JP7370520B2 - radiopharmaceutical - Google Patents

Description

The present invention relates to a novel compound, a radiopharmaceutical containing the same, a drug for preparing the radiopharmaceutical, and the like.

Compounds labeled with radioactive iodine (I) and astatine (At) are used in the diagnosis and treatment of diseases. For example, ¹²³ I and ¹³¹ I are used for Single Photon Emission Computed Tomography (SPECT), ¹²⁴ I is used for Positron Emission Tomography (PET), and ¹³¹ I is used for treatment. ²¹¹ At, which emits alpha particles, has recently attracted much attention as a therapeutic radionuclide. Radioactive iodine labels are mainly introduced into aromatic compounds under oxidative conditions. However, even when using a matrix that provides a stable label with radioactive iodine, it is difficult to create a stable ²¹¹ At label in vivo, and it is difficult to find a label matrix that maintains stable binding in vivo. (For example, Non-Patent Document 1). As one of these methods, a method of introducing it into a boron cage has been developed (Non-Patent Document 2).

Chemical Society Reviews 34: 153-163, 2005 Current Radiopharmaceuticals 1: 144-176, 2008

It is preferable that the radiolabeled compound has little non-specific accumulation in the body, selectively accumulates at the target site, and is stable in the body. Furthermore, it is preferable that a highly versatile introduction reaction exists. Furthermore, the aromatic astatine derivatives that have been developed so far have insufficient stability in vivo. Furthermore, since oxidative conditions are used to introduce these halogens into aromatic rings, it is difficult to introduce these halogens into compounds that are unstable under oxidative conditions.
On the other hand, although boron cages have a highly water-soluble structure that can supply astatine derivatives that are stable in vivo, they have problems in that it is difficult to control selective accumulation in target affected areas and that they have high retention in normal tissues. Become.
Therefore, one embodiment of the present invention relates to a new substance.
One embodiment of the present invention relates to compounds and the like that exhibit high in vivo stability.

〔式中、
Ｘは、⁷⁵Ｂｒ、⁷⁶Ｂｒ、⁷⁷Ｂｒ、⁸²Ｂｒ、¹²³Ｉ、¹²⁴Ｉ、¹²⁵Ｉ、¹³¹Ｉ、¹³³Ｉ、²⁰⁹Ａｔ、²¹⁰Ａｔ又は²¹¹Ａｔであり、
Ｒ₁は、式（ａ）：

〔式中、Ｒ₂は、標的分子認識素子と結合可能な官能基を有する基、標的分子認識素子の連結基と結合可能な官能基を有する基、又は、炭素数6～20のアリール基であり、ａ１は、0～6の整数であり、ａ２は、0又は1であり、*は、結合部位である。〕で表される基である。〕
〔２〕式（Ａ２）又は式（Ｂ２）で表される化合物、又はその薬理学的に許容可能な塩。

〔式中、Ｘは、式（Ａ１）、式（Ｂ１）と同定義であり、
Ｒ₁’は、下記式（ａ２－１）：

〔式中、ａ３は、0～6の整数であり、＊は結合部位である〕で表される基であり、
Ｌ₁は、連結基であり、
ｐ１は、0又は1であり、
ｐ２は、0又は1であり、
Ｐ₁は、標的分子認識素子である。〕
〔３〕式（Ａ３）又は式（Ｂ３）で表される化合物、又はその薬理学的に許容可能な塩。

〔式中、
Ｌは、式（ｃ）：

〔式中、Ｒ₅₀は、炭素数1～10のアルキル基、炭素数1～10のフルオロアルキル基、炭素数6～60のアリール基であり、*は、結合部位である。〕で表される基であり、
Ｒ₁は、式（ａ）：

〔式中、Ｒ₂は、標的分子認識素子と結合可能な官能基を有する基、又は標的分子認識素子の連結基と結合可能な官能基を有する基であり、ａ１は、0～6の整数であり、ａ２は、0又は1であり、*は、結合部位である。〕で表される基である。〕
〔４〕式（Ａ４）又は式（Ｂ４）で表される化合物、又はその薬理学的に許容可能な塩。

〔式中、Ｌは、式（ｃ）：

〔式中、Ｒ₅₀は、炭素数1～10のアルキル基、炭素数1～10のフルオロアルキル基、炭素数6～60のアリール基であり、*は、結合部位である。〕で表される基であり、
Ｒ₁’は、下記式（ａ２－１）：

〔式中、ａ３は、0～6の整数であり、＊は結合部位である〕で表される基であり、
Ｌ₁は、連結基であり、
ｐ１は、0又は1であり、
ｐ２は、0又は1であり、
Ｐ₁は、標的分子認識素子であり、
但し、Ｐ₁が、式（ｂ－５１）：

〔式中、ｂ９は、0又は1であり、*は、結合部位である。〕で表される基であり、且つ、ｐ１＝ｐ２＝0である場合を除く。〕
〔５〕上記〔１〕又は〔２〕に記載の化合物、又はその薬理学的に許容可能な塩を含む、放射性医薬。
〔６〕上記〔１〕又は〔２〕に記載の化合物、又はその薬理学的に許容可能な塩を含む、放射線治療薬。
〔７〕上記〔１〕又は〔２〕に記載の化合物、又はその薬理学的に許容可能な塩を含む、放射線画像診断薬。
〔８〕上記〔１〕又は〔２〕に記載の化合物、又はその薬理学的に許容可能な塩の放射性医薬の製造のための使用。
〔９〕上記〔１〕又は〔２〕に記載の化合物、又はその薬理学的に許容可能な塩の放射線治療のための使用。
〔１０〕上記〔１〕又は〔２〕に記載の化合物、又はその薬理学的に許容可能な塩の放射線画像診断のための使用。
〔１１〕上記〔１〕又は〔２〕に記載の化合物、又はその薬理学的に許容可能な塩を投与する放射線治療方法。
〔１２〕上記〔１〕又は〔２〕に記載の化合物、又はその薬理学的に許容可能な塩を投与する放射線画像診断方法。
〔１３〕上記〔３〕又は〔４〕に記載の化合物、又はその薬理学的に許容可能な塩を含む、放射性医薬の調製用薬剤。
〔１４〕上記〔３〕又は〔４〕に記載の化合物又はその薬理学的に許容可能な塩と、^７５Ｂｒ、^７６Ｂｒ、^７７Ｂｒ、^８２Ｂｒ、^１２３Ｉ、^１２４Ｉ、^１２５Ｉ、^１３１Ｉ、^１３３Ｉ、^２０９Ａｔ、^２１０Ａｔ又は^２１１Ａｔを含む薬剤とを、別々の包装単位として含む、キット。
〔１５〕上記〔１〕又は〔２〕に記載の化合物又はその薬理学的に許容可能な塩の製造方法であって、
式（Ｂ３）で表される化合物若しくはその薬理学的に許容可能な塩、又は、
式（Ｂ４）：

〔式中、Ｌは、式（ｃ）：

〔式中、Ｒ₅₀は、炭素数1～10のアルキル基、炭素数1～10のフルオロアルキル基、炭素数6～60のアリール基であり、*は、結合部位である。〕で表される基であり、
Ｒ₁’は、下記式（ａ２－１）：

〔式中、ａ３は、0～6の整数であり、＊は結合部位である〕で表される基であり、
Ｌ₁は、連結基であり、
ｐは、0又は1であり、
Ｐ₁は、標的分子認識素子である。〕で表される化合物若しくはその薬理学的に許容可能な塩を、⁷⁵Ｂｒ、⁷⁶Ｂｒ、⁷⁷Ｂｒ、⁸²Ｂｒ、¹²³Ｉ、¹²⁴Ｉ、¹²⁵Ｉ、¹³¹Ｉ、¹³³Ｉ、²⁰⁹Ａｔ、²¹⁰Ａｔ又は²¹¹Ａｔのイオンと反応させることを含む、製造方法。
〔１６〕式（Ｂ５）で表される化合物、又はその薬理学的に許容可能な塩。

〔式中、Ｒ₈₀は、ヒドロキシ基、＊－ＯＣＨ₂Ｒ₈₁（式中、Ｒ₈₁は、置換又は無置換の2-ナフチル基、又はp-メトキシフェニル基であり、*は、結合部位である。）で表される基、又は、＊－ＯＳｉ（Ｒ₈₂）₃（式中、Ｒ₈₂は、炭素数1～4のアルキル基、又はフェニル基であり、*は、結合部位である。）で表される基であり、
Ｒ₁は、式（ａ－１１）、（ａ－１２）、（ａ－１３）又は（ａ－１４）：

〔式中、ａ５は、前記ａ１と同定義であり、Ｒ₂₃，Ｒ₂₄，Ｒ₂₅，Ｒ₂₆及びＲ₂₇は、それぞれ独立に、水素、フッ素又はニトロ基であり、Ｒ₂₈及びＲ₂₉は、それぞれ独立に、水素、スルホ基又はスルホ基の塩であり、Ｘ¹⁰は、ＣＨ基又は窒素であり、*は、結合部位である。〕で表される基である。〕
〔１７〕式（Ｂ６）で表される化合物、又はその薬理学的に許容可能な塩。

〔式中、Ｒ₈₀は、式（Ｂ５）と同定義であり、
Ｒ₁’は、下記式（ａ２－１）：

〔式中、ａ３は、0～6の整数であり、＊は結合部位である〕で表される基であり、
Ｌ₁は、連結基であり、
ｐ１は、0又は1であり、
ｐ２は、0又は1であり、
Ｐ₁は、標的分子認識素子であり、
但し、Ｐ₁が、式（ｂ－５１）：

〔式中、ｂ９は、0又は1であり、*は、結合部位である。〕で表される基であり、且つ、ｐ１＝ｐ２＝0である場合を除く。〕Embodiments of the present invention relate to the following matters.
[1] A compound represented by formula (A1) or formula (B1), or a pharmacologically acceptable salt thereof.

[During the ceremony,
X is ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ At,
R ₁ is represented by formula (a):

[In the formula, R ₂ is a group having a functional group capable of binding to the target molecule recognition element, a group having a functional group capable of binding to the linking group of the target molecule recognition element, or an aryl group having 6 to 20 carbon atoms. , a1 is an integer from 0 to 6, a2 is 0 or 1, and * is a binding site. ] is a group represented by ]
[2] A compound represented by formula (A2) or formula (B2), or a pharmacologically acceptable salt thereof.

[wherein, X has the same definition as formula (A1) and formula (B1),
R ₁ ' is the following formula (a2-1):

A group represented by [wherein a3 is an integer of 0 to 6 and * is a bonding site],
L ₁ is a linking group,
p1 is 0 or 1,
p2 is 0 or 1,
P ₁ is a target molecule recognition element. ]
[3] A compound represented by formula (A3) or formula (B3), or a pharmacologically acceptable salt thereof.

[During the ceremony,
L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by
R ₁ is represented by formula (a):

[In the formula, R ₂ is a group having a functional group capable of binding to the target molecule recognition element, or a group having a functional group capable of binding to the linking group of the target molecule recognition element, and a1 is an integer of 0 to 6. , a2 is 0 or 1, and * is a binding site. ] is a group represented by ]
[4] A compound represented by formula (A4) or formula (B4), or a pharmacologically acceptable salt thereof.

[In the formula, L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by
R ₁ ' is the following formula (a2-1):

A group represented by [wherein a3 is an integer of 0 to 6 and * is a bonding site],
L ₁ is a linking group,
p1 is 0 or 1,
p2 is 0 or 1,
P ₁ is a target molecule recognition element,
However, P ₁ is the formula (b-51):

[In the formula, b9 is 0 or 1, and * is a binding site. ] except when p1=p2=0. ]
[5] A radiopharmaceutical comprising the compound described in [1] or [2] above, or a pharmacologically acceptable salt thereof.
[6] A radiotherapeutic agent comprising the compound described in [1] or [2] above, or a pharmacologically acceptable salt thereof.
[7] A radiological imaging diagnostic agent comprising the compound according to [1] or [2] above, or a pharmacologically acceptable salt thereof.
[8] Use of the compound according to [1] or [2] above, or a pharmacologically acceptable salt thereof, for the production of a radiopharmaceutical.
[9] Use of the compound according to [1] or [2] above, or a pharmacologically acceptable salt thereof, for radiotherapy.
[10] Use of the compound according to [1] or [2] above, or a pharmacologically acceptable salt thereof, for radiographic imaging diagnosis.
[11] A radiation therapy method comprising administering the compound according to [1] or [2] above, or a pharmacologically acceptable salt thereof.
[12] A method for radiological imaging diagnosis, comprising administering the compound according to [1] or [2] above, or a pharmacologically acceptable salt thereof.
[13] A drug for preparing a radiopharmaceutical, comprising the compound described in [3] or [4] above, or a pharmacologically acceptable salt thereof.
[14] The compound described in [3] or [4] above or a pharmacologically acceptable salt thereof, and ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I , ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ At as separate packaging units.
[15] A method for producing the compound described in [1] or [2] above or a pharmacologically acceptable salt thereof, comprising:
A compound represented by formula (B3) or a pharmacologically acceptable salt thereof, or
Formula (B4):

[In the formula, L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by
R ₁ ' is the following formula (a2-1):

A group represented by [wherein a3 is an integer of 0 to 6 and * is a bonding site],
L ₁ is a linking group,
p is 0 or 1,
P ₁ is a target molecule recognition element. ] or a pharmacologically acceptable salt thereof, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ^{82 Br, 123} I ^{, 124} I, ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At Or a manufacturing method comprising reacting with ions of ²¹¹ At.
[16] A compound represented by formula (B5) or a pharmacologically acceptable salt thereof.

[In the formula, R ₈₀ is a hydroxy group, *-OCH ₂ R ₈₁ (wherein, R ₈₁ is a substituted or unsubstituted 2-naphthyl group or p-methoxyphenyl group, and * is a bonding site) ), or *-OSi(R ₈₂ ) ₃ (wherein R ₈₂ is an alkyl group having 1 to 4 carbon atoms or a phenyl group, and * is a bonding site. ) is a group represented by
R ₁ is formula (a-11), (a-12), (a-13) or (a-14):

[In the formula, a5 has the same definition as a1 above, R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ and R ₂₇ are each independently hydrogen, fluorine or a nitro group, and R ₂₈ and R ₂₉ are , each independently hydrogen, a sulfo group, or a salt of a sulfo group, X ¹⁰ is a CH group or nitrogen, and * is a bonding site. ] is a group represented by ]
[17] A compound represented by formula (B6) or a pharmacologically acceptable salt thereof.

[In the formula, R ₈₀ has the same definition as the formula (B5),
R ₁ ' is the following formula (a2-1):

A group represented by [wherein a3 is an integer of 0 to 6 and * is a bonding site],
L ₁ is a linking group,
p1 is 0 or 1,
p2 is 0 or 1,
P ₁ is a target molecule recognition element,
However, P ₁ is the formula (b-51):

[In the formula, b9 is 0 or 1, and * is a binding site. ] except when p1=p2=0. ]

One embodiment of the invention provides a novel substance.
One embodiment of the present invention relates to compounds and the like that exhibit high in vivo stability.

FIG. 1 shows the results of urine analysis after administration of labeled compound 3. FIG. 2 shows the results of urine analysis after administration of labeled compound 4.

[Definition of terms, etc.]
First, the meanings of various terms used in this specification will be explained.
"At" is astatine.
"*" means a binding site.
"Group having a functional group capable of binding to a target molecule recognition element" means a group having a functional group capable of binding a target molecule recognition element such as a polypeptide to the compound of the present invention via the functional group. .
"A group having a functional group capable of binding to a linking group of a target molecule recognition element" refers to a functional group capable of binding a linking group of a target molecule recognition element such as a polypeptide to a compound of the present invention via a functional group. means a group having a group.

The number of carbon atoms in each group is the total number of carbon atoms including carbon atoms in substituents.
The alkyl group may be any linear, branched, or cyclic alkyl group.
Examples of the alkyl group having 1 to 30 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, and heptyl group. , octyl group, nonyl group, decyl group, tetradecyl group, hexadecyl group, octadecyl group, icosyl group, docosyl group, hexacosyl group, octacosyl group, and triacontyl group.
Examples of the alkyl group having 1 to 20 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, and heptyl group. , octyl group, nonyl group, decyl group, tetradecyl group, hexadecyl group, octadecyl group, and icosyl group.
Examples of the alkyl group having 1 to 10 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, and heptyl group. , octyl group, nonyl group, and decyl group.

Examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, and tert-butyl group.
Examples of the alkoxy group having 1 to 4 carbon atoms include methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, sec-butyloxy group, and tert-butyloxy group.

The aryl group may be an unsubstituted or substituted aryl group, and may be a monocyclic or fused polycyclic aryl group.
In the case of an aryl group having 6 to 20 carbon atoms, examples of the substituent include an alkyl group having 1 to 4 carbon atoms, fluorine, and a nitro group.
Examples of the aryl group having 6 to 20 carbon atoms include phenyl group, o-methylphenyl group, m-methylphenyl group, p-methylphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group. group, o-fluorophenyl group, m-fluorophenyl group, p-fluorophenyl group, naphthyl group, and anthracenyl group.

In the case of an aryl group having 6 to 60 carbon atoms, examples of the substituent include an alkyl group having 1 to 20 carbon atoms, a fluoroalkyl group having 1 to 20 carbon atoms, and a dialkyl group having an alkyl group having 1 to 30 carbon atoms. Examples include a carbamoyl group, a diarylcarbamoyl group in which the aryl group has 6 to 20 carbon atoms, and fluorine.
The aryl group having 6 to 60 carbon atoms is preferably an alkyl group having 1 to 20 carbon atoms, a fluoroalkyl group having 1 to 20 carbon atoms, a dialkylcarbamoyl group in which the alkyl group has 1 to 30 carbon atoms, or an aryl group having 1 to 30 carbon atoms. A diarylcarbamoyl group having 6 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms substituted with at least one group selected from fluorine, or an unsubstituted aryl group having 6 to 20 carbon atoms.
Examples of the aryl group having 6 to 60 carbon atoms include phenyl group, p-methylphenyl group, p-dodecylphenyl group, p-dodecylphenyl group, p-(dibutylcarbamoyl)phenyl group, and p-(dioctylcarbamoyl)phenyl group. group, p-(diheptadecylcarbamoyl)phenyl group, p-(didocosylcarbamoyl)phenyl group, p-([(1-naphthalenyl)methyl]methylcarbamoyl)phenyl group, p-(di-[(1-naphthalenyl) ) methyl]carbamoyl)phenyl group, and p-(dinaphthalenylcarbamoyl)phenyl group.

Examples of the substituent of the substituted or unsubstituted 2-naphthyl group include an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms.

The aliphatic hydrocarbon ester group having 1 to 10 carbon atoms has the formula: *-C(=O)OR ₆₁ (wherein R ₆₁ is an alkyl group having 1 to 8 carbon atoms, and * is a bonding site. ).
Examples of the alkyl group having 1 to 8 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, and heptyl group. , octyl group.

The aromatic hydrocarbon ester group having 8 to 20 carbon atoms has the formula: *-C(=O)OR ₆₂ (wherein R ₆₂ is an aryl group having 6 to 18 carbon atoms, and * is a bonding site. ).
Examples of the aryl group having 6 to 18 carbon atoms include phenyl group, o-methylphenyl group, m-methylphenyl group, p-methylphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group. group, o-fluorophenyl group, m-fluorophenyl group, p-fluorophenyl group, and naphthyl group.

A fluoroalkyl group means an alkyl group in which one or more hydrogen atoms are substituted with fluorine. The fluoroalkyl group is preferably a perfluoroalkyl group. Note that the perfluoroalkyl group means an alkyl group in which all hydrogens are substituted with fluorine.
Examples of the fluoroalkyl group having 1 to 20 carbon atoms include trifluoromethyl group, pentafluoroethyl group, perfluoro n-propyl group, perfluoroisopropyl group, perfluoro n-butyl group, perfluoro sec-butyl group, and perfluoro sec-butyl group. tert-butyl group, perfluoropentyl group, perfluorohexyl group, perfluoroheptyl group, perfluorooctyl group, perfluorononyl group, perfluorodecyl group, perfluorotetradecyl group, perfluorohexadecyl group, perfluorooctadecyl group group, and perfluoroicosyl group.
Examples of the fluoroalkyl group having 1 to 10 carbon atoms include trifluoromethyl group, pentafluoroethyl group, perfluoro n-propyl group, perfluoroisopropyl group, perfluoro n-butyl group, perfluoro sec-butyl group, and perfluoro sec-butyl group. Examples include tert-butyl group, perfluoropentyl group, perfluorohexyl group, perfluoroheptyl group, perfluorooctyl group, perfluorononyl group, and perfluorodecyl group.

[Compound A1, Compound B1, etc.]
One embodiment of the present invention provides a compound represented by formula (A1) or formula (B1), or a pharmacologically acceptable salt thereof (hereinafter referred to as compound or pharmacologically acceptable salt thereof). The compound represented by formula (A1) is also referred to as "compound A1." The compound represented by formula (B1) is also referred to as "compound B1."

を有することで、高い生体内安定性を示すことが明らかになった。なお、化合物Ｂ１は、生体内で分解され、化合物Ａ１の形態となると考えられる。According to one embodiment of the invention, a novel substance is provided. According to one embodiment of the present invention, labeling with radioactive iodine and astatine is possible using a highly versatile introduction reaction.
According to one embodiment of the present invention, compounds and the like that exhibit high in vivo stability are provided. According to one embodiment of the present invention, a non-aromatic carbon can be labeled with radioactive iodine or astatine. Normally, when a halogen compound such as iodine or astatine is substituted on the SP3 carbon such as an alkyl chain, it is thought that these are likely to be eliminated and the stability in vivo is impaired, but the structural site of compound A1 is:

It has been revealed that by having this, high in-vivo stability is exhibited. Note that Compound B1 is considered to be decomposed in vivo to form Compound A1.

In formula (A1) or formula (B1), each substituent is as follows.
X is ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ At, preferably ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ At, more preferably ²⁰⁹ At, ²¹⁰ At or ²¹¹ At.

R ₁ is a group represented by formula (a).

〔式中、Ｒ₂は、標的分子認識素子と結合可能な官能基を有する基、標的分子認識素子の連結基と結合可能な官能基を有する基、又は、炭素数6～20のアリール基でありであり、ａ１は、0～6の整数であり、ａ２は、0又は1であり、*は、結合部位である。〕で表される基である。
標的分子認識素子と結合可能な官能基、又は、標的分子認識素子の連結基と結合可能な官能基（つまり、「標的分子認識素子若しくはその連結基と結合可能な官能基」であり、以下「官能基ａ」ともいう）としては、例えば、カルボキシ基又はその活性エステル；マレイミド基、アクリロイル基等のC=C結合を有する基；カルバモイル基、イソチオシアナート基、及びアミノ基からなる群から選ばれる少なくとも１種の官能基が挙げられる。カルボキシ基の活性エステルとしては、例えば、炭素数1～10の脂肪族炭化水素エステル基、炭素数8～20の芳香族炭化水素エステル基、クロロアセチル基、ブロモアセチル基、ヨードアセチル基が挙げられる。[Group of formula (a)]
From the viewpoint of derivative synthesis, R ₁ is preferably represented by formula (a):

[In the formula, R ₂ is a group having a functional group capable of binding to the target molecule recognition element, a group having a functional group capable of binding to the linking group of the target molecule recognition element, or an aryl group having 6 to 20 carbon atoms. , a1 is an integer from 0 to 6, a2 is 0 or 1, and * is a binding site. ] is a group represented by
A functional group capable of binding to a target molecule recognition element or a functional group capable of binding to a linking group of a target molecule recognition element (that is, a "functional group capable of binding to a target molecule recognition element or its linking group", hereinafter referred to as " Examples of the functional group a) include carboxy groups or active esters thereof; groups having a C═C bond such as maleimide groups and acryloyl groups; carbamoyl groups, isothiocyanate groups, and amino groups. At least one kind of functional group is mentioned. Examples of active esters of carboxy groups include aliphatic hydrocarbon ester groups having 1 to 10 carbon atoms, aromatic hydrocarbon ester groups having 8 to 20 carbon atoms, chloroacetyl groups, bromoacetyl groups, and iodoacetyl groups. .

〔式中、Ｒ₂₁₁は、水素、炭素数1～10のアルキル基、又は炭素数6～20のアリール基であり、Ｘ₁は、塩素、臭素、ヨウ素であり、Ｒ₂₁₂は、水素、又はメチル基であり、Ｒ₂₁₃は、水素、炭素数1～10のアルキル基、又は炭素数6～20のアリール基であり、Ｒ₂₁₄は、水素、又は炭素数1～4のアルキル基であり、ａ２０は、1～6の整数である。〕で表される基である。Examples of the functional group capable of binding to the target molecule recognition element or the functional group capable of binding to the linking group of the target molecule recognition element include formulas (a1), (a2), (a3), (a4), and (a5). ), (a6), (a7), (a8) or (a9):

[In the formula, R ₂₁₁ is hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 20 carbon atoms, X ₁ is chlorine, bromine, or iodine, and R ₂₁₂ is hydrogen, or is a methyl group, R ₂₁₃ is hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 20 carbon atoms, R ₂₁₄ is hydrogen or an alkyl group having 1 to 4 carbon atoms, a20 is an integer from 1 to 6. ] is a group represented by

a1 is an integer from 0 to 6, preferably 1.
a2 is 0 or 1, preferably 1.

で表される基であってもよい。
Ｒ₁は、好ましくは式（ａ－１）：

〔式中、Ｒ₂₁は、水素、標的分子認識素子若しくはその連結基と結合可能な官能基を有していてもよい炭素数1～20のアルキル基、又は、標的分子認識素子若しくはその連結基と結合可能な官能基を有していてもよい炭素数6～20のアリール基であり、ａ３は、前記ａ１と同定義であり、*は、結合部位である。〕で表される基である。R ₁ is, for example, of the formula:

It may be a group represented by
R ₁ preferably represents formula (a-1):

[In the formula, R ₂₁ is hydrogen, an alkyl group having 1 to 20 carbon atoms which may have a functional group capable of bonding to the target molecule recognition element or its connecting group, or a target molecule recognition element or its connecting group is an aryl group having 6 to 20 carbon atoms which may have a functional group capable of bonding with, a3 has the same definition as a1 above, and * is a bonding site. ] is a group represented by

〔式中、ａ５は、前記ａ１と同定義であり、Ｒ₂₃，Ｒ₂₄，Ｒ₂₅，Ｒ₂₆及びＲ₂₇は、それぞれ独立に、水素、フッ素又はニトロ基であり、Ｒ₂₈及びＲ₂₉は、それぞれ独立に、水素、スルホ基又はスルホ基の塩であり、Ｘ¹⁰は、ＣＨ基又は窒素であり、*は、結合部位である。〕で表される基である。
Ｒ₂₃、Ｒ₂₄、Ｒ₂₅、Ｒ₂₆及びＲ₂₇のうち少なくとも1つが、フッ素又はニトロ基であることが好ましく、ニトロ基であることがより好ましい。
Ｒ₂₄、及びＲ₂₆が水素であり、且つＲ₂₃、Ｒ₂₅、及びＲ₂₇のうち少なくとも1つが、ニトロ基であることが好ましく、Ｒ₂₃、Ｒ₂₄Ｒ₂₆、及びＲ₂₇が水素であり、且つＲ₂₅がニトロ基であることが好ましい。R ₁ is more preferably represented by formula (a-11), (a-12), (a-13) or (a-14):

[In the formula, a5 has the same definition as a1 above, R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ and R ₂₇ are each independently hydrogen, fluorine or a nitro group, and R ₂₈ and R ₂₉ are , each independently hydrogen, a sulfo group, or a salt of a sulfo group, X ¹⁰ is a CH group or nitrogen, and * is a bonding site. ] is a group represented by
At least one of R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ and R ₂₇ is preferably fluorine or a nitro group, more preferably a nitro group.
R ₂₄ and R ₂₆ are hydrogen, and at least one of R ₂₃ , R ₂₅ and R ₂₇ is preferably a nitro group, and R ₂₃ , R ₂₄ R ₂₆ and R ₂₇ are hydrogen; , and R ₂₅ is preferably a nitro group.

〔式中、＊は結合部位である。〕が挙げられる。As R ₁ , for example,

[In the formula, * is a binding site. ].

Specific examples of the above compound A1 or B1 include the following compounds A1-1 to A1-18 and compounds B1-1 to B1-18.

Compound A1, compound B1, etc. can be synthesized using a known method, and can be produced, for example, by the method described in the Examples of this specification.

A method for using compound A1, compound B1, or a pharmacologically acceptable salt thereof includes, for example, binding a target molecule recognition element to compound A1, compound B1, or a pharmacologically acceptable salt thereof. or a pharmacologically acceptable salt thereof. By inducing this compound, it can be used as a radiopharmaceutical such as a radiation therapy drug or a radiation imaging diagnostic drug, similar to Compound A2 or Compound B2.

Compound A1 or compound B1 may be a pharmacologically acceptable salt of the above compound.
Examples of pharmacologically acceptable salts include acid addition salts and base addition salts.
The acid addition salt may be either an inorganic acid salt or an organic acid salt.
Examples of inorganic acid salts include hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate.
Examples of organic acid salts include citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, and benzenesulfonate. salts, para-toluenesulfonates.
The base addition salt may be either an inorganic base salt or an organic base salt.
Examples of inorganic base salts include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts.
Examples of the organic base salt include triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt.

若しくは
式：

で表される基と、連結基を介して結合していてもよいし、直接結合していてもよい。
連結基としては、2-イミノチオランから誘導されるイミノチオールが挙げられる。[Compound A2 or Compound B2, etc.]
Compound A2, compound B2, or the like is a compound formed by binding a target molecule recognition element to compound A1, compound B1, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof.
The target molecule recognition element has the formula:

Or formula:

It may be bonded to the group represented by via a linking group or may be bonded directly.
The linking group includes iminothiol derived from 2-iminothiolane.

[Target molecule recognition element]
A "target molecule recognition element" is a molecule, substituent, functional group, or atomic group that can recognize a target molecule by binding to it in vivo.
Examples of target molecule recognition elements include polypeptides and other ligands that bind to target molecules.
The polypeptide is usually a polypeptide that binds to a target molecule, preferably a polypeptide that specifically binds to a target molecule. Specifically binding means binding to a target molecule, but not binding to molecules other than the target molecule, or binding weakly.
Other examples of ligands that bind to target molecules include nitroimidazole groups and the like.
The target molecule refers to a molecule that exists in a target site to be diagnosed using a radioactive drug, such as a tissue or a cell, and preferably a molecule that is specifically expressed. "Specifically expressed" means that it is expressed at the target site, but not or at low expression at sites other than the target site.

Target molecule recognition elements include, for example, proteins that are highly expressed in tissue structures associated with inflammation and tumor cell infiltration, and ligands that bind to proteins that are specifically expressed in tumor cells, as well as antibodies and antigen-binding regions of antibodies. Fragments are mentioned.

Examples of antibodies include monoclonal antibodies such as anti-CD25 antibodies and anti-CD20 antibodies.
Antibody antigen-binding region fragments include, for example, Fab fragments (hereinafter also simply referred to as "Fab"), F(ab') ₂ fragments, F(ab) ₂ fragments, and variable region fragments (hereinafter also referred to as "Fv fragments"). ).
Fab fragment means an N-terminal product produced by papain degradation of an antibody and a fragment having a domain structure similar to this product.
The F(ab') ₂ fragment refers to a fragment obtained by reducing the disulfide bond in the hinge region of F(ab') ₂ of an antibody and a fragment having a domain structure similar to this.
The F(ab) ₂ fragment refers to a dimer in which two molecules of Fab fragments are bonded to each other through disulfide bonds.
Fv fragment refers to the smallest fragment of an antibody that has antigen-binding activity.
More specifically, the antigen-binding region fragment of an antibody includes an antibody against a protein specifically expressed in a specific cancer cell, and its Fab fragment or Fv fragment.

Other target molecule recognition elements include cyclic pentapeptides, such as cyclo-Arg-Gly-Asp-D-Phe-Lys (hereinafter referred to as "c( ``RGDfK)''). Other properties include bisphosphonic acid, oligoaspartic acid, and oligoglutamic acid, which have affinity for hydroxyapatite, which is often present in osteoblastic cancers (bone metastases), and receptors for scanning factors present on the surface of macrophages. These include fMet-Leu-Phe (fMLP), which is a peptide with a certain level of folic acid, and folic acid and its derivatives, which bind to folate receptors that are found to be expressed in cancer cells.
Note that the target molecule recognition element is not limited to these exemplified polypeptides, and any polypeptide that binds to the target molecule can be used.

The target molecule recognition element may be bonded by introducing a linking group that reacts with the functional group of the compound using, for example, a thiolating reagent such as 2-iminothiolane. The linking group can be introduced into the Fab fragment by adding a sulfhydryl group to the amino group of the Fab cross section by reacting the above thiolating reagent at pH 7-9.

〔式中、Ｒ₇₀，Ｒ₇₁，Ｒ₇₂は、それぞれ独立に、水素、炭素数1～4のアルキル基であり、＊は結合部位である。〕で表される基である。
Glu-urea-Lys 部位とは、式（ｅ２）：

〔式中、Ｒ₇₀，Ｒ₇₁，Ｒ₇₂は、それぞれ独立に、水素、炭素数1～4のアルキル基であり、＊は結合部位である。〕で表される基である。As the target molecule recognition element, for example, a ligand having an Asp-urea-Lys site or a Glu-urea-Lys site may be used. The ligand selectively binds to the receptor for prostate specific membrane antigen, whose expression is significantly increased in prostate cancer.
The Asp-urea-Lys site is the formula (e1):

[In the formula, R ₇₀ , R ₇₁ , and R ₇₂ are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and * is a bonding site. ] is a group represented by
The Glu-urea-Lys moiety is the formula (e2):

[In the formula, R ₇₀ , R ₇₁ , and R ₇₂ are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and * is a bonding site. ] is a group represented by

Examples of the Asp-urea-Lys moiety include groups of the following formulas.

Examples of the Glu-urea-Lys moiety include groups of the following formula.

In addition to the above, for example, the above-mentioned polypeptide into which a specific functional group f ₁ has been introduced, and other proteins and tumor cells that have ligands that bind to target molecules that are highly expressed in tissue construction associated with inflammation and tumor cell infiltration, etc. A compound (2) having a functional group f _{2 that reacts with the functional group f 1 to} form a bond is administered as a target molecule recognition element, and the target molecule is [Chemical Society Reviews 45: 6409-6658, 2016, Chemical Society Reviews 42: 5131-5142, 2013]

〔式中、＊は結合部位である。〕Examples of the functional group f ₁ include groups represented by the following formula (f ₁ -1), formula (f ₁ -2), or formula (f ₁ -3).

[In the formula, * is a binding site. ]

〔式中、＊は結合部位である。〕Examples of the functional group f ₂ include the following formula (f ₂ -1), formula (f ₂ -2), formula (f ₂ -3), formula (f ₂ -4), or formula (f ₂ -5). ).

[In the formula, * is a binding site. ]

Examples of the compound A2 or B2 include a compound represented by the following formula (A2) or formula (B2), or a pharmacologically acceptable salt thereof.

〔式中、Ｘは、式（Ａ１）、式（Ｂ１）と同定義であり、
Ｒ₁’は、下記式（ａ２－１）：

〔式中、ａ３は上記式（ａ－１）と同様であり、＊は結合部位である〕で表される基であり、
Ｌ₁は、連結基であり、
ｐ１は、0又は1であり、
ｐ２は、0又は1であり、
Ｐ₁は、標的分子認識素子である。〕
Ｌ₁は、
（１）Ｒ₁’とＰ₁を連結する連結基、又は
（２）式：

若しくは
式：

で表される基とＰ₁を連結する連結基である。
Ｌ₁は、例えば、Ｒ₁’の連結基と連結可能な官能基により結合を形成し、Ｐ₁の標的分子認識素子とも結合を形成する。

[wherein, X has the same definition as formula (A1) and formula (B1),
R ₁ ' is the following formula (a2-1):

A group represented by [wherein a3 is the same as the above formula (a-1) and * is a bonding site],
L ₁ is a linking group,
p1 is 0 or 1,
p2 is 0 or 1,
P ₁ is a target molecule recognition element. ]
_L1 is
(1) A linking group that connects R ₁ ' and P ₁ or (2) Formula:

Or formula:

It is a connecting group that connects the group represented by and P ₁ .
L ₁ forms a bond, for example, with a functional group that can be connected to the linking group of R ₁ ', and also forms a bond with the target molecule recognition element of P ₁ .

〔式中、Ｒ₃₁及びＲ₃₂は、水素、炭素数1～4のアルキル基、又は炭素数1～4のアルコキシ基であり、Ｒ₃₃は、水素、又は炭素数1～4のアルキル基であり、ｂ１は、0～6の整数であり、ｂ２は、0又は1であり、ｂ３は、0又は1であり、但しｂ２＝1の場合ｂ３は0であり、ｂ３＝1の場合ｂ２は0であり、*は、結合部位である。〕で表される基である。
式（ｂ）中、Ｒ₃₁及びＲ₃₂は、好ましくは水素である。
Ｒ₃₃は、好ましくは水素である。
ｂ１は、0～6の整数であり、好ましくは0である。
ｂ２は、0又は1であり、好ましくは0である。
ｂ３は、0又は1であり、但しｂ２＝1の場合ｂ３は0であり、ｂ３＝１の場合ｂ２は0である。ｂ３は、好ましくは0である。
Ｐ₁が、式（ｂ）で表される基である場合、ｐ１は、好ましくは0である。[Group of formula (b)]
From the viewpoint of increasing organ specificity, P ₁ is preferably represented by formula (b):

[Wherein, R ₃₁ and R ₃₂ are hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R ₃₃ is hydrogen or an alkyl group having 1 to 4 carbon atoms. Yes, b1 is an integer from 0 to 6, b2 is 0 or 1, b3 is 0 or 1, however, when b2=1, b3 is 0, and when b3=1, b2 is 0 and * is the binding site. ] is a group represented by
In formula (b), R ₃₁ and R ₃₂ are preferably hydrogen.
R ₃₃ is preferably hydrogen.
b1 is an integer from 0 to 6, preferably 0.
b2 is 0 or 1, preferably 0.
b3 is 0 or 1, provided that b3 is 0 when b2=1, and b2 is 0 when b3=1. b3 is preferably 0.
When P ₁ is a group represented by formula (b), p1 is preferably 0.

〔式中、ｂ５は、ｂ１と同定義であり、ｂ６は、ｂ２と同定義であり、ｂ７は、ｂ３と同定義であり、Ｒ₃₅は、Ｒ₃₃と同定義であり、*は、結合部位である。〕で表される基であり、より好ましくは式（ｂ－１１）：

〔式中、ｂ８は、ｂ１と同定義であり、*は、結合部位である。〕で表される基である。P ₁ preferably represents formula (b-1):

[In the formula, b5 has the same definition as b1, b6 has the same definition as b2, b7 has the same definition as b3, R ₃₅ has the same definition as R ₃₃ , * represents a bond It is a part. ], more preferably formula (b-11):

[In the formula, b8 has the same definition as b1, and * is a binding site. ] is a group represented by

これらの中でも置換基（ｂ－１）が好ましい。Examples of P ₁ include the following substituents (b-1) to (b-3).

Among these, substituent (b-1) is preferred.

〔式中、Ｒ₇₀，Ｒ₇₁，Ｒ₇₂は、それぞれ独立に、水素、炭素数1～4のアルキル基であり、＊は結合部位である。〕で表される基である。P ₁ preferably represents formula (e1) or formula (e2):

[In the formula, R ₇₀ , R ₇₁ , and R ₇₂ are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and * is a bonding site. ] is a group represented by

〔式中、Ａ₁は、アミノ酸の残基、又は、エステル化されたカルボキシ基を側鎖に有するアミノ酸の残基であり、ａ１１は0～5の整数であり、ａ１２は、0又は1であり、＊は結合部位である。ただし、Ａ₁及びａ１２で繰り返し単位数が示される単位の配列順序は特に限定されない。〕
Ａ₁のアミノ酸の残基は、例えば、天然アミノ酸の残基であり、好ましくはグルタミン酸である。
エステル化されたカルボキシ基を側鎖に有するアミノ酸の残基は、グルタミン酸又はアスパラギン酸のように側鎖にカルボキシ基を有するアミノ酸であって当該カルボキシ基がエステル化されたアミノ酸の残基を意味する。なお当該エステル化は、炭素数1～4のアルコールでエステル化されていることが好ましい。炭素数1～4のアルコールとしては、例えば、メタノール、エタノール、n-プロパノール、イソプロパノール、n-ブタノール、sec-ブタノール、tert-ブタノールが挙げられる。
ｐ１は、好ましくは0であり、ｐ２は、好ましくは1である。
Ａ₁末端は、Ｒ₁’、又は、式：

又は
式：

で表される基と結合することが好ましい。
ａ１２で繰り返し単位数が示される単位は、上記式（ｅ１）又は式（ｅ２）で表される基と結合することが好ましい。When P ₁ is a group represented by formula (e1) or formula (e2), L ₁ is preferably a group represented by formula (a2-2):

[In the formula, _A1 is an amino acid residue or an amino acid residue having an esterified carboxy group in the side chain, a11 is an integer from 0 to 5, and a12 is 0 or 1. Yes, * is the binding site. However, the arrangement order of the units whose repeating unit numbers are indicated by _A1 and a12 is not particularly limited. ]
The amino acid residue of A ₁ is, for example, a natural amino acid residue, preferably glutamic acid.
An amino acid residue having an esterified carboxyl group in its side chain refers to an amino acid residue having a carboxyl group in its side chain, such as glutamic acid or aspartic acid, in which the carboxy group has been esterified. . Note that the esterification is preferably performed with an alcohol having 1 to 4 carbon atoms. Examples of the alcohol having 1 to 4 carbon atoms include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol.
p1 is preferably 0 and p2 is preferably 1.
The A ₁ terminal is R ₁ ' or the formula:

Or formula:

It is preferable to bond with a group represented by
The unit whose number of repeating units is represented by a12 is preferably bonded to a group represented by the above formula (e1) or formula (e2).

Examples of the group represented by formula (a2-2) include the following substituents (a22-1) to (a22-3).

As specific examples of the above compound A2 or B2, for example, the following compounds A2-1 to Compound A2-2, Compounds B2-1 to B2-2, Compounds A2-11 to Compound A2-18, Compounds B2-11 to B2- 18 are listed.

Compound A2, compound B2, etc. can be synthesized using a known method, and can be produced, for example, by the method described in the Examples of this specification.

[Application]
Compound A2, compound B2, etc. can be used in medicines such as radiopharmaceuticals.
The radiopharmaceutical can be prepared as a pharmaceutical composition containing Compound A2 or Compound B2 as an active ingredient and, if necessary, one or more pharmaceutically acceptable carriers (pharmaceutical carriers). Pharmaceutical carriers include aqueous buffers, pH regulators such as acids and bases, stabilizers such as ascorbic acid and p-aminobenzoic acid, excipients such as D-mannitol, tonicity agents, and preservatives. etc. can be exemplified. Compounds such as citric acid, tartaric acid, malonic acid, sodium gluconate, sodium glucoheptonate, etc. may also be added to help improve radiochemical purity. Radiopharmaceuticals can be provided in the form of an aqueous solution, a frozen solution, or a lyophilized product.

[Usage capacity]
Compound A2, compound B2, etc. are used, for example, as a radioactive drug used in radiotherapy or radiographic image diagnosis.

Compound A2, Compound B2, etc. can be used in radiotherapy to suppress cancer by administering an effective amount thereof to mammals including humans. When used as an anticancer agent, for example, it has a preventive effect of preventing the occurrence, metastasis, implantation, and recurrence of cancer, as well as suppressing the proliferation of cancer cells and shrinking cancer. It has the broadest meaning, including both therapeutic effects such as inhibiting the progression of cancer and improving symptoms, and should not be construed in a restrictive manner in any case.
Examples of the substituent X used as a radiotherapeutic drug include alpha-ray-emitting nuclides, beta-ray-emitting nuclides, gamma-ray-emitting nuclides, and positron-emitting nuclides. Among these, for use in radiotherapy, alpha-emitting nuclides (that is, nuclides that emit α-rays) are preferred, and ²⁰⁹ At, ²¹⁰ At, or ²¹¹ At are more preferred.

Examples of radiological image diagnosis include Single Photon Emission Computed Tomography (hereinafter also simply referred to as "SPECT") and Positron Emission Tomography (hereinafter simply referred to as "PET"). It will be done.
Diagnosis is not particularly limited, and is used for radiographic diagnosis of various diseases such as tumors, inflammation, infectious diseases, cardiovascular diseases, brain/central system diseases, and organs/tissues, and is preferably used for radiation imaging of cancer. Used for image diagnosis.
By selecting a target molecule recognition element according to the characteristics of the target to be diagnosed, it is possible to diagnose and treat a wide variety of targets, and the radiopharmaceutical of the present invention can be used as a radiation imaging diagnostic agent in the field of diagnosis. Can be used widely.

Administration routes for the radiopharmaceutical of the present invention include, for example, parenteral administration such as intravenous administration or intraarterial administration, and oral administration, with intravenous administration being preferred.
The administration route is not limited to these routes, and any route can be used as long as the radioactive drug can effectively exert its action after administration.

The radioactivity intensity of the radioactive drug is arbitrary as long as it is strong enough to achieve the purpose by administering the drug and the radiation exposure of the subject is at the lowest possible clinical dose.
The radioactivity intensity can be determined with reference to the radioactivity intensity used in general diagnostic methods and treatment methods that use radioactive drugs. The dose is determined by considering various conditions such as the patient's age, weight, appropriate radiation imaging equipment, and the state of the target disease, and determines the radioactivity and dose that are considered to be capable of imaging.

When targeting humans, the amount of radioactivity in a radiopharmaceutical is as follows.
Usually, it is assumed that it will be used for radiotherapy, and the dosage of the diagnostic agent is not particularly limited, but for example, the amount of radioactivity of the radioactive element (for example, ²¹¹ At) is 1.0 MBq/kg to 3.0 MBq/kg. .

As described above, according to Compound A1, Compound A2, Compound B1, and Compound B2, compounds that exhibit high stability in vivo can be provided.

[Compound A3 or Compound B3, etc.]
One embodiment of the present invention provides a compound represented by formula (A3) or formula (B3), or a pharmacologically acceptable salt thereof (hereinafter, compound or pharmacologically acceptable salt thereof). The compound represented by formula (A3) is also referred to as "compound A3." The compound represented by formula (B3) is also referred to as "compound B3."
The compound A3 and compound B3 can be induced into the above-mentioned compound A1 and compound B1 by a mild reaction.

〔式中、Ｒ₅₀は、炭素数1～10のアルキル基、炭素数1～10のフルオロアルキル基、炭素数6～60のアリール基であり、*は、結合部位である。〕で表される基である。L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by

〔式中、Ｒ₅₁は、炭素数1～10のフルオロアルキル基であり、Ｒ₅₂，Ｒ₅₃，Ｒ₅₄，Ｒ₅₅，Ｒ₅₆は、それぞれ独立に、水素、炭素数1～20のアルキル基、炭素数1～20のフルオロアルキル基、又は－Ｃ（＝Ｏ）ＮＲ₅₇Ｒ₅₈であり、Ｒ₅₇，Ｒ₅₈は、それぞれ独立に炭素数1～30のアルキル基、又は炭素数6～20のアリール基であり、*は、結合部位である。〕で表される基である。
Ｒ₅₁としては、トリフルオロメチル基、パーフルオロn-ブチル基、パーフルオロn-オクチル基、p-ニトロフェニル基、p-フルオロフェニル基が好ましい。
Ｒ₅₂，Ｒ₅₃，Ｒ₅₅，Ｒ₅₆は、好ましくは水素である。
Ｒ₅₄は、好ましくは、炭素数1～20のアルキル基、炭素数1～20のフルオロアルキル基、又は＊－Ｃ（＝Ｏ）ＮＲ₅₇Ｒ₅₈であり、より好ましくは＊－Ｃ（＝Ｏ）ＮＲ₅₇Ｒ₅₈である。L preferably represents formula (c-1), formula (c-2) or formula (c-3):

[In the formula, R ₅₁ is a fluoroalkyl group having 1 to 10 carbon atoms, and R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , and R ₅₆ are each independently hydrogen or an alkyl group having 1 to 20 carbon atoms. , a fluoroalkyl group having 1 to 20 carbon atoms, or -C(=O)NR ₅₇ R ₅₈ , and R ₅₇ and R ₅₈ are each independently an alkyl group having 1 to 30 carbon atoms, or a fluoroalkyl group having 6 to 20 carbon atoms. is an aryl group, and * is a bonding site. ] is a group represented by
R ₅₁ is preferably a trifluoromethyl group, perfluoro n-butyl group, perfluoro n-octyl group, p-nitrophenyl group, or p-fluorophenyl group.
R ₅₂ , R ₅₃ , R ₅₅ and R ₅₆ are preferably hydrogen.
R ₅₄ is preferably an alkyl group having 1 to 20 carbon atoms, a fluoroalkyl group having 1 to 20 carbon atoms, or *-C(=O)NR ₅₇ R ₅₈ , more preferably *-C(=O ) NR ₅₇ R ₅₈ .

Examples of L include the following groups.

In addition, in formula (A3) or formula (B3), R ₁ is a group represented by formula (a).
Examples of the compound represented by formula (A3) or formula (B3) include the following compounds B3-1 to B3-11.

Compound A3, compound B3, etc. can be synthesized using a known method, and can be produced, for example, by the method described in the Examples of this specification.
Compound A3 or compound B3 is NaX [X in the formula has the same definition as in formula (A1). ] etc., L is substituted with X, making it easy to synthesize Compound A1 and Compound B1.

Compound A3, compound B3, etc. can be synthesized using a known method, and can be produced, for example, by the method described in the Examples of this specification.

A method for using compound A3, compound B3, or a pharmacologically acceptable salt thereof includes, for example, binding a target molecule recognition element to compound A4, compound B4, or a pharmacologically acceptable salt thereof. or a pharmacologically acceptable salt thereof. A radioactive atom may be further introduced into the compound and the like. By inducing this compound, it can be used as a radiopharmaceutical such as a radiation therapy drug or a radiation imaging diagnostic drug, similar to Compound A2 or Compound B2.

若しくは
式：

で表される基と、連結基を介して結合していてもよいし、直接結合していてもよい。
連結基としては、2-イミノチオランから誘導されるイミノチオールが挙げられる。
標的分子認識素子の例は、上述のとおりである。[Compound A4 or Compound B4, etc.]
Compound A4, compound B4, or the like is a compound formed by binding a target molecule recognition element to compound A3, compound B3, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof.
The target molecule recognition element has the formula:

Or formula:

It may be bonded to the group represented by via a linking group or may be bonded directly.
The linking group includes iminothiol derived from 2-iminothiolane.
Examples of target molecule recognition elements are as described above.

Examples of the compound A4 or B4 include a compound represented by the following formula (A4) or formula (B4), or a pharmacologically acceptable salt thereof.

〔式中、Ｌは、式（Ａ３）、式（Ｂ３）と同様であり、
Ｒ₁’は、下記式（ａ２－１）：

〔式中、ａ３は上記式（ａ－１）と同定義であり、＊は結合部位である〕で表される基であり、Ｌ₁，ｐ１，ｐ２，Ｐ₁は、式（Ａ２）、式（Ｂ２）と同定義である。〕
但し、化合物Ａ４及びＢ４のうち、新規性を有する化合物Ａ４又はＢ４は、上述の化合物Ａ４及びＢ４において、Ｐ₁が、式（ｂ－５１）：

〔式中、ｂ９は、0又は1であり、*は、結合部位である。〕で表される基であり、且つ、ｐ１＝ｐ２＝0である場合を除く。
新規性を有する化合物Ａ４又はＢ４は、上述の化合物Ａ４及びＢ４において、好ましくは、Ｐ₁が、式（ｂ－５２）：

〔式中、ｂ９は、0又は1であり、Ｒ_３８は、水素、メチル基、ヒドロキシメチル基であり、*は、結合部位である。〕で表される基であり、且つ、ｐ１＝ｐ２＝0である場合を除く。

[In the formula, L is the same as in formula (A3) and formula (B3),
R ₁ ' is the following formula (a2-1):

[In the formula, a3 has the same definition as the above formula (a-1), * is a bonding site], and L ₁ , p1, p2, P ₁ are the formula (A2), This is the same definition as formula (B2). ]
However, among compounds A4 and B4, the novel compound A4 or B4 is the above-mentioned compound A4 and B4, in which P ₁ is represented by the formula (b-51):

[In the formula, b9 is 0 or 1, and * is a binding site. ] except when p1=p2=0.
In the above-mentioned compounds A4 and B4, the novel compound A4 or B4 preferably has P ₁ of the formula (b-52):

[In the formula, b9 is 0 or 1, _R38 is hydrogen, a methyl group, or a hydroxymethyl group, and * is a bonding site. ] except when p1=p2=0.

〔式中、Ｒ₃₁及びＲ₃₂は、水素、炭素数1～4のアルキル基、又は炭素数1～4のアルコキシ基であり、Ｒ₃₃は、水素、又は炭素数1～4のアルキル基であり、ｂ１は、1～6の整数であり、*は、結合部位である。〕で表される基である。
式（ｂ’）で表される基としては、例えば、下記の基が挙げられる。

P ₁ preferably has the formula (b'):

[In the formula, R ₃₁ and R ₃₂ are hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R ₃₃ is hydrogen or an alkyl group having 1 to 4 carbon atoms. , b1 is an integer from 1 to 6, and * is a binding site. ] is a group represented by
Examples of the group represented by formula (b') include the following groups.

Specific examples of the above compound A4 or B4 include the following compounds A4-1 to A4-8 and compounds B4-1 to B4-8.

Compound A4, compound B4, etc. can be synthesized using a known method, and can be produced, for example, by the method described in the Examples of this specification.
Compound A4 or compound B4 is NaX [X in the formula has the same definition as in formula (A1). ] etc., L is substituted with X, making it easy to synthesize Compound A2 and Compound B2.

[Method for producing compound A1, etc., compound B1, etc., compound A2, etc., or compound B2, etc.]
A manufacturing method according to an embodiment of the present invention will be described below.
A method for producing compound A1, etc., compound B1, etc., compound A2, etc., or compound B2, etc., involves converting compound B3, etc., or compound B4, etc. into ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, ¹²³ I, ¹²⁴ I , ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ At ions.

The method for producing compound A1, etc., compound B1, etc., compound A2, etc., or compound B2, etc. preferably includes:
(i) Compound B3, etc., or Compound B4, etc. as NaX [X in the formula has the same definition as in formula (A1). ] to react with
(ii) mixing with acidic substances;
including.

In the above production method, the following reactions are assumed.

According to (i) above, L in compounds B3 and B4 is substituted with X.
When compound B3 or the like is used as a starting material, compound B1 is obtained in (i).
When compound B4 or the like is used as a starting material, compound B2 is obtained in (i).
The ratio of the molar amount of NaX to the molar amount of Compound B3 etc. or Compound B4 etc. [NaX/Compound B3 etc. or Compound B4 etc.] is preferably 1 or more, more preferably 2 or more, still more preferably 5 or more, even more preferably It is 8 or more, and preferably 20 or less, more preferably 18 or less, even more preferably 15 or less, and still more preferably 12 or less.
The temperature of the reaction (i) above is preferably 60 to 140°C, more preferably 80 to 120°C, and even more preferably 90 to 110°C.

Subsequently, in step (ii), the protecting group in the compound is deprotected to obtain compound A1 or the like or compound A2 or the like.
When compound B3 or the like is used as a starting material, compound A1 is obtained in (ii).
When compound B4 or the like is used as a starting material, compound A2 is obtained in (ii).
(ii) is preferably carried out after (i).
The acidic substance may be either an organic acid or an inorganic acid.
Examples of the organic acid include trifluoroacetic acid and para-toluenesulfonic acid.
The temperature of the reaction (ii) above is preferably 10 to 100°C, more preferably 20 to 80°C, and even more preferably 20 to 70°C.

The manufacturing method may include (iii) adjusting pH. Moreover, a purification step may be included between (i), (ii), and (iii).

[Compound B5 etc.]
One embodiment of the present invention relates to a compound represented by formula (B5) or a pharmacologically acceptable salt thereof (hereinafter, the compound represented by formula (B5) is also referred to as "compound B5"). . Compound B5 and the like facilitate the synthesis of the above-mentioned compound A3 and the like, or the synthesis of compound B4 by introducing the above-mentioned target molecule recognition element.

In formula (B5), each substituent is as follows.
In the formula, R ₈₀ is a hydroxy group, *-OCH ₂ R ₈₁ (wherein, R ₈₁ is a substituted or unsubstituted 2-naphthyl group or a p-methoxyphenyl group, and * is a bonding site. ), or *-OSi(R ₈₂ ) ₃ (wherein R ₈₂ is an alkyl group having 1 to 4 carbon atoms or a phenyl group, and * is a bonding site.) It is a group represented by
In formula (B5), a compound in which R ₈₀ is a hydroxy group (hereinafter also referred to as "compound B5-OH") facilitates the introduction of the above-mentioned L group and facilitates the synthesis of compound B3.
In formula (B5), R ₈₀ is *-OCH ₂ R ₈₁ (wherein R ₈₁ is a substituted or unsubstituted 2-naphthyl group or p-methoxyphenyl group, and * is a bonding site. ), or *-OSi(R ₈₂ ) ₃ (wherein R ₈₂ is an alkyl group having 1 to 4 carbon atoms or a phenyl group, and * is a bonding site). The compound (hereinafter also referred to as "compound B5-OR") that is the group represented facilitates the introduction of a target molecule recognition element.
Moreover, compound B5-OR facilitates the induction of the above-mentioned R ₈₀ group into an OH group, facilitating the synthesis of compound B5-OH.

が挙げられる。
＊－ＯＳｉ（Ｒ₈₂）₃で表される基としては、例えば、

が挙げられる。
Ｒ₁は、式（ａ－１１）、（ａ－１２）、（ａ－１３）又は（ａ－１４）で表される基である。式（ａ－１１）、（ａ－１２）、（ａ－１３）又は（ａ－１４）は、上述と同定義である。Examples of the group represented by *-OCH ₂ R ₈₁ include:

can be mentioned.
Examples of the group represented by *-OSi(R ₈₂ ) ₃ include:

can be mentioned.
R ₁ is a group represented by formula (a-11), (a-12), (a-13) or (a-14). Formula (a-11), (a-12), (a-13) or (a-14) has the same definition as above.

Specific examples of the above compound B5 include the following compounds B5-1 to B5-8 and B5-11 to B5-18.

It may also be a compound formed by binding a target molecule recognition element to compound B5 or the like, or a pharmacologically acceptable salt thereof. A radioactive atom may be further introduced into the compound and the like.

Ｒ₈₀は、式（Ｂ５）と同定義である。
Ｒ₁’は、式（Ａ４）、式（Ｂ４）と同定義であり、Ｌ₁，ｐ１，ｐ２，Ｐ₁は、式（Ａ２）、式（Ｂ２）と同定義である。
但し、化合物Ｂ６のうち、新規性を有する化合物Ｂ６は、上述の化合物Ａ６において、Ｐ₁が、式（ｂ－５１）：

〔式中、ｂ９は、0又は1であり、*は、結合部位である。〕で表される基であり、且つ、ｐ１＝ｐ２＝0である場合を除く。
新規性を有する化合物Ｂ６は、上述の化合物Ｂ６において、好ましくは、Ｐ₁が、式（ｂ－５２）：

〔式中、ｂ９は、0又は1であり、Ｒ_３８は、水素、メチル基、ヒドロキシメチル基であり、*は、結合部位である。〕で表される基であり、且つ、ｐ１＝ｐ２＝0である場合を除く。[Compound B6 etc.]
One embodiment of the present invention relates to a compound represented by formula (B6) or a pharmacologically acceptable salt thereof (hereinafter, the compound represented by formula (B6) is also referred to as "compound B6"). . Compound B6 and the like facilitate the synthesis of the above-mentioned compound A4 and the like.

R ₈₀ has the same definition as in formula (B5).
R ₁ ' has the same definition as formula (A4) and formula (B4), and L ₁ , p1, p2, and P ₁ have the same definition as formula (A2) and formula (B2).
However, among compounds B6, the novel compound B6 is the above-mentioned compound A6, where P ₁ is represented by formula (b-51):

[In the formula, b9 is 0 or 1, and * is a binding site. ] except when p1=p2=0.
Compound B6 having novelty is the above-mentioned compound B6, wherein P ₁ is preferably represented by formula (b-52):

[In the formula, b9 is 0 or 1, _R38 is hydrogen, a methyl group, or a hydroxymethyl group, and * is a bonding site. ] except when p1=p2=0.

In formula (B6), a compound in which R ₈₀ is a hydroxy group (hereinafter also referred to as "compound B6-OH") facilitates the introduction of the above-mentioned L group and facilitates the synthesis of compound B4.
In formula (B6), R ₈₀ is *-OCH ₂ R ₈₁ (wherein R ₈₁ is a substituted or unsubstituted 2-naphthyl group or p-methoxyphenyl group, and * is a bonding site. ), or *-OSi(R ₈₂ ) ₃ (wherein R ₈₂ is an alkyl group having 1 to 4 carbon atoms or a phenyl group, and * is a bonding site). The compound represented by the group (hereinafter also referred to as "compound B6-OR") facilitates the induction of the above-mentioned R ₈₀ group into an OH group, facilitating the synthesis of compound B6-OH.

Specific examples of the compound B6 include the following compounds B6-1 to B6-2 and B6-11 to B6-18.

[Method for producing compound A3, etc., compound B3, etc., compound A4, etc., or compound B4, etc.]
A manufacturing method according to an embodiment of the present invention will be described below.
The method for producing compound A3, etc., or compound B3, etc. includes reacting compound B5-OH with sulfonic acid anhydride.

The method for producing compound A3 etc. is as follows:
(i) reacting compound B5-OH with sulfonic anhydride; (ii) mixing with an acidic substance;
including.
The sulfonic anhydride can be selected depending on the type of L group to be introduced into compound A3 etc. or compound B3 etc., for example, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-toluenesulfonic anhydride. Can be mentioned.

The method for producing compound A4, etc. or compound B4, etc. includes reacting compound B6-OH with sulfonic acid anhydride or sulfonyl chloride.

The method for producing compound A4 etc. is as follows:
(i) reacting compound B6-OH with sulfonic acid anhydride or sulfonyl chloride; (ii) mixing with an acidic substance;
including.
The sulfonic anhydride is the same as the method described above.
The sulfonyl chloride can be selected depending on the type of L group introduced into compound A4 etc. or compound B4, and examples thereof include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and p-toluenesulfonyl chloride.

[kit]
The kit of the present invention comprises the above-mentioned compound and the above-mentioned metal-containing agent as separate packaging units.
The kit of the present invention includes, for example, Compound B3 or Compound B4, etc., and a drug containing a radioactive atom as separate packaging units.
Both the compound and the drug contained in the kit can contain one or more pharmaceutically acceptable carriers (pharmaceutical carriers) as described above, if necessary.

The embodiments of the invention described below are for illustrative purposes only and are not intended to limit the scope of the invention. The following experiments were conducted after being approved by the Animal Ethics Committee of Chiba University.

In the Examples and Comparative Examples below, the following abbreviations were used for substituents, compounds, and organic solvents.
tBu: Tertiary butyl group
TfO: trifluoromethanesulfonate group
Fmoc: Fluorenylmethoxycarbonyl group
DMF: dimethylformamide
TFA: trifluoroacetic acid
MeCN: Acetonitrile
HOBt: 1-hydroxybenzotriazole
PBS: phosphate buffered saline
EDC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[Measurement method, experimental animals]
In the following Examples and Comparative Examples, various physical properties were measured using the following methods.

[NMR (Nuclear Magnetic Resonance)]
^1H -NMR analysis was performed using a JEOL ECS-400 spectrometer (JEOL Ltd.).

[ESI-MS (electrospray ionization mass spectrometry)]
For ESI-MS analysis, HPLC1200 series-6130 quadrupole LC/MS mass spectrometer (Agilent Technologies, Inc.) was used.

[Reversed phase high performance liquid chromatography (RP-HPLC) and molecular sieve high performance liquid chromatography (SE-HPLC)]
For analysis by reversed phase high performance liquid chromatography (hereinafter also referred to as "RP-HPLC"), we used the UV detector "L-7405" (Hitachi, Ltd.), the liquid pump "L-7100" (Hitachi, Ltd.), "Imtakt US C-18" (4.6 mm x 150 mm, Intakt Co., Ltd.) was used as an analytical column.
Using water (phase A) and methanol (phase B) as mobile phases, from 40% (v/v) of phase A, 60% (v/v) of phase B to 0% (v/v) of phase A in 0-25 min. ), B phase is changed to 100% (v/v) using a linear gradient method (system A), using 0.01 M phosphate buffer (pH 7.0) (A phase) and methanol (B phase) as the mobile phase, 0- How to change A phase 40% (v/v) and B phase 60% (v/v) to A phase 0% (v/v) and B phase 100% (v/v) in 25 min. Using water (phase A) and acetonitrile (phase B), from 40% (v/v) of phase A, 60% (v/v) of phase B to 0% (v/v) of phase A, B Linear gradient method (system C) to change the phase to 100% (v/v), using water (phase A) and acetonitrile (phase B) as mobile phases, change phase A to 90% (v/v) in 0-20 min. , B phase 10% (v/v), A phase 70% (v/v), B phase 30% (v/v), A phase 0% (v/v), B phase in 20-30 min. Linear gradient method (system D) in which the phase is changed to 100% (v/v), or the mobile phase is water (A phase) and acetonitrile (B phase), and the A phase is changed for 0-5 min to 95% (v/v). v), B phase is maintained at 5% (v/v), and is changed to A phase 70% (v/v) and B phase 30% (v/v) in 5-20 min, and A in 20-30 min. Elution was performed at a flow rate of 1.0 mL/min using a linear gradient method (system E) in which phase B was changed to 0% (v/v) and phase B was changed to 100% (v/v).
The absorbance of the eluate was measured at 254 nm, and ¹²⁵ I-labeled compounds were analyzed by connecting the gamma ray detector Gabi star (Raytest) online.

[Experimental animals]
For the animal experiments, 6-week-old male ddY strain SPF mice and 6-week-old male ICR strain SPF mice (Japan SLC Co., Ltd.) were used.

[Synthesis of compound B1 (labeled substance 1), compound A1 (labeled substance 2)]
Synthesis Example A1: Synthesis of Compound A1 and Compound B1

Synthesis Example A1(a): Synthesis of Labeled Compound 1 After dissolving Compound 1 (100 μg) in 50 μL of acetonitrile, 1.0 μL of [ ¹²⁵ I]NaI was added and reacted at 110° C. for 1 hour. After the solution was returned to room temperature, the reaction solution was purified by HPLC, and the fraction containing the target product was concentrated under reduced pressure to obtain an aqueous solution of labeled substance 1. (Radiochemical yield 91.9%)
HPLC retention time: 24.5 min (system A)
TLC Rf value: 0.75-0.8 (hexane/ethyl acetate = 1/2)

Synthesis example A1 (b): Synthesis of labeled compound 2 After adding 50 μL of acetonitrile to the concentrated solution of labeled compound (1), add para-toluenesulfonic acid aqueous solution (0.2 mg/10 μL) and incubate at 60 μC for 30 minutes. I reacted. After the solution was returned to room temperature, the solution was neutralized and purified by HPLC. The solution was concentrated under reduced pressure to obtain an aqueous solution of labeled substance 2. (Radiochemical yield >99%, radiochemical purity >99%)
HPLC retention time: 15.7 min (system B)
TLC Rf value: 0.55-0.6 (hexane/ethyl acetate = 1/4)

[Synthesis of compound B2 (labeled substance 3), compound A2 (labeled substance 4)]
Synthesis example B1: Synthesis of compound 3 and compound 4

Synthesis Example B1(a): Synthesis of Labeled Compound 3 Compound 21 (1 mg) was dissolved in 100 μL of acetonitrile, and then 0.5 μL of [ ¹²⁵ I]NaI was added and reacted at 120 μC for 1 hour. After the solution was returned to room temperature, completion of the reaction was confirmed by TLC analysis. The reaction solution was applied to a solid phase extraction column "Sep-pak C-18" (Nippon Waters Co., Ltd.) equilibrated with methanol and then water, and after washing with water, the fraction eluted with methanol was concentrated under reduced pressure and labeled. Obtained body 3. (Radiochemical yield 87.3%)
In addition, compound 21 can be synthesized according to the method described in JP-A-2017-052713.
HPLC retention time: 9.6 min (system C)
TLC Rf value: 0.5-0.55 (toluene/ethyl acetate = 1/1)

Synthesis Example B1(b): Synthesis of Labeled Body 4 An aqueous solution of para-toluenesulfonic acid was added to the concentrated solution of Labeled Body 3, and the mixture was reacted at 60°C for 30 minutes. After the solution was returned to room temperature, completion of the reaction was confirmed by TLC analysis, and the solution was neutralized and purified by HPLC. The solution was concentrated under reduced pressure to obtain an aqueous solution of labeled substance 4. (Radiochemical yield>99%)
HPLC retention time: 16.2 min (system D)
TLC Rf value: 0.55-0.6 (toluene/ethyl acetate = 2/1)

Synthesis example B2: Synthesis of labeled body 5
0.1 N NaOH (0.5 μL) was added to a container in which chloroform had been distilled off with a nitrogen stream from a chloroform solution of ²¹¹ At. Compound 21 (20 μg) was dissolved in 100 μL of acetonitrile, added to the ²¹¹ At aqueous solution, and reacted at 120° C. for 1 hour. After the solution was returned to room temperature, an aqueous para-toluenesulfonic acid solution was added and reacted at 60°C for 30 minutes. After the solution was returned to room temperature, it was neutralized and purified by HPLC. After adding half the amount of ethanol to the solution of the purified fraction, the solution was concentrated under reduced pressure to obtain an aqueous solution of labeled substance 5. (Radiochemical yield 13.9%, radiochemical purity 98.1%)
HPLC retention time: 16.3 min (system D)

[Synthesis of compound B5 (compound 25)]
Synthesis Example C1: Synthesis of Compound 25

Synthesis Example C1(a): Synthesis of Compound 22 Sodium hydride (55%, 4.33g, 105 mmol) was washed with dry hexane and suspended in DMF (10.0 mL) under an argon atmosphere. Compound 21 (14.0 g, 87.4 mmol) dissolved in DMF (46 mL) was added dropwise to the suspension under ice cooling. After stirring for 1 hour, 2-(bromomethyl)naphthalene dissolved in DMF (20 mL) was added dropwise into the reaction solution at the same temperature. After confirming the completion of the reaction by TLC analysis (toluene/acetone = 7/3), ethanol and water were added to stop the reaction. Then, after adding an aqueous NaCl solution, the aqueous phase was extracted using ethyl acetate. The obtained organic phase was concentrated under reduced pressure and then azeotroped with toluene to remove DMF. After dissolving the obtained residue in methanol (100 mL), 3 M HCl aqueous solution (10.0 mL) was added, and the mixture was heated at 40°C. After confirming the completion of the reaction by TLC analysis (hexane/ethyl acetate = 4/1 or chloroform/methanol = 9/1), the reaction solution was concentrated under reduced pressure.Finally, toluene was added and methanol was azeotropically reduced under reduced pressure. . The obtained residue was recrystallized using diethyl ether and methanol to obtain Compound 22 (22.3 g, 70.4 mmol, yield 81%).
^13C NMR (400 MHz CD ₃ OD): δ 137.5, 134.8, 134.4, 129.2, 129.0, 128.8, 127.2, 127.1, 126.8, 126.7, 74.6, 71.1, 63.3, 46.9

Synthesis Example C1(b): Synthesis of Compound 23 Compound 22 (2.98 g, 10.9 mmol) and (-)-camphorsulfonic acid (0.199 mmol, 46.2 mg) were replaced with argon and dissolved in DMF (21.8 mL). 2,2-dimethoxypropane (1.40 m, 14.2 mmol) was added dropwise to the mixed solution under ice cooling. After stirring at room temperature, the completion of the reaction was confirmed by TLC analysis (chloroform/methanol = 9/1 or hexane/ethyl acetate = 1/1), and the reaction solution was neutralized with triethylamine. After pouring into saturated brine, the aqueous phase was extracted using ethyl acetate. The obtained organic phase was dried with magnesium sulfate, and the magnesium sulfate was filtered off. The obtained solution was depressurized, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1), and the obtained residue was purified using a chloroform:dichloromethane:ethyl acetate:hexane solution. Compound 23 (1.93 g, 6.65 mmol, yield 61%) was obtained by recrystallization.
¹ H NMR (400 MHz, CD ₃ Cl): δ 7.90-1.83 (m, 3H), 7.75 (brs, 1H), 7.50-7.45 (m, 2H), 7.43 (d, 1H, J = 8.4 Hz), ¹³ C NMR (400 MHz CD ₃ Cl): δ 135.4, 133.3, 133.2, 128.5, 128.0, 127.8, 126.7, 126.3, 126.1, 125.6, 98.6, 74.0,72.3, 65.1, 63.0, 39.1, 24.2, 23 .5

Synthesis Example C1(c): Synthesis of Compound 24 Sodium hydride (55%, 566 mg, 12.6 mmol) was washed with dry hexane and suspended in DMF under an argon atmosphere. Compound 23 (2.0 g, 6.32 mmol) dissolved in DMF (17.6 mL) was added dropwise to the suspension under ice cooling. After stirring for 30 minutes, tert-butyl bromoacetate (1.39 mL, 9.48 mmol) was added dropwise to the reaction solution under ice cooling. After reacting at room temperature for 1 hour, ethanol and water were added to stop the reaction, the aqueous phase was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. Compound 24 (1.55 g, 3.60 mmol, yield 57%).
¹ H NMR (400 MHz, CD ₃ Cl): δ 7.83-7.80 (m, 3H), 7.76 (brs, 1H), 7.48-7.43 (m, 3H), 4.68 (s, 2H), 3.94 (s, 2H) ), 3.83 (s, 4H), 3.57 (d, 2H, J = 15 Hz), 3.56 (d, 2H, J = 15 Hz), 1.47 (s, 9H), 1.42 (s, 3H), 1.40 (s , 3H)

Synthesis Example C1(d): Synthesis of Compound 25 Compound 24 (450 mg, 1.04 mmol) was dissolved in a mixed solution of dioxane (3.50 mL) and 1 M NaOH aqueous solution and heated to 100°C. After confirming the completion of the reaction by TLC analysis (hexane/ethyl acetate = 5/2 or chloroform/methanol = 9/1), water and dioxane were completely removed by adding toluene and concentrating under reduced pressure. After dissolving the residue in water, it was made into a two-phase system with ethyl acetate, and then 1 M hydrochloric acid was added under ice cooling for neutralization. After confirming that the pH was approximately 6.0, the aqueous phase was extracted with ethyl acetate. After concentrating the obtained organic phase under reduced pressure, the obtained residue was recrystallized from ether and hexane to obtain Compound 25 (274 mg, 0.733 mmol, yield 70%).
¹ H NMR (400 MHz, CD ₃ Cl): δ 7.85-7.83 (m, 3H), 7.75 (brs, 1H), 7.50-7.43 (m, 3H), 4.70 (s, 2H), 4.09 (s, 2H) ), 3.74 (s, 4H), 3.66 (s, 2H), 3.50 (s, 2H), 1.40 (s, 3H), 1.38 (s, 3H)

[Synthesis of compound B3 (compound 28)]
Synthesis Example C2: Synthesis of Compound 28

Synthesis Example C2(a): Synthesis of Compound 26
In a dichloromethane solution (0.55 mL) of 4-nitrophenol (18.5 mg, 0.133 mmol), diylopropylethylamine (0.05 mL, 0.290 mmol), compound 25 (29.3 mg, 0.0783 mmol) and 1-ethyl-3-( 3-dimethylaminopropyl)carbodiimide (20.3 mg, 0.106 mmol) was added at room temperature. After reacting at room temperature, the reaction solution was poured into a saturated ammonium chloride aqueous solution, the aqueous phase was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over magnesium sulfate. The residue obtained by concentration under reduced pressure was purified using silica gel column chromatography (hexane/ethyl acetate = 1/1). The resulting mixture was further purified using gel permeation chromatography (GPC) to obtain Compound 26 (5.70 mg, 0.015 mmol, yield 15%).
¹ H NMR (400 MHz, CD ₃ Cl): δ 8.21 (d, 2H, J = 8.0 Hz), 7.83-7.75 (m, 3H), 7.38 (s, 1H), 7.45-7.41 (m, 3H), 7.25 (d, 2H, J = 8.0 Hz), 4.67 (s, 2H), 4.33 (s, 2H), 3.84 (s, 4H), 3.74 (s, 2H), 3.55 (s, 2H), 4.46 (s , 6H).

Synthesis Example C2(b): Synthesis of Compound 27 Water (0.20 mL) was added to a solution of Compound 26 (86.9 mg, 0.175 mmol) in methylene chloride (1.60 mL). Furthermore, dichlorodicyanoquinone (50.2 mg, 0.221 mmol) was added under ice cooling. After confirming the completion of the reaction by TLC analysis (hexane/ethyl acetate = 2/1), the reaction solution was poured into aqueous sodium bicarbonate solution. After extracting the aqueous phase with dichloromethane, the organic phase was dried over magnesium sulfate. The magnesium sulfate was filtered off and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1) to obtain compound 27 (34 mg, 0.0957 mmol, yield). 55%).
¹ H NMR (400 MHz, CD ₃ Cl): δ 8.30 (d, 2H, 9.2 Hz), 7.34 (d, 2H, J = 9.2 Hz), 4.41 (s, 2H), 3.78 (s, 2H), 3.76 (d, 2H, J = 12.0 Hz), 3.75 (d, 2H, J = 12.0 Hz)

Synthesis Example C2(c): Synthesis of Compound 28 To a methylene chloride solution (0.315 mL) of Compound 27 (8.3 mg, 0.0234 mmol) was added 2,6-lutidine (0.00712 mL, 0.0618 mmol). Furthermore, trifluoromethanesulfonic anhydride (0.00599 mL, 0.0355 mmol) was added to the solution under ice cooling. After confirming the completion of the reaction by TLC analysis (hexane/ethyl acetate = 2/1), the reaction solution was poured into water. After the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine. The organic phase obtained was dried over magnesium sulfate. The magnesium sulfate was filtered off and the residue obtained was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1) to obtain compound 28 (6.2 mg, 0.0127 mmol, 54%). ).
¹ H NMR (400 MHz, CD ₃ Cl): δ 8.30 (d, 2H, 9.2 Hz), 7.33 (d, 2H, J = 9.2 Hz), 4.74 (s, 2H), 4.38 (s, 2H), 3.87 (d, 2H, J = 12.4 Hz), 3.76 (d, 2H, J = 12.4 Hz), 3.61 (s, 2H), 1.44 (s, 3H), 1.42 (s, 3H)

[Synthesis of compound 35 and compound 36]
Synthesis example D1: Synthesis of compound 35 and compound 36

Synthesis Example D1(a): Synthesis of Compound 32 Compound 25 (27.3 mg, 73.0 μmol), Compound 31 (50.0 mg, 73.0 μmol), and HOBt.H ₂ O (11.2 mg, 73.0 μmol) were dissolved in chloroform. EDC.HCl (14.0 mg, 73.0 μmol) was added under ice cooling. After returning to room temperature and stirring for 1.5 hours, the solvent was distilled off under reduced pressure. The residue was redissolved in ethyl acetate, washed three times with a 5% by mass aqueous citric acid solution and three times with a 5% by mass aqueous sodium bicarbonate solution, and then dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure, and compound 32 was obtained by purification by preparative TLC using chloroform/methanol = 30/1 as a developing solvent (53.3 mg, yield 70.1%).
Note that Compound 31 was synthesized according to Journal of Medicinal Chemistry 2009, 52, 347-357. (ESI-MS: [M + H] ⁺ : 685.4, Found 685.5)

Synthesis Example D1(b): Synthesis of Compound 33 Compound 32 (61.1 mg, 58.7 μmol) was dissolved in methylene chloride (3 mL), and 2,3-dichloro-5,6 was added to a solution of water (0.15 mL). -dicyano-p-benzoquinone (26.6 mg, 117 μmol) was added, and the mixture was stirred at room temperature for 4 hours. A 5% by mass citric acid aqueous solution was added to the reaction solution, the organic layer was collected, and then extracted twice with chloroform. The organic layers were combined and dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure and purified by preparative TLC using chloroform/methanol = 20/1 as a developing solvent to obtain Compound 33 (42.6 mg, yield 80.6%).

Synthesis Example D1(c): Synthesis of Compound 34 Compound 33 (15.3 mg, 17.0 μmol) was dissolved in methylene chloride (51.8 μL), triethylamine (3.6 μL, 25.8 μmol) was added, and the mixture was heated to −20 μL under an argon atmosphere. Methanesulfonyl chloride (1.4 μL, 18.7 μmol) was added at °C. After the solution was returned to room temperature and stirred for 1.5 hours, ethyl acetate (40 μL) and water (2 mL) were added to the solution and stirred for about 10 minutes. Thereafter, the organic layer was washed once with water and saturated brine, and then dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 34 (11.6 mg, yield 69.7%).

Synthesis Example D1(d): Synthesis of Compound 35 Compound 34 (22.6 mg, 23.1 μmol) was dissolved in acetonitrile (1 mL), NaI (34.6 mg, 0.231 mmol) was added, and the mixture was stirred at 100° C. for 24 hours. After distilling off the acetonitrile, the residue was redissolved in ethyl acetate. Thereafter, it was washed three times with saturated sodium thiosulfate and three times with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 35. This compound was used as it was in the next reaction without purification. ESI-MS: [M+H] ⁺ : 1011, Found 1011

Synthesis Example D1(e): Synthesis of Compound 36 Compound 36 was dissolved in TFA (900 μL), water (50 μL), and triethylsilane (50 μL), and stirred at room temperature for 1 hour. The solvent was distilled off using N ₂ gas, and the residue was purified by RP-HPLC to obtain Compound 36.
ESI-MS: [MH] ^- : 801, Found 801

[Synthesis of compound B2 (labeled substance 6) and compound A2 (labeled substance 7)]

Synthesis Example D2(a): Synthesis of Labeled Compound 6 Compound 34 (0.45 mg) was dissolved in acetonitrile (49 μL), [ ¹²⁵ I]NaI (1 μL) was added, and the mixture was heated to 100 °C and left undisturbed for 3 hours. I placed it. Thereafter, it was purified by RP-HPLC to obtain labeled compound 6 (radiochemical yield: 88.1%).
RP-HPLC: Using Cadenza 5CW-C18 (150 x 10 mm), water:acetonitrile (40:60) was changed to (0:100) over 40 minutes at a flow rate of 2 mL/min. In this analysis system, the retention time of Label 6 was 21.68 minutes.

Synthesis Example D2(b): Synthesis of Labeled Compound 7 Labeled Compound 6 was dissolved in TFA (900 μL), water (50 μL), and triethylsilane (50 μL), and allowed to stand at room temperature for 1 hour. The solvent was distilled off using N ₂ gas, and the residue was purified by RP-HPLC to obtain Labeled Compound 7 (95.3% radiochemical yield, 100% radiochemical purity).
RP-HPLC: Using Cadenza 5CW-C18 (150 × 10 mm), water containing 0.1% TFA: acetonitrile containing 0.1% TFA (10:90) was mixed (60:40) over 40 minutes at a flow rate of 2 mL/min. ) was changed to In this analysis system, the retention time of labeled substance 7 was 29.40 minutes.

[Synthesis of compound 49 and compound 50]
Synthesis example E1: Synthesis of compound 50

Synthesis Example E1(a): Synthesis of Compound 42 Compound 41 was synthesized according to Journal of Medicinal Chemistry 2009, 52, 347-357. (ESI-MS: [M + H] ⁺ : 685.4, Found 685.5)
Compound 41 (200 mg, 0.410 mmol), N-α-(9-Fluorenylmethoxycarbonyl)-β-(2-naphthyl)-L-alanine (179 mg, 0.410 mmol), HOBt ^. H ₂ O (62.8 mg, 0.410 mmol) ) in DMF (5 mL) was added ^EDC.HCl (78.6 mg, 0.410 mmol) under ice cooling. After returning to room temperature and stirring for 2 hours, the solvent was distilled off under reduced pressure. The residue was redissolved in ethyl acetate, washed three times with a 5% aqueous citric acid solution and three times with a 5% aqueous sodium bicarbonate solution, and then dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC using chloroform/methanol=30/1 as a developing solvent to obtain Compound 42 (262 mg, 70.5%).
ESI-MS: [M + Na] ⁺ : 1114.6, Found 1114.7

Synthesis Example E1(b): Synthesis of Compound 43 Compound 42 (262 mg, 0.289 mmol) was dissolved in 20% piperidine/DMF (5 mL) and stirred at room temperature for 0.5 hour. After distilling off the solvent under reduced pressure, compound 43 was obtained by purification by preparative TLC using chloroform/methanol=15/1 as a developing solvent (198 mg, 91.3%).
ESI-MS: [M + H] ⁺ :870.5 , Found 870.6

Synthesis Example E1(c): Synthesis of Compound 44 Compound 43 (75.1 mg, 86.3 μmol), N-α-(9-Fluorenylmethoxycarbonyl)-β-(2-naphthyl)-L-alanine (38.3 mg, 86.3 μmol), EDC·HCl (16.5 mg, 86.3 μmol) was added to a solution of HOBt·H ₂ O (13.2 mg, 86.3 μmol) in chloroform (2 mL) under ice cooling. After returning to room temperature and stirring for 2 hours, the solvent was distilled off under reduced pressure. The residue was redissolved in ethyl acetate, washed three times with a 5% aqueous citric acid solution and three times with a 5% aqueous sodium bicarbonate solution, and then dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC using chloroform/methanol=20/1 as a developing solvent to obtain Compound 44 (54.4 mg, 52.6%).
ESI-MS: [M + Na] ⁺ : 1299.7, Found 1299.8

Synthesis Example E1(d): Synthesis of Compound 45 Compound 44 (48.4 mg, 37.9 μmol) was dissolved in 20% piperidine/DMF (2 mL) and stirred at room temperature for 0.5 hour. After distilling off the solvent under reduced pressure, compound 45 (34.7 mg, 86.8%) was obtained by purification by preparative TLC using chloroform/methanol=15/1 as a developing solvent.
ESI-MS: [M+H] ⁺ : 1055.6, Found 1055.8

Synthesis Example E1 (e): Synthesis of Compound 46 Compound 25 (10.2 mg, 27.2 μmol), Compound 45 (34.8 mg, 27.2 μmol), HOBt ^. H ₂ O (4.2 mg, 27.2 μmol) in chloroform (1 mL) ^EDC.HCl (5.2 mg, 27.2 μmol) was added to the dissolved solution under ice cooling. After returning to room temperature and stirring for 1.5 hours, the solvent was distilled off under reduced pressure. The residue was redissolved in ethyl acetate, washed three times with a 5% by mass aqueous citric acid solution and three times with a 5% by mass aqueous sodium bicarbonate solution, and then dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC using chloroform/methanol=30/1 as a developing solvent to obtain Compound 46 (34.7 mg, 65.7%).
ESI-MS: [M + Na] ⁺ : 1433.8, Found 1434.1

Synthesis Example E1 (f): Synthesis of Compound 47 Compound 46 (30.5 mg, 21.6 μmol) was dissolved in methylene chloride (3 mL), and water (0.15 mL) was added to the solution, and 2,3-dichloro-5,6 was added to the solution. -dicyano-p-benzoquinone (9.8 mg, 43.2 μmol) was added, and the mixture was stirred at room temperature for 4 hours. A 5% by mass citric acid aqueous solution was added to the reaction solution, the organic layer was collected, and then extracted twice with chloroform. The organic layers were combined and dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure, and compound 47 was obtained by purification by preparative TLC using chloroform/methanol=20/1 as a developing solvent (15.3 mg, 55.7%). ESI-MS: [M + Na] ⁺ :1293.7, Found 1293.9

Synthesis Example E1 (g): Synthesis of Compound 48 Compound 47 (15.3 mg, 17.0 μmol) was dissolved in methylene chloride (51.8 μL), triethylamine (3.6 μL, 25.8 μmol) was added, and the mixture was heated to −20 μm under an argon atmosphere. Methanesulfonyl chloride (1.4 μL, 18.7 μmol) was added at °C. After the solution was returned to room temperature and stirred for 1.5 hours, ethyl acetate (40 μL) and water (2 mL) were added to the solution and stirred for about 10 minutes. Thereafter, the organic layer was washed once with water and saturated brine, and then dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 48 (11.6 mg, 71.4%).
ESI-MS: [M + Na] ⁺ : 1371.7, Found 1371.8

Synthesis Example E1 (h): Synthesis of Compound 49 Compound 48 (22.6 mg, 23.1 μmol) was dissolved in acetonitrile (1 mL), NaI (34.6 mg, 0.231 mmol) was added, and the mixture was stirred at 100° C. for 24 hours. After distilling off the acetonitrile, the residue was redissolved in ethyl acetate. Thereafter, it was washed three times with saturated sodium thiosulfate and three times with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 49. This compound was used as it was in the next reaction without purification. ESI-MS: [M + Na] ⁺ : 1403.6, Found 1403.8

Synthesis Example E1(i): Synthesis of Compound 50 Compound 49 was dissolved in TFA (900 μL), water (50 μL), and triethylsilane (50 μL), and stirred at room temperature for 1 hour. The solvent was distilled off using N ₂ gas, and the residue was purified by RP-HPLC to obtain Compound 50.
ESI-MS: [M - H] ^- :1059.3 , Found 1059.3

[Synthesis of compound B2 (labeled substance 11) and compound A2 (labeled substance 12)]

Synthesis Example E2(h): Synthesis of Labeled Compound 11 Compound 48 (0.45 mg) was dissolved in acetonitrile (49 μL), [ ¹²⁵ I]NaI (1.0 μL) was added, and the mixture was heated to 100 °C and left still for 3 hours. I placed it. Thereafter, it was purified by RP-HPLC to obtain labeled compound 11 (radiochemical yield: 41.6%).
RP-HPLC: Using Cadenza 5CW-C18 (150 x 10 mm), water:acetonitrile (40:60) was changed to (0:100) over 40 minutes at a flow rate of 2 mL/min. In this analysis system, the retention time of labeled substance 11 was 19.9 minutes.

Synthesis Example E2(i): Synthesis of labeled body 12 Labeled body 11 was dissolved in TFA (900 μL) and water (100 μL), and the mixture was left standing at room temperature for 1 hour. The solvent was distilled off using N ₂ gas, and the residue was purified by RP-HPLC to obtain labeled body 12 (radiochemical yield: 54.7%, radiochemical purity: 91.0%).
RP-HPLC: Using Cadenza 5CW-C18 (150 × 10 mm), water containing 0.1% TFA: Acetonitrile containing 0.1% TFA (90: 10) was mixed (60: 40) over 30 minutes at a flow rate of 1 mL/min. ) and then took another 10 minutes to change it to (0:100). In this analysis system, the retention time of labeled substance 12 was 26.1 minutes.

[Study of characteristics]
[Study of the pharmacokinetics of ¹²⁵ I-labeled substance in normal mice]
Each ¹²⁵ I-labeled solution was diluted with PBS, and 11.1 kBq/100 μL was administered per mouse. Labeled compound 2: 10 min, 1, 3, 24 h (n=3) after administration, Labeled compound 3: 1, 3, 24 h (n=3) after administration, Labeled compound 4: 10 min after administration , 1, 3, 24 h (n=5), labeled compound 7 1 h after administration (n=3), labeled compound 12 10 min, 1, 3, 6 h (n=3) after administration After sacrificing the mouse, the organ of interest was extracted, and its weight and radioactivity were measured. In addition, urine collected up to 6 hours after administration of 370 kBq/100 μL was subjected to ultrafiltration using Microcon (10 kDa) and then analyzed using reversed phase HPLC (System E).
For the tumor-bearing model mouse, ^5x105 LNCap cells (100 μL, RPMI medium/Matrigel: 1/1) were transplanted into the left leg of a nude mouse (Balbc nu/nu, male, 5 weeks old), and 2 months later. Labeled compound (12) was administered at 11.1 kBq/100 μL per mouse. Mice were sacrificed 1 h after administration, organs of interest were removed, and weight and radioactivity were measured.
The results are shown in FIGS. 1 and 2. FIG. 1 shows the results of urine analysis after administration of labeled compound 3. FIG. 2 shows the results of urine analysis after administration of labeled compound 4.

[Study of the pharmacokinetics of ²¹¹ At-labeled substance in normal mice]
The aqueous solution of ²¹¹ At-labeled compound 5 was diluted with PBS, and 50 kBq/100 μL was administered to each mouse. After administration, the mice were sacrificed at 10 min, 1, 3, and 24 h (n=3), and the organs of interest were removed, and their weight and radioactivity were measured.

Labeled Form 5 exhibits high in vivo stability because it exhibits similar dynamics to Labeled Form 4, which was analyzed in the urine above, and has little accumulation in organs where free At is known to accumulate. It can be understood if shown.

Claims (24)

A compound represented by formula (A1) or formula (B1), or a pharmacologically acceptable salt thereof.

[During the ceremony,
X is ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ At,
R ₁ is of the formula:

A group represented by or formula (a):

[wherein R ₂ is formula (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8) or (a9):

[In the formula, R ₂₁₁ is hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 20 carbon atoms, X ₁ is chlorine, bromine, or iodine, and R ₂₁₂ is hydrogen, or is a methyl group, R ₂₁₃ is hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 20 carbon atoms, R ₂₁₄ is hydrogen or an alkyl group having 1 to 4 carbon atoms, a20 is an integer from 1 to 6. ]
or an aryl group having 6 to 20 carbon atoms, a1 is an integer of 0 to 6, a2 is 1, and * is a bonding site. ] is a group represented by ] A compound represented by formula (A1) or formula (B1), or a pharmacologically acceptable salt thereof.

[During the ceremony,
X is ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I , ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ At,
Said R ₁ is
Formula (a-11), (a-12), (a-13), (a-14) or (a15-1):

[In the formula, a5 is an integer of 0 to 6, R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ and R ₂₇ are each independently hydrogen, fluorine or a nitro group, and R ₂₈ and R ₂₉ are , each independently hydrogen, a sulfo group, or a salt of a sulfo group, X ¹⁰ is a CH group or nitrogen, and * is a bonding site. ] is a group represented by ] The said X is ^{one two three} I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof, which is At. A compound obtained by binding a target molecule recognition element to the compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof. A compound represented by formula (A2) or formula (B2), or a pharmacologically acceptable salt thereof.

[During the ceremony,
X is ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At or ²¹¹ At,
R ₁ ' is the following formula (a2-1):

[In the formula, a3 is an integer from 0 to 6, * ^l1 is a bonding site with an adjacent methylene group, * ^r1 is a bonding site with an adjacent -(L ₁ ) _p2 -P ₁ group . ] is a group represented by
L ₁ is a linking group,
p1 is 1 ,
p2 is 0 or 1,
P ₁ is a target molecule recognition element. ] Said P ₁ is the formula (b):

[Wherein, R ₃₁ and R ₃₂ are hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R ₃₃ is hydrogen or an alkyl group having 1 to 4 carbon atoms. Yes, b1 is an integer from 0 to 6, b2 is 0 or 1, b3 is 0 or 1, however, when b2=1, b3 is 0, and when b3=1, b2 is 0 and * is the binding site. ] The compound according to claim 5, or a pharmacologically acceptable salt thereof. Said P ₁ is the formula (b-1):

[In the formula, R ₃₅ is hydrogen or an alkyl group having 1 to 4 carbon atoms, b5 is an integer of 0 to 6 , b6 is 0 or 1 , and b7 is 0 or 1. , where b7 is 0 when b6=1, b6 is 0 when b7=1, and * is a binding site. ] The compound according to claim 5 or 6, or a pharmacologically acceptable salt thereof. The above P ₁ is represented by the formula (b-11):

[In the formula, b8 is an integer from 0 to 6 , and * is a binding site. ] The compound according to claim 7, or a pharmacologically acceptable salt thereof. Said P ₁ is formula (e1) or formula (e2):

[In the formula, R ₇₀ , R ₇₁ , and R ₇₂ are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and * is a bonding site. ] The compound according to claim 5, or a pharmacologically acceptable salt thereof. The above L ₁ is represented by the formula (a2-2):

[In the formula, _A1 is an amino acid residue or an amino acid residue having an esterified carboxy group in the side chain, a11 is an integer from 0 to 5, and a12 is 0 or 1 , * ^l2 is a bonding site with the adjacent -(R ₁ ') _p1 - group, and * ^r2 is a bonding site with the adjacent -P ₁ group. However, the arrangement order of the units whose repeating unit numbers are indicated by _A1 and a12 is not particularly limited. ] The compound according to claim 9, or a pharmacologically acceptable salt thereof. 6. The compound according to claim 4 or 5, or a pharmacologically acceptable salt thereof, wherein the target molecule recognition element is a polypeptide. 6. The compound according to claim 4 or 5, or a pharmacologically acceptable salt thereof, wherein the target molecule recognition element is an antibody or an antigen-binding region fragment of an antibody. A radiopharmaceutical comprising the compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof. A radiotherapeutic agent comprising the compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof. A radiological imaging diagnostic agent comprising the compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof. Use of a compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof, for the manufacture of a radiopharmaceutical. A radiopharmaceutical comprising the compound represented by formula (A3) or formula (B3), or a pharmacologically acceptable salt thereof, according to claim 1 , or a pharmacologically acceptable salt thereof. Preparative drug for preparing.

[During the ceremony,
L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by
R ₁ is of the formula:

A group represented by or formula (a):

[wherein R ₂ is formula (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8) or (a9):

[In the formula, R ₂₁₁ is hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 20 carbon atoms, X ₁ is chlorine, bromine, or iodine, and R ₂₁₂ is hydrogen, or is a methyl group, R ₂₁₃ is hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 20 carbon atoms, R ₂₁₄ is hydrogen or an alkyl group having 1 to 4 carbon atoms, a20 is an integer from 1 to 6. ]
or an aryl group having 6 to 20 carbon atoms, a1 is an integer of 0 to 6, a2 is 1, and * is a bonding site. ] is a group represented by ] A radiopharmaceutical comprising the compound represented by formula (A3) or formula (B3), or a pharmacologically acceptable salt thereof, according to claim 2, or a pharmacologically acceptable salt thereof. Preparative drug for preparing.

[During the ceremony,
L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by
Said R ₁ is
Formula (a-11), (a-12), (a-13), (a-14) or (a15-1):

[In the formula, a5 has the same definition as a1 above, R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ and R ₂₇ are each independently hydrogen, fluorine or a nitro group, and R ₂₈ and R ₂₉ are , each independently hydrogen, a sulfo group, or a salt of a sulfo group, X ¹⁰ is a CH group or nitrogen, and * is a bonding site. ] is a group represented by ] The above L is the formula (c-1), the formula (c-2) or the formula (c-3):

[In the formula, R ₅₁ is a fluoroalkyl group having 1 to 10 carbon atoms, and R ₅₂ ,R ₅₃ ,R ₅₄ ,R ₅₅ ,R ₅₆ are each independently hydrogen, an alkyl group having 1 to 20 carbon atoms, a fluoroalkyl group having 1 to 20 carbon atoms, or -C(=O)NR ₅₇ R ₅₈ and R ₅₇ ,R ₅₈ are each independently an alkyl group having 1 to 30 carbon atoms or an aryl group having 6 to 20 carbon atoms, and * is a bonding site. ] The drug for preparation according to claim 17 or 18, which is a group represented by the following. The compound according to any one of claims 4 to 12, comprising a compound represented by formula (A4) or formula (B4), or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof. Preparative agent for preparing radiopharmaceuticals including possible salts.

[In the formula, L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by
R ₁ ' is the following formula (a2-1):

[In the formula, a3 is an integer from 0 to 6, * ^l1 is a bonding site with an adjacent methylene group, * ^r1 is a bonding site with an adjacent -(L ₁ ) _p2 -P ₁ group . ] is a group represented by
L ₁ is a linking group,
p1 is 1 ,
p2 is 0 or 1,
P ₁ is a target molecule recognition element. ] Said P ₁ is the formula (b'):

[Wherein, R ₃₁ and R ₃₂ are hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R ₃₃ is hydrogen or an alkyl group having 1 to 4 carbon atoms. , b1 is an integer from 1 to 6, and * is a binding site. The preparation drug according to claim 20, which is a group represented by the following. Said P ₁ is formula (e1) or formula (e2):

[In the formula, R ₇₀ , R ₇₁ , and R ₇₂ are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and * is a bonding site. The preparation drug according to claim 20, which is a group represented by the following. The above L ₁ is represented by the formula (a2-2):

[In the formula, _A1 is an amino acid residue or an amino acid residue having an esterified carboxy group in the side chain, a11 is an integer from 0 to 5, and a12 is 0 or 1 , * ^l2 is a bonding site with the adjacent -(R ₁ ') _p1 - group, and * ^r2 is a bonding site with the adjacent -P ₁ group. However, the arrangement order of the units whose repeating unit numbers are indicated by _A1 and a12 is not particularly limited. ]
The preparation drug according to claim 22, which is a group represented by: A method for producing the compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof, comprising:
Formula (B3):

[During the ceremony,
L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by
R ₁ is
formula:

A group represented by or formula (a):

[wherein R ₂ is formula (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8) or (a9):

[In the formula, R ₂₁₁ is hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 20 carbon atoms, X ₁ is chlorine, bromine, or iodine, and R ₂₁₂ is hydrogen, or is a methyl group, R ₂₁₃ is hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 20 carbon atoms, R ₂₁₄ is hydrogen or an alkyl group having 1 to 4 carbon atoms, a20 is an integer from 1 to 6. ]
or an aryl group having 6 to 20 carbon atoms, a1 is an integer of 0 to 6, a2 is 1, and * is a bonding site. ], or
Formula (a-11), (a-12), (a-13), (a-14) or (a15-1):

[In the formula, a5 has the same definition as a1 above, R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ and R ₂₇ are each independently hydrogen, fluorine or a nitro group, and R ₂₈ and R ₂₉ are , each independently hydrogen, a sulfo group, or a salt of a sulfo group, X ¹⁰ is a CH group or nitrogen, and * is a bonding site. ], or
Formula (B4):

[In the formula, L is the formula (c):

[In the formula, R ₅₀ is an alkyl group having 1 to 10 carbon atoms, a fluoroalkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 60 carbon atoms, and * is a bonding site. ] is a group represented by
R ₁ ' is the following formula (a2-1):

[In the formula, a3 is an integer from 0 to 6, * ^l1 is a bonding site with an adjacent methylene group, * ^r1 is a bonding site with an adjacent -(L ₁ ) _p2 -P ₁ group ]
is a group represented by
L ₁ is a linking group,
p1 is 1 ,
p2 is 0 or 1,
P ₁ is a target molecule recognition element. ] or a pharmacologically acceptable salt thereof, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, 123 I ^{, 124} I, ¹²⁵ I, ¹³¹ I, ¹³³ I, ²⁰⁹ At, ²¹⁰ At Or a manufacturing method comprising reacting with ions of ²¹¹ At.

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