100° C. overnight along with the corresponding amine or alcohol. After the reaction, the solvent was distilled off, and the residue was purified by column chromatography.
tert-butyl (S)-4-((2-hydroxy-1-phenylethyl)amino)-5,8-dihydropyrido[4',3':4,5]thieno[2,3-d]pyrimidine-7( 6H)carboxylate (compound 5a)
Compound 5a was obtained by heating compound 4 and (S)-(+)-2-amino-2-phenylethanol under reflux in ethanol. Yield 732 mg (97.1 %), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ8.14 (1H, s), 7.36 (2H, d, J = 7.4Hz), 7.22 (2H, t, J = 7.6) Hz), 7.13 (1H, t, J = 7.3Hz), 6.46 (1H, d, J = 7.4Hz), 5.29 (1H, q, J = 5.9 Hz), 5.15 (1H, t, J = 5.6Hz) , 4.56 (2H, d, J = 5.7Hz), 3.78-3.66 (4H, m), 3.10 (2H, s), 1.37 (9H, s).
tert-butyl (R)-4-((1-phenylethyl)amino)-5,8-dihydropyrido[4',3':4,5]thieno[2,3-d]pyrimidine-7(6H)carboxylate ( Compound 5b)
Compound 5b was obtained by heating compound 4 and (R)-(+)-1-phenylethylamine in ethanol under reflux. Yield 102 mg (81.1 %), ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.40 (1H, s), 7.40-7.26 (5H, m), 5.55 (1H, br), 5.39 (1H, br), 4.65 (1H, br), 1.63 (2H, d, J = 6.6Hz), 1.49 (9H, s).
tert-butyl (S)-4-(2,2,2-trifluoro-1-phenylethoxy)-5,8-dihydropyrido[4',3':4,5]
thieno[2,3-d]pyrimidine-7(6H)carboxylate (Compound 5c)
Compound 5c was obtained by heating compound 4 and (S)-(+)-1-phenyl-2,2,2-trifluoroethanol in ethanol under reflux. Yield 137 mg (95.4 %), ¹ H NMR (400 MHz, CDCl ₃ ) δ8.49 (1H, s), 7.59-7.38 (5H, m), 6.84 (1H, q, J = 6.8Hz), 4.78- 4.64 (2H, m), 3.94-3.76
(2H, m), 3.21 (2H, br), 1.52 (9H, s).
tert-butyl (S)-4-((2-methoxy-1-phenylethyl)amino)-5,8-dihydropyrido[4',3':4,5] thieno[2,3-d]pyrimidine-7( 6H)carboxylate (compound 5d)
Compound 5a (300 mg, 0.704 mmol) was dissolved in anhydrous THF (7 mL), and sodium hydride (52.0 mg, 1.41 mmol, 60% oily) was slowly added at 0°C. After 15 minutes, methyl iodide (48.2 mL, 0.774 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with a saturated aqueous solution of ammonium chloride at 0° C., and extracted with ethyl acetate. The organic layer was collected and dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by column chromatography. Yield 123 mg (24.9 %), ¹ H NMR (400 MHz, CDCl ₃ ) δ8.33 (1H, s), 7.41-7.27 (5H, m), 6.14 (1H, br), 5.55 (1H, br), 4.72-4.64 (2H, m), 3.83-3.77 (4H, m), 3.41 (3H, s), 3.10 (2H,
br), 1.51 (9H, s).

Synthesis of Compound 6a-d To compound 5a-d (1.12 mmol) was added 4M HCl/dioxane (150 mL, 0.610 mmol) at 0°C, and then the mixture was reacted at room temperature for 1 hour. Water was added to the reaction solution, and an aqueous solution of sodium hydrogen carbonate was added at 0° C. to make it neutral, followed by extraction with ethyl acetate. The organic layer was collected and dried over sodium sulfate, and then the solvent was distilled off.
(S)-2-phenyl-2-((5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)amino)ethan- 1-ol (Compound 6a)
As the compound 6a, the compound 5a was used as a raw material. Yield 68.6 mg (89.7 %), LCMS (ESI): m/z 327.05 [M+H] ⁺ .
(R)-N-(1-phenylethyl)-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-amine (Compound 6b)
As the compound 6b, the compound 5b was used as a raw material. Yield 35.5 mg (93.9 %), LCMS (ESI): m/z 311.13 [M+H] ⁺ .
(S)-4-(2,2,2-trifluoro-1-phenylethoxy)-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidine ( Compound 6c)
The compound 6c used the compound 5c as a raw material. Yield 107 mg (98.9 %), LCMS (ESI): m/z 406
.95 [M+H+CH ₃ CN] ⁺ .
(S)-N-(2-methoxy-1-phenylethyl)-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]
pyrimidin-4-amine (Compound 6d)
As the compound 6d, the compound 5d was used as a raw material. Yield 30.0 mg (64.7 %), LCMS (ESI): m/z 340.95 [M+H] ⁺ .

(S)-2-((7-fluoroethyl)-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)amino)- Synthesis of 2-phenylethan-1-ol (Compound 7:P1) Compound 6a (124 mg, 0.381 mmol) was dissolved in anhydrous DMF (2 mL), and Cs ₂ CO ₃ (124 mg, 0.381 mmol) and 2-fluoroethyl were used. Tosylate (83.2 mg, 0.381 mmol) was added, and the mixture was stirred at 60° C. overnight and further at room temperature overnight. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with saturated saline and then dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by reverse phase HPLC. Yield 7.00 mg (4.92 %), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ8.28 (1H, s), 7.43 (2H, d, J = 7.4 Hz), 7.31 (2H, t, J = 7.4) Hz), 7.23 (1H, t, J = 7.3 Hz),
6.64 (1H, t, J = 7.2 Hz), 5.37 (1H, q, J = 6.1 Hz), 4.97 (1H, br), 4.88 (1H, br), 4.64 (2H, br), 3.80 (3H, d , J = 5.7 Hz), 3.72-3.67 (4H, m), 3.53-3.49 (2H, m), HRMS (ESI): m/z calcd for C ₁₉ H ₂₁ FN ₄ OS [M+H] ⁺ 373.1420, found.

Synthesis of compound 8-13 (P2-7)
After dissolving 4-bromo crotonic acid, 2-bromo ethanoic acid or 3-bromo propanoic acid (0.097 mmol) in anhydrous THF (1 mL) and adding Et ₃ N (13.4 μL, 0.097 mmol) to make it basic, Iso-butyl chloroformate (IBCF: 12.1 μL, 0.097 mmol) was slowly added at 15° C., and the mixture was reacted for 15 minutes. On the other hand, anhydrous THF (1 mL) in which compound 6a-d (0.107 mmol) and Et ₃ N (14.9 μL, 0.107 mmol) were dissolved was added to the previously prepared reaction solution, and the mixture was stirred at 0° C. for 10 minutes. , Further reacted at room temperature for 2 hours. Furthermore, a mixed solution of anhydrous THF (0.5 mL) and water (1 mL) in which 1-(2-fluoroethyl)piperazine (14.2 mg, 0.107 mmol) and Et ₃ N (44.8 μL, 0.322 mmol) were dissolved was added, and the mixture was stirred at room temperature. And reacted for 2 hours. A small amount of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by reverse phase HPLC.
(S,E)-4-(4-(2-fluoroethyl)piperazin-1-yl)-1-(4-((2-hydroxy-1phenylethyl)amino)-5,8-dihydropyrido[4',3' :4,5]thieno[2,3-d]pyrimidin-7(6H)-yl)but-2-en-1-one (Compound
(Object 8: P2)
Compound 8 (P2) was synthesized using compound 6a and 2-bromo crotonic acid. Yield 14.8 mg (11.2 %), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ8.24 (1H, s), 7.42 (2H, d, J = 7.7 Hz), 7.30 (2H, t, J = 7.6) Hz), 7.22 (1H, t, J = 7.3 Hz), 7.03-6.89 (1H, m), 6.73-6.66 (1H, m), 6.57-6.53 (1H, m), 5.34 (1H, s), 4.94 -4.76 (3H, m), 4.66 (1H, m), 4.00-3.96 (2H, m), 3.83-3.69 (4H, m), 3.28-3.15 (12H, br), HRMS (ESI): m/z calcd for C ₂₇ H ₃₃ FN ₆ O ₂ S [M+H] ⁺ 525.2370, found.
(S)-2-(4-(2-fluoroethyl)piperazin-1-yl)-1-(4-((2-hydroxy-1phenylethyl)amino)-5,8-dihydropyrido[4',3':4 ,5]thieno[2,3-d]pyrimidin-7(6H)-yl)ethan-1-one (Compound 9: P3)
Compound 9 (P3) was synthesized using compound 6a and 2-bromo ethanoic acid. Yield 13.0 mg (10.4 %), ¹ H NMR (500 MHz, DMSO-d ₆ )δ8.24 (1H, s), 7.42 (2H, d, J = 7.4 Hz), 7.33-7.29 (2H, m), 7.23 (1H, m), 6.56 (1H, dd, J = 7.2 and 10 Hz), 5.34 (1H, m), 4.87-4.75 (4H, m), 4.66 (1H, br), 3.94-3.75 (4H, m), 3.53-3.17 (14H, br), HRMS (ESI): m/z calcd for C ₂₅ H ₃₁ FN ₆ O ₂ S [M+H] ⁺ 499.2213, found.
(S)-3-(4-(2-fluoroethyl)piperazin-1-yl)-1-(4-((2-hydroxy-1phenylethyl)amino)-5,8-dihydropyrido[4',3':4 ,5]thieno[2,3-d]pyrimidin-7(6H)-yl)propan-1-one (Compound 10:
(P4)
Compound 10 (P4) was synthesized using compound 6a and 3-bromo propanoic acid. Yield 5.90 mg (4.60 %), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ8.23 (1H, s), 7.42 (2H, d, J = 7.4 Hz), 7.31 (2H, t, J = 7.6) Hz), 7.23 (1H, m), 6.55 (1H, t, J = 7.6 Hz), 5.34 (1H, m), 4.86-4.74 (3H, m), 4.68 (2H, br), 4.59 (2H, br ), 4.47 (1H, br), 3.94-3.84 (6H, m), 3.57-3.51 (2H, m), 3.34 (3H, br), 3.19 (1H, br), 3.00 (2H, br), 2.92 ( 2H, br), HRMS (ESI): m/z calcd for C ₂₆ H ₃₃ FN ₆ O ₂ S [M+H] ⁺ 513.2370, found.
(R,E)-4-(4-(2-fluoroethyl)piperazin-1-yl)-1-(4-((1-phenylethyl)amino)-5,8-dihydropyrido[4',3':4 ,5]thieno[2,3-d]pyrimidin-7(6H)-yl)but-2-en-1-one (Compound 11: P5)
Compound 11 (P5) was synthesized using compound 6b and 4-bromo crotonic acid. Yield 9.98 mg (18.3 %), ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.27 (1H, s), 7.45 (2H, d, J = 7.2 Hz), 7.31 (2H, t, J = 7.7) Hz), 7.23 (1H, br), 6.93 (1H, br), 6.69 (1H, br), 6.52 (1H, br), 5.45 (1H, q, J = 7.1 Hz), 4.92-4.76 (3H, m ), 4.64 (1H, br), 3.92 (2H, br), 3.65 (1H, br), 3.24-3.14 (12H, br), 1.56 (3H, d, J = 7.0 Hz), HRMS (ESI): m /z calcd for C ₂₇ H ₃₃ FN ₆ OS [M+H] ⁺ 509.2421, found.
(S,E)-4-(4-(2-fluoroethyl)piperazin-1-yl)-1-(4-(2,2,2-trifluoro-1-phenylethoxy)-5,8-dihydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-7(6H)-yl)but-2-en-1-one (Compound 12: P6)
Compound 12 (P6) was synthesized using compound 6c and 4-bromo crotonic acid. Yield 14.0 mg (16.9 %), ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.59 (1H, s), 7.66 (2H, br), 7.46 (3H, br), 7.08 (1H, q, J = 6.8 Hz), 6.86 (1H, br), 6.70 (1H, br), 5.01-4.83 (2H, m), 4.57 (1H, t, J = 4.8 Hz), 4.45 (1H, t, J = 4.8 Hz ), 4.01 (1H, br), 3.80 (1H, br), 3.41-3.34 (11H, br), 3.15-3.10 (3H, br), HRMS (ESI): m/z calcd for C ₂₇ H ₂₉ F ₄ N ₅ O ₂ S [M+H] ⁺ 564.1978 found.
(S,E)-4-(4-(2-fluoroethyl)piperazin-1-yl)-1-(4-((2-methoxy-phenylethyl)amino)-5,8-dihydropyrido[4',3' :4,5]thieno[2,3-d]pyrimidin-7(6H)-yl)but-2-en-1-one (Compound 13: P7)
Compound 13 (P7) was synthesized using compound 6d and 4-bromo crotonic acid. Yield 7.57 mg (16.0 %), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (1H, s), 7.47 (2H, d, J = 7.0 Hz), 7.33 (2H, t, J = 7.4) Hz), 7.26 (1H, br), 6.90-6.82 (1H, m), 6.70 (1H, d, J = 7.0 Hz), 6.27 (1H, d, J = 16 Hz), 5.60 (1H, q, J = 6.7 Hz), 4.94 (1H, br), 4.85 (1H,br), 4.76 (1H, br), 4.64 (3H, br), 4.16 (2H, d, J = 5.8 Hz), 3.97 (1H, br ), 3.87-3.82 (2H, m), 3.71-3.68 (3H, m), 3.55 (2H, br), 3.41-3.30 (9H, m), HRMS (ESI): m/z calcd for C ₂₈ H ₃₅ FN ₆ O ₂ S [M+H] ⁺ 539.2526, found.

(Process C)
Compound 15 ([ ¹⁸ F]P1), compound 18a ([ ¹⁸ F]P2) and compound 18b ([ ¹⁸ F]P5) were synthesized as compounds 15, 18a and 18b ([ ¹⁸ F]P1,2,5) Was synthesized according to the following Scheme 3.

Synthesis of compounds 16a and 16b
4-Bromo crotonic acid (8.58 mg, 0.052 mmol) was dissolved in anhydrous THF (1 mL), Et ₃ N (7.30 μL, 0.052 mmol) was added to make it basic, and IBCF (6.90 μL, 0.052 mmol) was added at -15°C. ) Was slowly added and reacted for 15 minutes. On the other hand, anhydrous THF (1 mL) in which compound 6a or 6b (0.058 mmol) and Et ₃ N (8.10 μL, 0.058 mmol) were dissolved was added to the previously prepared reaction solution, and the mixture was stirred at 0° C. for 10 minutes. , Further reacted at room temperature for 2 hours. Furthermore, a mixed solution of anhydrous THF (0.5 mL) and water (1 mL) in which 1-(tert-butyloxycarbonyl)piperazine (9.77 mg, 0.052 mmol) and Et ₃ N (21.9 μL, 0.157 mmol) were dissolved was added, and 2 Reacted for hours. A small amount of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over sodium sulfate. The solvent was distilled off, and the obtained residue was used in the next reaction without being purified.

tert-butyl (S,E)-4-(4-(4-((2-hydroxy-1phenylethyl)amino)-5,8-dihydropyrido[4',3':4,5,thieno[2,3- d]pyrimidin-7(6H)-yl)-4-oxobut-2-en-1-yl)piperazine-1-carboxylate (Compound 16a)
The compound 16a used the compound 6a as a raw material. Yield 25.3 mg (75.1 %), LCMS (ESI): m/z 579.14 [M+H] ⁺ .

tert-butyl (R,E)-4-(4-oxo-4-(4-((1-phenylethyl)amino)-5,8-dihydropyrido[4',3':4,5]thieno[2, 3-d]pyrimidin-7(6H)-yl)but-2-en-1-yl)piperazine-1-carboxylate
Compound 16b)
The compound 16b used the compound 6b as a raw material. Yield 46.7 mg (72.5 %), LCMS (ESI): m/z 563.30 [M+H] ⁺ .

General Synthesis of Compounds 17a and 17b TFA (54.2 μL, 0.730 mmol) was added to Compound 16a or 16b (0.073 mmol) at 0° C., and then the mixture was reacted at room temperature for 1 hour. Water was added to the reaction solution and extracted with ether. The aqueous layer was collected and the solvent was evaporated, then water and methanol were added to the residue and the solvent was evaporated. This operation was repeated three times to remove TFA. The obtained residue was dried sufficiently with a vacuum pump and used in the next reaction.
(S,E)-1-(4-((2-hydroxy-1-phenylethyl)amino)-5,8-dihydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 7(6H)-yl)-4-(piperazin-1-yl)but-2-en-1-one (Compound 17a)
Yield 24.5 mg (70.0 %), LCMS (ESI): m/z 479.10 [M+H] ⁺ .
(R,E)-1-(4-((1-phenylethyl)amino)-5,8-dihydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-7(6H) -yl)-4-(piperazin-1-yl)but-2-en-1-one (Compound 17b)
Yield 34.5 mg (90.0 %), LCMS (ESI): m/z 463.20 [M+H] ⁺ .

[ Radiochemical synthesis]
Synthesis of 2-[ ¹⁸ F]fluoroethyl-4-toluene sulfonate (Compound 14)
Kryptofix 2.2.2. (4.50 mg) and acetonitrile (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. Acetonitrile was added again, and azeotropic dehydration was repeated. This was dissolved in anhydrous acetonitrile (0.25 mL), ethylenglycol-1,2-ditosylate (6.75 μmol, 2.50 mg) was added, and the mixture was reacted at 90° C. for 5 minutes. Water (0.12 mL) was added to the reaction solution, which was then 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 cartridge was dried under N ₂ flow and the target substance was eluted by passing through acetonitrile.

Synthesis of radiolabels 15, 18a and 18b ([ ¹⁸ F] P1,2 and 5) For each of the radiolabels 18a and 18b, each precursor 17a or 17b (2.10 μmol) and K ₂ CO ₃ (210 μmol, 29.0 mg) ) In anhydrous DMF (60 μL) was added to a solution of 14 in acetonitrile (90 μL). Et ₃ N (10 μL) was further added, and the mixture was reacted at 110° C. for 20 minutes. Only the radiolabel 15 had the precursor 6a reacted with the acetonitrile solution (150 μL) of the compound 14 under non-basic condition. After drying the reaction solution under Ar flow, the obtained residue was dissolved in water/acetonitrile mixed solvent (v/v = 70/30, 0.15 mL) and purified by reverse phase HPLC [COSMOSIL 5C18-AR -II ,10 x 250 mm, gradient of 85:15 (0 min) → 70:30 (5 min) → 65:35 (15 min) → 0:100 (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 fraction was applied to Sep-Pak C18 Light Cartridge (Japan Waters Co., Ltd.), and then TFA was removed by passing water. The cartridge was dried under N ₂ flow and the target substance was eluted by passing through acetonitrile. Further, after distilling off the solvent, it was dissolved in physiological saline and used for biological evaluation. The radiochemical yields of [ ¹⁸ F]P1, 2 and 5 were 5.4%, 3.6% and 2.1%, respectively, and the radiochemical purities were all >99%.

[Measurement of EGFR tyrosine kinase inhibitory activity]
The inhibitory activity of each compound (P1 to P10) on EGFR tyrosine kinase was 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 20 μM (final concentration containing 1% DMSO) and was diluted 5 times with a buffer to prepare 10 concentrations. 2 μL of the obtained compound at each concentration was added to each well of the 384-well plate. Further, 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 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, Kinase Detection Reagent (ADP-Glo TM Kinase Assay, Promega) was added in 20μL to each well, after reacting at room temperature for one hour, the light emission amount with Luminescence Counter 1420 ARVO ^TM Light (LTD PerkinElmer) It 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.

As shown in Table 1, all of P1 to P10 show a relatively high binding affinity for the L858R mutant EGFR, but have a binding affinity for the L858R/T790M mutant EGFR (DM in Table 1). Was not shown.

[Cell uptake experiment]
H3255 cells (4.0×10 ⁵ cells/well), which are L858R mutant cells, were cultured on a 12-well plate for 24 hours. After removing the medium, the cells were washed once with PBS(-). Fetal bovine serum-free DMEM/Ham's F-12 medium supplemented with [ ¹⁸ F]P2 and gefitinib (0, 0.5, 1, 2.5 μM) was added to each well, and incubated in a CO ₂ incubator 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.

As shown in FIG. 1, [ ¹⁸ F]P2 uptake into H3255 cells was inhibited by the addition of EGFR-TKI gefitinib.

[PET/CT imaging]
(1) Imaging using H3255 (L858R mutation) cancer-bearing mice
[ ¹⁸ F]P2 (14.3 MBq/140 μL) was administered to H3255 tumor-bearing mice via the tail vein of the mice. Isoflurane (2.0%) was anesthetized from 175 minutes after the administration, and imaging was performed for 20 minutes using the PET/CT apparatus (FX-3300) from 180 minutes after the administration. After that, CT imaging (60 kV, 320 μA) was performed. Image reconstruction was performed using 3D-OSEM. After the completion of imaging, each organ was slaughtered, each organ was removed, 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, the tumor/blood ratio was 3.23, the tumor/muscle ratio was 5.97, and the tumor/lung ratio was 2.66, which was a high adjacent organ ratio. Moreover, the image obtained by imaging is shown in FIG. 2A. The circled portion in FIG. 2A is the portion where H3255 was transplanted. As shown in FIG. 2A, [ ¹⁸ F]P2 was specifically accumulated in L858R mutant EGFR, and L858R mutant EGFR could be imaged by [ ¹⁸ F]P2.
<Imaging conditions>
Animal : balb/c nu/nu mouse, 8 w, male, 21.0 g
Cell : H3255 (1 x 10 ⁷ cells/100 mL)
Injection dose : 14.25 MBq/140 mL
PET/CT : FX-3300 (GMI)
Image acquisition : 180-200 min after administration
Reconstruction : 3D-OSEM
Condition of CT : 60 kV, 320 mA

(2) Imaging using H1975 (L858R/T790M mutant) tumor-bearing mice
[ ¹⁸ F]P2 (9.1 MBq/140 μL) was administered to H1975 cancer-bearing mice through the tail vein of the mice. Isoflurane (2.0%) was anesthetized from 175 minutes after the administration, and imaging was performed for 20 minutes using the PET/CT apparatus (FX-3300) from 180 minutes after the administration. After that, CT imaging (60 kV, 320 μA) was performed. Image reconstruction was performed using 3D-OSEM. After the completion of imaging, each organ was slaughtered, each organ was removed, 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, the tumor/blood ratio was 1.29, the tumor/muscle ratio was 2.04, and the tumor/lung ratio was 0.98, which was a significantly lower proximal organ ratio than that of the H3255 tumor-bearing mice. In addition, an image obtained by imaging is shown in FIG. 2B. The circled portion in FIG. 2B is the portion where H1975 was transplanted. As shown in FIG. 2B, it was confirmed that [ ¹⁸ F]P2 did not accumulate in L858R/T790M mutant EGFR.
<Imaging conditions>
Animal : balb/c nu/nu mouse, 8 w, male, 20.7 g
Cell : H1975 (5×10 ⁶ cells/100 mL)
Injection dose : 9.125 MBq/140 mL
PET/CT : FX-3300 (GMI)
Image acquisition : 180-200 min after administration
Reconstruction : 3D-OSEM
Condition of CT : 60 kV, 320 mA

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]P2. From this, 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 (7)

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).
[In Formula (1),
R ₁ is a group represented by the following formula (a), (b) or (c),
R ₂ is a group represented by the following formula (d) or (e),
Y is -NH- or -O-,
In formulas (a) and (b), L ₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less,
In the formulas (b) and (c), n is an integer of 1 or more and 3 or less,
In formulas (a), (b) and (c), X ₁ is a radioactive halogen atom or —[ ¹¹ C]CH ₃ ,
In the formula (d), R ₃ is an alkyl group which may be halogen-substituted and has 1 to 4 carbon atoms,
A hydroxyalkyl group having 1 to 4 carbon atoms or an alkoxyalkyl group having 1 to 4 carbon atoms,
In formulas (d) and (e), R ₄ is a hydrogen atom or a halogen atom. ] The nuclear medicine diagnostic imaging agent according to claim 1, wherein L ₁ is an ethanediyl group, an ethyleneoxyethylene group, or an ethylenetrioxyethylene group. The nuclear medicine diagnostic imaging agent according to claim 1, wherein R ₃ is a methyl group, a trifluoromethyl group, a hydroxymethyl group or a methoxymethyl group. The nuclear medicine image diagnostic agent according to claim 1, wherein R ₄ is a hydrogen atom or a bromine atom. A compound represented by the following formula (1) or a pharmaceutically acceptable salt of the compound represented by the formula (1).
[In Formula (1),
R ₁ is a group represented by the following formula (a), (b) or (c),
R ₂ is a group represented by the following formula (d) or (e),
Y is -NH- or -O-,
In formulas (a) and (b), L ₁ is a bond, an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less,
In the formulas (b) and (c), n is an integer of 1 or more and 3 or less,
In formulas (a), (b) and (c), X ₁ is a radioactive halogen atom or —[ ¹¹ C]CH ₃ ,
In the formula (d), R ₃ is an alkyl group which may be halogen-substituted and has 1 to 4 carbon atoms,
A hydroxyalkyl group having 1 to 4 carbon atoms or an alkoxyalkyl group having 1 to 4 carbon atoms,
In formulas (d) and (e), R ₄ is a hydrogen atom or a halogen atom. ] Use of a compound represented by formula (2) or a compound represented by formula (2), which is used as a labeled precursor for synthesizing the nuclear medicine diagnostic imaging drug according to any one of claims 1 to 4. A composition comprising an acceptable salt .
[In the formula (2),
R ₁₁ is a group represented by the following formula (f) or (g),
R ₁₂ is a group represented by the following formula (h) or (i),
Y is -NH- or -O-,
In formulas (f) and (g), R ₁₅ is a hydrogen atom or —L ₁₁ —X ₁₁ , and L ₁₁ is an alkanediyl group having 1 to 10 carbon atoms, or
And l is 0 or more and 5 or less, m is the number of repeating ethyleneoxy groups (—OC ₂ H ₄ —) and 1 or more and 5 or less, and X ₁₁ is a chlorine atom, a bromine atom, or an iodine atom. , A nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group, and in the formula (g), n is an integer of 1 or more and 3 or less,
In formula (h), R ₁₃ is an optionally substituted halogen-substituted alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group having 1 to 4 carbon atoms. ,
In formulas (h) and (i), R ₁₄ is a hydrogen atom or a halogen atom. ] A kit for preparing the compound of claim 5 comprising the composition of claim 6 .