Radiolabeled FAPα-affinity compound and use thereof

Abstract

The purpose of the present invention is to provide a medical agent which specifically binds to FAPα, is effective in the treatment and diagnosis of tumors or cancers expressing FAPα, for example, in the treatment and diagnosis of solid cancers such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colon cancer, neuroendocrine tumors, thyroid cancer, uterine cancer, liver cancer, etc. (in particular, pancreatic cancer), and has a lower risk of prolonged side effects.　The present invention provides a conjugate comprising: a bioactive part comprising an aryl group substituted with a radionuclide selected from among 211At, 210At, 131I, 125I, 124I, 123I, 77Br, and 76Br; and a bioactive part having affinity to fibroblast activation protein α (FAPα).

Description

Radiolabeled FAPα affinity compound and its uses

[0001] The present invention relates to a radiolabeled FAPα affinity compound useful as a therapeutic and / or diagnostic agent for tumors or cancers, and a method for producing the same.

[0002] In pancreatic cancer lesions, cancer cells are thickly covered with connective tissue called the stroma, making it difficult for anticancer drugs to reach the cancer cells. As a result, the five-year survival rate for pancreatic cancer is extremely low, less than 10%. The stroma is a supportive tissue that supplies nutrients to cancer cells and supports their structure. The stroma is also well-developed in many solid cancers other than pancreatic cancer. Therefore, there is a need to develop treatments for stroma-rich cancers. Cancer-associated fibroblasts (CAFs), which make up the stroma, highly express fibroblast activation protein α (FAPα). Therefore, drugs that can specifically bind to FAPα are expected to be effective in diagnosing solid cancers, and if they can destroy the stroma and tumors, they may also be effective in treating solid cancers.

[0003] Patent Document 1 describes a drug that targets FAPα, which is a chelating agent such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). ６８ Ga (half-life 67.6 hours), ９０ Y (half-life 64.0 hours), ２０３ A drug containing a complex moiety formed with a radionuclide such as Pb (half-life 51.9 hours) is disclosed, and it is stated that the drug can be used for diagnostic imaging of cancer. １８ Drugs in which F is introduced by chemical bonding have also been reported.

[0004] Furthermore, Patent Document 2 discloses a drug that targets FAPα, which is α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-GA). １１１ A drug containing a complex moiety formed with In (half-life 67.3 hours) is disclosed, and it is stated that the drug can be used for imaging diagnosis of cancer.

[0005] Furthermore, Non-Patent Document 1 lists drugs that target FAPα as a chelating agent such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and ６４ Cu or ２２５ A drug containing a complex moiety formed with Ac is disclosed, and it has been demonstrated that the drug is effective in the treatment and imaging diagnosis of pancreatic cancer in mice xenografted with human pancreatic cancer.

[0006] It is an alpha-emitting nuclide ２１１ At is the same alpha-emitting nuclide ２２５ Because it has a shorter half-life than Ac ( ２１１ At: 7.2 hours, ２２５ Ac: 10 days), ２１１ At-labeled drugs have a short duration of action, allowing for outpatient treatment. In addition, because they are short-lived nuclides, they have the advantage of having a lower risk of prolonged side effects, and are therefore expected to be useful as new anticancer drugs.

[0007] WO2019 / 154886WO2019 / 083990

[0008] J Nucl Med. 2020;61:563-569

[0009] An object of the present invention is to provide a drug that specifically binds to FAPα and is effective in the treatment and diagnosis of tumors or cancers that express FAPα, for example, solid cancers (particularly pancreatic cancer) such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, and liver cancer, and that has a low risk of prolonged side effects.

[0010] As a result of extensive research to solve the above problems, the present inventors have found a compound represented by the following formula (I-1) or (I-2): ２１１The inventors have discovered that novel compounds radiolabeled with short-lived nuclides such as At specifically bind to FAPα and are effective in the treatment and diagnosis of tumors or cancers that express FAPα, for example, solid cancers (particularly pancreatic cancer) such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colon cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, and liver cancer, and have completed the invention.

[0011] That is, the present invention is as follows.

[0012] [1] ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ [2] A conjugate comprising: a radioactive moiety comprising an aryl group substituted with a radionuclide selected from Br; and a biologically active moiety having affinity for fibroblast activation protein α (FAPα).

[0013]

[0014] [3] The conjugate according to the above-mentioned [1], comprising a structure represented by: ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ aryl-C substituted with a radionuclide selected from Br; １－３ The conjugate according to the above [1] or [2], which contains an alkyl group.

[0015] [4] A radiolabeled compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as compound (I-1)).

[0016]

[0017] [In the formula, X１ teeth, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Ar 1 is C ６－１４ represents an aryl group; p is an R ａ１ and R ｂ１ are each independently a hydrogen atom or C １－６ represents an alkyl group; m represents one R ｃ１ are each independently C １－６ represents an alkyl group or a hydroxy group; n1 R ｄ１ each independently represents a halogen atom; Z １ is an oxygen atom, a sulfur atom, or NR ｆ１ (In the formula, R ｆ１ is a hydrogen atom or C １－３ represents an alkyl group; L １ (1) *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * represents a bonding site with CO, and ** represents Z １ indicates the binding site with L ａ１ (i) C １－６ an alkylene group, or (ii) —CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (wherein q1 represents an integer of 0 to 5), L ｂ１ represents a bond or —CO—, L ｃ１ (i) NR ｇ１ (In the formula, R ｇ１ is a hydrogen atom or C １－３ (ii) a divalent cyclic amino group; (iii) an oxygen atom; or (iv) a sulfur atom; L ｄ１ (i) bond, (ii) *-(NH-A ａ１ -CO) ｒ１-*** (wherein r1 NH-A ａ１ -CO each independently represents an amino acid residue, r1 represents an integer of 1 to 3, * represents a bonding site with CO, and *** represents L ｃ１ ), or (iii) *-NH-B ａ１ -O-B ｂ１ -CO-*** (in the formula, -NH-B ａ１ -O- represents a divalent residue derived from an amino sugar or a derivative thereof, and B ｂ１ is C １－６ represents an alkylene group, * represents a bonding site with CO, and *** represents L ｃ１ (2) *-(NH-A ｂ１ -CO) ｓ１ -** (wherein * represents a bonding site with CO, and ** represents Z １ It shows the binding site with s1 NH-A ｂ１ -CO each independently represents an amino acid residue; s1 represents an integer of 1 to 3; p1 represents an integer of 1 to 3; m1 represents an integer of 0 to 3; and n1 represents an integer of 0 to 3.]

[0018] [5] Z １ is an oxygen atom or a sulfur atom, and L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ The compound according to the above-mentioned [4], wherein the linker is represented by -** (each symbol in the formula has the same meaning as defined above), or a pharmaceutically acceptable salt thereof.

[0019] [6] Z １ But NR ｆ１ (The symbols in the formula have the same meanings as defined above.) and L １ However, *-(NH-A ｂ１ -CO) ｓ１ The compound according to the above-mentioned [4], wherein the linker is represented by -** (the symbols in the formula have the same meanings as defined above), or a pharmaceutically acceptable salt thereof.

[0020] [7] L １ However, *-Lｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But C １－６ is an alkylene group, ｂ１ is a bond or —CO—, and L ｃ１ is a divalent cyclic amino group, and L ｄ１ (i) bond, (ii) *-(NH-A ａ１ -CO) ｒ１ -*** (wherein each symbol has the same meaning as defined above), or (iii) *-NH-B ａ１ -O-B ｂ１ [8] The compound according to the above-mentioned [5], or a pharmaceutically acceptable salt thereof, wherein L is a linker represented by the formula: —CO-*** (wherein each symbol has the same meaning as defined above). ｃ１ The compound or a pharmaceutically acceptable salt thereof according to any one of the above-mentioned [4], [5] and [7], wherein the divalent cyclic amino group represented by the formula: is a divalent 3- to 8-membered cyclic diamino group.

[0021] [9] L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But -CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (the symbols in the formula have the same meanings as defined above), and L ｂ１ is a bond, and L ｃ１ But NR ｇ１ (The symbols in the formula are as defined above), an oxygen atom or a sulfur atom, and L ｄ１ is a bond.) The compound or a pharmaceutically acceptable salt thereof according to the above-mentioned [5],

[0022]

[10] The compound according to the above-mentioned [4] or [6], wherein s1 is 1, or a pharmaceutically acceptable salt thereof.

[0023]

[11] A radiolabeled compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as compound (I-2)).

[0024]

[0025] [In the formula, X ２ teeth, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Ar ２ is C ６－１４ represents an aryl group; p2 R ａ２ and R ｂ２ are each independently a hydrogen atom or C １－６ m represents an alkyl group; ｃ２ are each independently C １－６ represents an alkyl group or a hydroxy group; n2 R ｄ２ each independently represents a halogen atom; Z ２ is an oxygen atom, a sulfur atom, or NR ｆ２ (In the formula, R ｆ２ is a hydrogen atom or C １－３ represents an alkyl group; ２ (1) *-L ｃ２ -L ｂ２ -L ａ２ -** (wherein * represents R ｅ２ ** indicates the binding site with Z ２ indicates the binding site with L ａ２ (i) C １－６ an alkylene group, or (ii) —CH ２ - (CH ２ -O-CH ２ ) ｑ２ -CH ２ - (wherein q2 represents an integer of 0 to 5), L ｂ２represents a bond or —CO—, L ｃ２ (i) NR ｇ２ (In the formula, R ｇ２ is a hydrogen atom or C １－３ (ii) a divalent cyclic amino group; (iii) an oxygen atom; or (iv) a sulfur atom; or (2) a linker represented by the formula *-(NH-A ａ２ -CO) ｒ２ -** (wherein * represents R ｅ２ ** indicates the binding site with Z ２ r2 NH-A ａ２ -CO each independently represents an amino acid residue, and r2 represents an integer of 1 to 3; ｅ２ is C １－６ represents an alkyl-carbonyl group; or a group R ｅ２ -L ２ -Z ２ - represents a hydrogen atom; ３ is ***-(NH-A ｂ２ -CO) ｓ２ -**** (wherein *** represents a bonding site with CO, **** represents a bonding site with NH, and s2 NH-A ｂ２ -CO each independently represents an amino acid residue, and s2 represents an integer of 0 to 3; R represents a hydrogen atom or C １－３ p2 represents an integer of 0 to 3; m2 represents an integer of 0 to 3; and n2 represents an integer of 0 to 3.]

[0026]

[12] Z ２ is an oxygen atom or a sulfur atom, and L ２ However, *-L ｃ２ -L ｂ２ -L ａ２ The compound according to the above-mentioned

[11] , wherein the linker is represented by -** (each symbol in the formula has the same meaning as defined above), or a pharmaceutically acceptable salt thereof.

[0027]

[13] Z ２ But NR ｆ２ (The symbols in the formula have the same meanings as defined above.) and L２ However, *-(NH-A ａ２ -CO) ｒ２ The compound according to the above-mentioned

[11] , wherein the linker is represented by -** (each symbol in the formula has the same meaning as defined above), or a pharmaceutically acceptable salt thereof.

[0028]

[14] The compound according to any one of the above-mentioned

[11] to

[13] , or a pharmaceutically acceptable salt thereof, wherein p2 is an integer of 1 to 3.

[15] The compound according to any one of the above-mentioned

[11] to

[14] , or a pharmaceutically acceptable salt thereof, wherein s2 is 0.

[0029]

[16] A pharmaceutical composition comprising the compound according to any one of

[11] to

[15] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[17] A therapeutic agent for a tumor or cancer expressing fibroblast activation protein α (FAPα), comprising the compound according to any one of

[11] to

[15] above or a pharmaceutically acceptable salt thereof.

[18] The therapeutic agent according to

[17] above, wherein the tumor or cancer expressing fibroblast activation protein α is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, or liver cancer.

[19] The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for use in treating a tumor or cancer expressing fibroblast activation protein α (FAPα).

[20] The compound according to

[19] or a pharmaceutically acceptable salt thereof, wherein the tumor or cancer expressing fibroblast activation protein α is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, or liver cancer.

[21] A method for treating a tumor or cancer expressing fibroblast activation protein α (FAPα) in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

[22] The method of treating a tumor or cancer expressing fibroblast activation protein α according to the above

[21] , wherein the tumor or cancer is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, or liver cancer.

[23] Use of the compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for a tumor or cancer expressing fibroblast activation protein α (FAPα).

[24] The use according to

[23] above, wherein the tumor or cancer expressing fibroblast activation protein alpha is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, or liver cancer.

[0030]

[25] A compound represented by formula (II-1) or a salt thereof (hereinafter also referred to as compound (II-1)).

[0031]

[0032] [In the formula, Y １ is a boryl group (-B(OH) ２ ) or an ester group thereof; Ar 1 is C ６－１４ represents an aryl group; p1 R ａ１ and R ｂ１ are each independently a hydrogen atom or C １－６ represents an alkyl group; m represents one R ｃ１ are each independently C １－６ represents an alkyl group or a hydroxy group; n1 R ｄ１ each independently represents a halogen atom; Z １ is an oxygen atom, a sulfur atom, or NR ｆ１ (In the formula, R ｆ１ is a hydrogen atom or C １－３ represents an alkyl group; １ (1) *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * represents a bonding site with CO, and ** represents Z １ indicates the binding site with L ａ１ (i) C １－６ an alkylene group, or (ii) —CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (wherein q1 represents an integer of 0 to 5), L ｂ１ represents a bond or —CO—, L ｃ１ (i) NR ｇ１(In the formula, R ｇ１ is a hydrogen atom or C １－３ (ii) a divalent cyclic amino group; (iii) an oxygen atom; or (iv) a sulfur atom; L ｄ１ (i) bond, (ii) *-(NH-A ａ１ -CO) ｒ１ -*** (wherein r1 NH-A ａ１ -CO each independently represents an amino acid residue, r1 represents an integer of 1 to 3, * represents a bonding site with CO, and *** represents L ｃ１ ), or (iii) *-NH-B ａ１ -O-B ｂ１ -CO-*** (in the formula, -NH-B ａ１ -O- represents a divalent residue derived from an amino sugar or a derivative thereof, and B ｂ１ is C １－６ represents an alkylene group, * represents a bonding site with CO, and *** represents L ｃ１ (2) *-(NH-A ｂ１ -CO) ｓ１ -** (wherein * represents a bonding site with CO, and ** represents Z １ It shows the binding site with s1 NH-A ｂ１ -CO each independently represents an amino acid residue; s1 represents an integer of 1 to 3; p1 represents an integer of 1 to 3; m1 represents an integer of 0 to 3; and n1 represents an integer of 0 to 3.]

[0033]

[26] A radiolabeled compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as compound (II-2)).

[0034]

[0035] [In the formula, Y ２ is a boryl group (-B(OH) ２ ) or an ester group thereof; Ar ２ is C ６－１４ represents an aryl group; p2 R ａ２ and R ｂ２are each independently a hydrogen atom or C １－６ m represents an alkyl group; ｃ２ are each independently C １－６ represents an alkyl group or a hydroxy group; n2 R ｄ２ each independently represents a halogen atom; Z ２ is an oxygen atom, a sulfur atom, or NR ｆ２ (In the formula, R ｆ２ is a hydrogen atom or C １－３ represents an alkyl group; L ２ (1) *-L ｃ２ -L ｂ２ -L ａ２ -** (wherein * represents R ｅ２ ** indicates the binding site with Z ２ indicates the binding site with L ａ２ (i) C １－６ an alkylene group, or (ii) —CH ２ - (CH ２ -O-CH ２ ) ｑ２ -CH ２ - (wherein q2 represents an integer of 0 to 5), L ｂ２ represents a bond or —CO—, L ｃ２ (i) NR ｇ２ (In the formula, R ｇ２ is a hydrogen atom or C １－３ (ii) a divalent cyclic amino group; (iii) an oxygen atom; or (iv) a sulfur atom; or (2) a linker represented by the formula *-(NH-A ａ２ -CO) ｒ２ -** (wherein * represents R ｅ２ ** indicates the binding site with Z ２ r2 NH-A ａ２ -CO each independently represents an amino acid residue, and r2 represents an integer of 1 to 3; ｅ２ is C １－６ represents an alkyl-carbonyl group; or a group R ｅ２ -L ２ -Z ２- represents a hydrogen atom; ３ is ***-(NH-A ｂ２ -CO) ｓ２ -**** (wherein *** represents a bonding site with CO, **** represents a bonding site with NH, and s2 NH-A ｂ２ -CO each independently represents an amino acid residue, and s2 represents an integer of 0 to 3; R represents a hydrogen atom or C １－３ p2 represents an integer of 0 to 3; m2 represents an integer of 0 to 3; and n2 represents an integer of 0 to 3.]

[0036]

[27] A method for producing a radiolabeled compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0037]

[0038] [In the formula, X １ teeth, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Y １ is a boryl group (-B(OH) ２ ) or an ester group thereof; Ar 1 is C ６－１４ represents an aryl group; p1 R ａ１ and R ｂ１ are each independently a hydrogen atom or C １－６ represents an alkyl group; m represents one R ｃ１ are each independently C １－６ represents an alkyl group or a hydroxy group; n1 R ｄ１ each independently represents a halogen atom; Z １ is an oxygen atom, a sulfur atom, or NR ｆ１ (In the formula, R ｆ１ is a hydrogen atom or C １－３ represents an alkyl group; １ (1) *-L ｄ１-L ｃ１ -L ｂ１ -L ａ１ -** (wherein * represents a bonding site with CO, and ** represents Z １ indicates the binding site with L ａ１ (i) C １－６ an alkylene group, or (ii) —CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (wherein q1 represents an integer of 0 to 5), L ｂ１ represents a bond or —CO—, L ｃ１ (i) NR ｇ１ (In the formula, R ｇ１ is a hydrogen atom or C １－３ (ii) a divalent cyclic amino group; (iii) an oxygen atom; or (iv) a sulfur atom; L ｄ１ (i) bond, (ii) *-(NH-A ａ１ -CO) ｒ１ -*** (wherein r1 NH-A ａ１ -CO each independently represents an amino acid residue, r1 represents an integer of 1 to 3, * represents a bonding site with CO, and *** represents L ｃ１ ), or (iii) *-NH-B ａ１ -O-B ｂ１ -CO-*** (in the formula, -NH-B ａ１ -O- represents a divalent residue derived from an amino sugar or a derivative thereof, and B ｂ１ is C １－６ represents an alkylene group, * represents a bonding site with CO, and *** represents L ｃ１ (2) *-(NH-A ｂ１ -CO) ｓ１ -** (wherein * represents a bonding site with CO, and ** represents Z １ It shows the binding site with s1 NH-A ｂ１each —CO independently represents an amino acid residue, and s1 represents an integer of 1 to 3; p1 represents an integer of 1 to 3; m1 represents an integer of 0 to 3; and n1 represents an integer of 0 to 3.] Step 1: A compound represented by formula (II-1) or a salt thereof is reacted with a compound represented by formula (II-2) or a salt thereof in water in the presence of a reagent selected from an alkali metal iodide, an alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br to obtain a radiolabeled compound of formula (I-1) or a pharmaceutically acceptable salt thereof.

[0039]

[28] A method for producing a radiolabeled compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0040]

[0041] [In the formula, X ２ teeth, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Y ２ is a boryl group (-B(OH) ２ ) or an ester group thereof; Ar ２ is C ６－１４ represents an aryl group; p2 R ａ２ and R ｂ２ are each independently a hydrogen atom or C １－６ m represents an alkyl group; ｃ２ are each independently C １－６ represents an alkyl group or a hydroxy group; n2 R ｄ２ each independently represents a halogen atom; Z２ is an oxygen atom, a sulfur atom, or NR ｆ２ (In the formula, R ｆ２ is a hydrogen atom or C １－３ represents an alkyl group; ２ (1) *-L ｃ２ -L ｂ２ -L ａ２ -** (wherein * represents R ｅ２ ** indicates the binding site with Z ２ indicates the binding site with L ａ２ (i) C １－６ an alkylene group, or (ii) —CH ２ - (CH ２ -O-CH ２ ) ｑ２ -CH ２ - (wherein q2 represents an integer of 0 to 5), L ｂ２ represents a bond or —CO—, L ｃ２ (i) NR ｇ２ (In the formula, R ｇ２ is a hydrogen atom or C １－３ (ii) a divalent cyclic amino group; (iii) an oxygen atom; or (iv) a sulfur atom; or (2) a linker represented by the formula *-(NH-A ａ２ -CO) ｒ２ -** (wherein * represents R ｅ２ ** indicates the binding site with Z ２ r2 NH-A ａ２ -CO each independently represents an amino acid residue, and r2 represents an integer of 1 to 3; ｅ２ is C １－６ represents an alkyl-carbonyl group; or a group R ｅ２ -L ２ -Z ２ - represents a hydrogen atom; ３ is ***-(NH-A ｂ２ -CO) ｓ２ -**** (wherein *** represents a bonding site with CO, **** represents a bonding site with NH, and s2 NH-A ｂ２-CO each independently represents an amino acid residue, and s2 represents an integer of 0 to 3; R represents a hydrogen atom or C １－３ represents an alkyl group; p2 represents an integer of 0 to 3; m2 represents an integer of 0 to 3; and n2 represents an integer of 0 to 3. Step 2: A compound represented by formula (II-2) or a salt thereof is reacted with a compound represented by formula (II-3) or a salt thereof in water in the presence of a reagent selected from an alkali metal iodide, an alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br to obtain a radiolabeled compound of formula (I-2) or a pharmaceutically acceptable salt thereof.

[0042] According to the present invention, it is possible to provide a radiolabeled compound that specifically binds to FAPα and is effective in the treatment and diagnosis of tumors or cancers that express FAPα, for example, the treatment and diagnosis of solid cancers (particularly pancreatic cancer) such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, and liver cancer, with a lower risk of prolonged side effects.

[0043] FIG. 1 is a diagram showing an outline of the basic procedure for radiolabeling a boronic acid compound in Examples 1 to 14. FIG. 2 is a diagram showing the results of thin-layer chromatography (TLC) analysis of the reaction solution in Example 1. FIG. 3 is a diagram showing the results of thin-layer chromatography (TLC) analysis of the reaction solution in Example 2. (a) shows the results of analysis when 1 μg of starting material is used, and (b) shows the results of analysis when 10 μg of starting material is used. FIG. 4 is a diagram showing the results of thin-layer chromatography (TLC) analysis of the reaction solution in Example 3. FIG. 5 is a diagram showing the results of analysis when 1 μg of starting material is used, and (b) shows the results of analysis when 100 μg of starting material is used. FIG. 6 is a diagram showing the results of thin-layer chromatography (TLC) analysis of the reaction solution in Example 5. FIG. 7 shows the results of thin-layer chromatography (TLC) analysis of the reaction solution in Example 6. (a) shows the results of analysis when 1 μg of raw material is used, and (b) shows the results of analysis when 10 μg of raw material is used. FIG. 8 shows the results of thin-layer chromatography (TLC) analysis of the reaction solution in Example 7. FIG. 9 shows the results of analysis when the reaction solution in Example 8 is used by thin-layer chromatography (TLC). FIG. 10 shows the results of analysis when the reaction solution in Example 9 is used by thin-layer chromatography (TLC). FIG. 11 shows the results of analysis when the reaction solution in Example 10 is used by thin-layer chromatography (TLC). (a) shows the results of analysis when 10 μg of raw material is used, and (b) shows the results of analysis when 100 μg of raw material is used. FIG. 12 shows the results of analysis when the reaction solution in Example 11 is used by thin-layer chromatography (TLC). Fig. 13 shows the results of thin layer chromatography (TLC) analysis of the reaction solution in Example 12. (a) shows the results of analysis when 1 μg of raw material is used, and (b) shows the results of analysis when 10 μg of raw material is used. Fig. 14 shows the results of analysis by thin layer chromatography (TLC) of the reaction solution in Example 13. Fig. 15 shows the results of analysis by thin layer chromatography (TLC) of the reaction solution in Example 14.Fig. 16 shows the results of thin layer chromatography (TLC) analysis of the reaction solution in Example 15. Fig. 17 shows the results of thin layer chromatography (TLC) analysis of the reaction solution and eluate in Example 16. (a) shows the results of analysis of the reaction solution, and (b) shows the results of analysis of the eluate. Fig. 18 shows. ２１１ 19(a) is a graph showing the uptake of At-labeled FAPI derivatives into FAPα / 293 cells. ２１１ FIG. 19(b) is a graph showing the uptake of At-labeled FAPI derivatives into lung cancer cells (A549). ２１１ 20 is a graph showing the uptake of At-labeled FAPI derivatives into breast cancer cells (MDA-MB-231). ２１１ 1 is a graph showing the tumor growth inhibitory effect of an At-labeled FAPI derivative in mice xenografted with human pancreatic cancer, where (a) is a graph showing tumor growth in the mice, and (b) is a graph showing changes in body weight.

[0044] The present invention will be described in detail below. In this specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. １－３ The term "alkyl group" refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, propyl, and isopropyl. １－６ The term "alkyl group" means a straight or branched chain alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. Preferably, "C １－３ "Alkyl group."

[0045] In the present specification, the term "aryl group" refers to a cyclic hydrocarbon group having aromaticity, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, etc. Preferably, C ６－１４An aryl group is more preferably a phenyl group. ６－１４ The term "aryl group" refers to a cyclic hydrocarbon group having aromaticity and 6 to 14 carbon atoms, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. A phenyl group is preferred.

[0046] In this specification, "C ６－１４ Aryl-C １－３ The term "alkyl group" refers to the above-mentioned "C ６－１４ The above "C" substituted with "aryl group" １－３ It means an "alkyl group", and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 2-(1-naphthyl)ethyl, etc. Preferably, phenyl-C １－３ In the present specification, "phenyl-C １－３ The term "alkyl group" refers to the above "C alkyl group substituted with phenyl." １－３ Examples of the alkyl group include benzyl, 1-phenylethyl, 2-phenylethyl, and 3-phenylpropyl.

[0047] In this specification, "C １－６ An "alkyl-carbonyl group" is a group of the formula R'C(O)-, where R' is C １－６ and represents an alkyl group.) Examples thereof include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl.

[0048] In this specification, "C １－６ The term "alkylene group" means a straight or branched chain alkylene group having 1 to 6 carbon atoms, for example, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ -, -(CH２ ) ６ -, -CH(CH ３ ) -, -C(CH ３ ) ２ -, -CH(C ２ H ５ ) -, -CH(C ３ H ７ )-,-CH(CH(CH ３ ) ２ )-,-(CH(CH ３ )) ２ -, -CH ２ -CH(CH ３ ) -, -CH(CH ３ )-CH ２ -, -CH ２ -CH ２ -C(CH ３ ) ２ -, -C(CH ３ ) ２ -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -C(CH ３ ) ２ -, -C(CH ３ ) ２ -CH ２ -CH ２ -CH ２ -, etc. Preferably, C ２－４ In the present specification, "C" is an alkylene group. ２－４ The term "alkylene group" means a straight or branched chain alkylene group having 2 to 4 carbon atoms, for example, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -CH(CH ３ ) -, -C(CH ３ ) ２ -, -CH(C ２ H ５ ) -, -CH(C ３ H ７ )-,-CH(CH(CH ３ ) ２ )-,-(CH(CH ３ ))２ -, -CH ２ -CH(CH ３ ) -, -CH(CH ３ )-CH ２ - etc.

[0049] In the present specification, the term "divalent cyclic amino group" means a divalent group obtained by removing H from the amino group (-NH-) of a cyclic amine and one H from another moiety, and is specifically represented by the following structure:

[0050]

[0051] (Wherein, ring D represents a 3- to 8-membered saturated or unsaturated cyclic amine which may contain, in addition to one nitrogen atom, a heteroatom selected from an oxygen atom, a sulfur atom, or a nitrogen atom and which may have a substituent; W represents a carbon atom, CR ｈ (In the formula, R ｈ is a hydrogen atom or C １－３represents an alkyl group.) or a nitrogen atom.) W is preferably a nitrogen atom. That is, the "divalent cyclic amino group" is preferably a divalent cyclic diamino group. Specific examples of the divalent cyclic diamino group include piperazine-1,4-diyl, dihydropyrazine-1,4-diyl, tetrahydropyrazine-1,4-diyl, tetrahydropyrimidine-1,3-diyl, hexahydropyrimidine-1,3-diyl, dihydropyridazine-1,2-diyl, tetrahydropyridazine-1,2-diyl, hexahydropyridazine-1,2-diyl, 1,2-diazepane-1,2-diyl, 1,3-diazepane-1,3-diyl, 1,4-diazepane-1,4-diyl, dihydro-1,2-diazepine-1,2-diyl, tetrahydro-1,2-diazepine-1,2-diyl, hexahydro-1,2-diazepine-1,2-diyl, dihydropyridazine-1,2-diyl, Examples of such divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino groups include dro-1,3-diazepine-1,3-diyl, tetrahydro-1,3-diazepine-1,3-diyl, hexahydro-1,3-diazepine-1,3-diyl, tetrahydro-1,4-diazepine-1,4-diyl, hexahydro-1,4-diazepine-1,4-diyl, 1,2-diazocane-1,2-diyl, 1,3-diazocane-1,3-diyl, 1,4-diazocane-1,4-diyl, 1,5-diazocane-1,5-diyl, pyrazoline-1,2-diyl, pyrazolidine-1,2-diyl, imidazoline-1,3-diyl, and imidazolidine-1,3-diyl. Of these, divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic saturated diamino groups are preferred, with piperazine-1,4-diyl being particularly preferred.

[0052] As used herein, "amino acid residue" refers to a divalent group formed by removing H from the amino group and OH from the carboxy group of an amino acid. The amino acid in the "amino acid residue" is not particularly limited as long as it has an amino group and a carboxy group, and may be a natural (L-type) or non-natural (D-type) amino acid, or may be an artificial amino acid. The amino acid may be any of α-amino acids, β-amino acids, γ-amino acids, etc. The "amino acid residue" may also be a residue of a cyclic amino acid such as those shown below.

[0053]

[0054] (The symbols in the formulae have the same meanings as defined above.) Examples of α-amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, arginine, histidine, glutamine, asparagine, phenylalanine, tyrosine, α-methyltyrosine, tryptophan, ornithine, thyroxine, proline, 3,4-dihydroxyphenylalanine, 3-(1-naphthyl)alanine, 3-(2-naphthyl)alanine, α-aminobutyric acid, norvaline, norleucine, homonorleucine, 1,2,4-triazole-3-alanine, 2-aminoadipic acid, propargylglycine, allylglycine, α-cyclobutylmethylglycine, 6-azidonorleucine, 4-azidophenylalanine, 4-fluoroglutamic acid, 4-iodophenylalanine, etc.; Examples of β-amino acids include β-alanine, 3-aminoadipic acid, etc.; and examples of γ-amino acids include γ-aminobutyric acid, etc. When the above-mentioned amino acids have a functional group in the side chain, the functional group may be protected / modified. Examples of such amino acids include δ-Boc-lysine, δ-Z-lysine, δ-Fmoc-lysine, β-Bn-aspartic acid, γ-Bn-glutamic acid, etc. Divalent groups formed by removing H from the amino group and OH from the carboxy group of such amino acids are also included in the "amino acid residue." Furthermore, the above-mentioned amino acids may have a substituent in the side chain. Examples of such amino acids include 4-azidophenylalanine, 3-azidophenylalanine, 3-azidotyrosine, 2-azidotyrosine, and α-methylamino acids thereof. Divalent groups formed by removing H from the amino group and OH from the carboxy group of such amino acids are also included in the "amino acid residue." The configuration of the above amino acids is not particularly limited, and may be any of D-, L-, or DL-configuration (that is, any of R-, S-, or R / S-configuration).

[0055] As used herein, the term "divalent residue derived from an amino sugar or a derivative thereof" refers to a divalent group obtained by removing H from the amino group and H from the hydroxyl group of an amino sugar or a derivative thereof. The amino sugar in the term "divalent residue derived from an amino sugar or a derivative thereof" refers to a saccharide in which at least one of its hydroxyl groups has been replaced with an amino group, and examples thereof include monosaccharides such as glucosamine and galactosamine, and disaccharides or higher sugars containing these monosaccharides. There are no particular limitations on the saccharide as long as it has a hydroxyl group and an amino group. Examples of amino sugar derivatives include those in which the hydroxyl group (not involved in the bond) of the amino sugar is protected / modified. There are no particular limitations on the configuration of the amino sugar or its derivative.

[0056] As used herein, the term "boryl group (-B(OH) ２ ) is also referred to as a dihydroxyboryl group. In this specification, examples of the "ester group of a boryl group" include the groups shown below.

[0057]

[0058] [In the formula, R ４ is C １－６represents an alkyl group.] As used herein, the term "protected amino acid residue" refers to an amino acid residue in which, when the amino acid residue has a functional group, the functional group is protected. When the amino acid residue has an amino group, it is protected with an amino-protecting group such as a tert-butoxycarbonyl group (Boc group), and when the amino acid residue has a carboxy group, it is protected with a carboxy-protecting group such as a tert-butyl group. These protecting groups are appropriately selected depending on the type of other protecting groups and resin for solid-phase synthesis, the synthesis strategy, and the like. As used herein, examples of a "hydroxy-protecting group" include a benzyl group, a p-methoxybenzyl group, a methoxymethyl group, a trimethylsilyl group, a triethylsilyl group, a trityl group, a tert-butyl group, a tert-butyldimethylsilyl group (TBS group), a tetrahydropyranyl group, a benzylidene group (forming a benzylidene acetal), an isopropylidene group (forming a dimethyl acetal), an acetyl group, a benzoyl group, and the like. As used herein, examples of the "amino-protecting group" include a 9-fluorenylmethyloxycarbonyl group (Fmoc group), a tert-butoxycarbonyl group (Boc group), a benzyloxycarbonyl group (Cbz group), a trichloroethoxycarbonyl group (Troc group), etc. As used herein, examples of the "carboxy-protecting group" include a tert-butyl group, a benzyl group, a C １－２ Examples of the "mercapto-protecting group" used herein include benzyl, p-methoxybenzyl, methoxymethyl, trimethylsilyl, triethylsilyl, trityl, tert-butyl, tert-butyldimethylsilyl (TBS), tetrahydropyranyl, isopropylidene (formation of dimethylthioacetal), acetyl, and benzoyl.

[0059] The conjugate of the present invention comprises: ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６a radioactive moiety comprising an aryl group substituted with a radionuclide selected from Br, and a biologically active moiety having affinity for fibroblast activation protein α (FAPα).

[0060] In the radioactive moiety, the aryl group is preferably C ６－１４ An aryl group is preferably a phenyl group, and more preferably a phenyl group. ２１１ At (α-ray emitting nuclide), ２１０ At (α-ray emitting nuclide), １３１ I (beta-ray emitting nuclide), １２５ I (X-ray emitting nuclide), １２４ I (positron-emitting nuclide), １２３ I (γ-ray emitting nuclide), ７７ Br (Auger electron emitting nuclide) and ７６ The aryl group is substituted with a radionuclide selected from Br (positron-emitting nuclide). The substitution position is not particularly limited, but for example, when the aryl group is a phenyl group, the 3- or 4-position is preferred. Examples of radioactive moieties containing such an aryl group include: ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ aryl-C substituted with a radionuclide selected from Br; ０－３ Alkyl groups (preferably aryl-C １－３ alkyl group, more preferably phenyl-C １－３ Specifically, it is preferable that the alkyl group contains the following formula:

[0061]

[0062] wherein X is ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Ar represents a radionuclide selected from C ６－１４represents an aryl group; ａ and R ｂ are each independently a hydrogen atom or C １－６ m R ｃ are each independently a substituent (e.g., C １－６ p represents an integer of 0 to 3 (preferably an integer of 1 to 3); and m represents an integer of 0 to 3.

[0063] The physiologically active portion is not limited as long as it has affinity for fibroblast activation protein α, and examples thereof include portions containing part or all of the compounds disclosed in WO2019 / 154866, WO2019 / 083990, etc., and preferred specific examples include those having the following formula:

[0064]

[0065] In one embodiment, the structure is a moiety having the formula:

[0066]

[0067] It is preferable that the structure is represented by the following formula:

[0068] One embodiment of the conjugate of the present invention is a radiolabeled compound (I-1).

[0069]

[0070] [Each symbol in the formula has the same meaning as defined above.] X １ teeth, ２１１ At (α-ray emitting nuclide), ２１０ At (α-ray emitting nuclide), １３１ I (beta-ray emitting nuclide), １２５ I (X-ray emitting nuclide), １２４ I (positron-emitting nuclide), １２３ I (γ-ray emitting nuclide), ７７ Br (Auger electron emitting nuclide) and ７６ Br (positron-emitting nuclide). The half-lives of these radionuclides are: ２１１ At 7.2 hours, ２１０ At 8.3 hours,１３１ I is 8.04 days, １２５ I is 59.4 days, １２４ I is 4.2 days, １２３ I is 13.2 hours, ７７ Br 57 hours, ７６ Br is 16 hours. Ar １ X above １ The bonding position of is not particularly limited, but for example, Ar １ When is a phenyl group, the 3- or 4-position is preferred.

[0071] Ar １ are respectively, C ６－１４ represents an aryl group. In one embodiment, Ar １ is preferably a phenyl group. ｃ１ are each independently C １－６ It represents an alkyl group (e.g., methyl) or a hydroxy group. m1 represents an integer of 0 to 3. In one embodiment, m1 is preferably 0.

[0072] p1 R ａ１ and R ｂ１ are each independently a hydrogen atom or C １－６ In one embodiment, p1 R ａ１ and R ｂ１ is preferably a hydrogen atom. p1 represents an integer of 1 to 3. In one embodiment, p1 is preferably 1 or 2 from the viewpoint of reaction yield and stability.

[0073] n1 R ｄ１ In one embodiment, n1 R ｄ１ is preferably a fluorine atom. n1 represents an integer of 0 to 3. In one embodiment, n1 is preferably an integer of 0 to 2.

[0074] Z １ is an oxygen atom, a sulfur atom, or NR ｆ１ (The symbols in the formula have the same meanings as defined above.) １ (1) *-L ｄ１ -L ｃ１ -L ｂ１ -Lａ１ -** (wherein each symbol has the same meaning as defined above), or (2) *-(NH-A ｂ１ -CO) ｓ１ -** (wherein each symbol has the same meaning as defined above) represents a linker.

[0075] Z １ and L １ Preferred combinations of (A1) and (B1) include the following: (A1) Z １ is an oxygen atom or a sulfur atom (preferably an oxygen atom), and L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein each symbol has the same meaning as defined above). (B1) Z １ But NR ｆ１ (The symbols in the formula have the same meanings as defined above.) and L １ However, *-(NH-A ｂ１ -CO) ｓ１ -** (the symbols in the formula are as defined above).

[0076] In the embodiment of (A1), L １ Preferred embodiments of the above include the following embodiments (A1-1) and (A1-2).

[0077] (A1-1) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But C １－６ is an alkylene group, ｂ１ is a bond or —CO—, and L ｃ１ is a divalent cyclic amino group, and L ｄ１ (i) bond, (ii) *-(NH-A ａ１ -CO) ｒ１ -*** (wherein each symbol has the same meaning as defined above), or (iii) *-NH-Bａ１ -O-B ｂ１ -CO-*** (wherein each symbol has the same meaning as defined above).

[0078] (A1-2) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But -CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (the symbols in the formula have the same meanings as defined above), and L ｂ１ is a bond, and L ｃ１ But NR ｇ１ (The symbols in the formula are as defined above), an oxygen atom or a sulfur atom, and L ｄ１ is (i) a bond, or (ii) *-NH-B ａ１ -O-B ｂ１ -CO-*** (wherein each symbol has the same meaning as defined above).

[0079] In the embodiment (A1-1), L ａ１ is C １－６ In one embodiment, L represents an alkylene group. ａ１ is preferably C ２－４ In the embodiment of (A1-1), L is an alkylene group. ｃ１ represents a divalent cyclic amino group. ｃ１ is preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group. ｃ１ is more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, and particularly preferably piperazine-1,4-diyl.

[0080] The "divalent cyclic amino group" is L in formula (I-1). ｂ１ and Lｄ１ It binds to the following structure

[0081]

[0082] In the formula, the nitrogen atom is L ｂ１ and W is L ｄ１ Alternatively, the nitrogen atom may be bonded to L ｄ１ and W is L ｂ１ However, the nitrogen atom may be bonded to L ｄ１ and W is L ｂ１ A preferred embodiment is to bind to

[0083] In the embodiment (A1-1), preferred embodiments include the following embodiments (A1-1-1) to (A1-1-5).

[0084] (A1-1-1) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But C １－６ Alkylene group (preferably C ２－４ alkylene group), and L ｂ１ is a bond, and L ｃ１ is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L ｄ１ is a bond.

[0085] (A1-1-2) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But C １－６ Alkylene group (preferably C２－４ alkylene group), and L ｂ１ is a bond, and L ｃ１ is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L ｄ１ However, *-NH-B ａ１ -O-B ｂ１ -CO-*** (each symbol in the formula has the same meaning as defined above). In this embodiment, the linker is represented by -NH-B ａ１ -O- represents a divalent residue derived from an amino sugar or a derivative thereof. ａ１ -O- is preferably a divalent residue derived from a monosaccharide such as glucosamine or galactosamine, and more preferably a divalent residue derived from glucosamine. ｂ１ is C １－６ In one embodiment, B represents an alkylene group. ｂ１ is preferably C ２－４ It is an alkylene group.

[0086] (A1-1-3) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But C １－６ Alkylene group (preferably C ２－４ alkylene group), and L ｂ１ is —CO—, and L ｃ１ is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L ｄ１ is a bond.

[0087] (A1-1-4) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But C １－６ Alkylene group (preferably C ２－４ alkylene group), and L ｂ１ is a bond, and L ｃ１ is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L ｄ１ However, *-(NH-A ａ１ -CO) ｒ１ -*** (wherein each symbol has the same meaning as defined above).

[0088] (A1-1-5) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But C １－６ Alkylene group (preferably C ２－４ alkylene group), and L ｂ１ is —CO—, and L ｃ１ is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L ｄ１ However, *-(NH-A ａ１ -CO) ｒ１ -*** (wherein each symbol has the same meaning as defined above).

[0089] In the embodiments (A1-1-4) and (A1-1-5), r1 NH-A ａ１ Each —CO independently represents an amino acid residue. ａ１ -CO is preferably a 4-azidophenylalanine residue. r1 represents an integer of 1 to 3. In one embodiment, r1 is preferably 1. In one embodiment, L ｄ１ is preferably a 4-azidophenylalanine residue.

[0090] In the embodiment (A1-2), L ａ１ is -CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ In one embodiment, q1 is preferably an integer of 1 to 3. In the embodiment (A1-2), L ｃ１ is NR ｇ１ (In the formula, R ｇ１ is a hydrogen atom or C １－３ represents an alkyl group; an oxygen atom or a sulfur atom. ｇ１ is preferably a hydrogen atom. ｃ１ is preferably NR ｇ１ (The symbols in the formula have the same meanings as defined above.) More preferably, it is NH.

[0091] In the embodiment (A1-2), preferred embodiments include the following embodiments (A1-2-1) and (A1-2-2).

[0092] (A1-2-1) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But -CH ２ - (CH ２ -O-CH ２ )ｑ１ -CH ２ - (the symbols in the formula have the same meanings as defined above), and L ｂ１ is a bond, and L ｃ１ But NR ｇ１ (The symbols in the formula have the same meanings as defined above.) and L ｄ１ is a bond.

[0093] (A1-2-2) L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein * is a bonding site with CO, and ** is Z １ is a binding site for L ａ１ But -CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (the symbols in the formula have the same meanings as defined above), and L ｂ１ is a bond, and L ｃ１ But NR ｇ１ (The symbols in the formula have the same meanings as defined above.) and L ｄ１ However, *-NH-B ａ１ -O-B ｂ１ -CO-*** (each symbol in the formula has the same meaning as defined above). In this embodiment, the linker is represented by -NH-B ａ１ -O- represents a divalent residue derived from an amino sugar or a derivative thereof. ａ１ -O- is preferably a divalent residue derived from a monosaccharide such as glucosamine or galactosamine, and more preferably a divalent residue derived from glucosamine. ｂ１ is C １－６ In one embodiment, B represents an alkylene group. ｂ１ is preferably C ２－４ It is an alkylene group.

[0094] In the embodiment of (B1), Z １ is NR ｆ１ (In the formula, R ｆ１ is a hydrogen atom or C １－３In one embodiment, R ｆ１ is preferably a hydrogen atom. １ is preferably NH. In embodiment (B1), L １ is *-(NH-A ｂ１ -CO) ｓ１ -** (wherein s1 NH-A ｂ１ Each —CO independently represents an amino acid residue, and s1 represents an integer of 1 to 3. In one embodiment, s1 NH-A ｂ１ -CO is preferably a glycine residue. In one embodiment, s1 is preferably 1. In one embodiment, L １ is preferably a glycine residue.

[0095] The chiral C atom in the radiolabeled compound (I-1) may be either S or R. The radiolabeled compound (I-1) has optical isomers based on the chiral C atom, and all optical isomers and mixtures thereof in any ratio are encompassed in the radiolabeled compound (I-1). In one embodiment, the compound (I-1) is represented by the following formula (I'-1):

[0096]

[0097] It is preferred that the steric configuration be represented by the following formula:

[0098] Specific examples of suitable radiolabeled compounds (I-1) include the following:

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] Another embodiment of the conjugate of the present invention is a radiolabeled compound (I-2).

[0106]

[0107] [Each symbol in the formula has the same meaning as defined above.] X ２ teeth, ２１１ At (α-ray emitting nuclide), ２１０ At (α-ray emitting nuclide), １３１ I (beta-ray emitting nuclide), １２５ I (X-ray emitting nuclide), １２４ I (positron-emitting nuclide), １２３ I (γ-ray emitting nuclide), ７７ Br (Auger electron emitting nuclide) and ７６ Br (positron-emitting nuclide). The half-lives of these radionuclides are: ２１１ At 7.2 hours, ２１０ At 8.3 hours, １３１ I is 8.04 days, １２５ I is 59.4 days, １２４ I is 4.2 days, １２３ I is 13.2 hours, ７７ Br 57 hours, ７６ Br is 16 hours. Ar ２ X above ２ The bonding position of is not particularly limited, but for example, Ar ２ When is a phenyl group, the 3- or 4-position is preferred.

[0108] Ar ２ are respectively, C ６－１４ represents an aryl group. In one embodiment, Ar ２ is preferably a phenyl group. ｃ２ are each independently C １－６ m2 represents an alkyl group (e.g., methyl) or a hydroxy group. m2 represents an integer of 0 to 3. In one embodiment, m2 is preferably 0.

[0109] p2 R ａ２ and R ｂ２ are each independently a hydrogen atom or C １－６ In one embodiment, p2 R ａ２and R ｂ２ is preferably a hydrogen atom. p2 represents an integer of 0 to 3. In one embodiment, p2 is preferably an integer of 1 to 3, and more preferably 1.

[0110] n2 R ｄ２ In one embodiment, n2 R ｄ２ is preferably a fluorine atom. n2 represents an integer of 0 to 3. In one embodiment, n2 is preferably an integer of 0 to 2.

[0111] Z ２ is an oxygen atom, a sulfur atom, or NR ｆ２ (The symbols in the formula have the same meanings as defined above.) ２ (1) *-L ｃ２ -L ｂ２ -L ａ２ -** (wherein each symbol has the same meaning as defined above), or (2) *-(NH-A ａ２ -CO) ｒ２ -** (wherein each symbol has the same meaning as defined above) represents a linker.

[0112] Z ２ and L ２ Preferred combinations of (A2) and (B2) include the following: (A2) Z ２ is an oxygen atom or a sulfur atom, and L ２ However, *-L ｃ２ -L ｂ２ -L ａ２ -** (wherein each symbol has the same meaning as defined above). (B2) Z ２ But NR ｆ２ (The symbols in the formula have the same meanings as defined above.) and L ２ However, *-(NH-A ａ２ -CO) ｒ２ -** (each symbol in the formula has the same meaning as defined above).

[0113] In the embodiment (A2), L ２ Preferred embodiments of the above include the following embodiments (A2-1) and (A2-2).

[0114] (A2-1) L ２ However, *-L ｃ２ -L ｂ２ -L ａ２ -** (wherein * is a bonding site with CO, and ** is Z ２ is a binding site for L ａ２ But C １－６ is an alkylene group, ｂ２ is a bond or —CO—, and L ｃ２ is a divalent cyclic amino group.

[0115] (A2-2) L ２ However, *-L ｃ２ -L ｂ２ -L ａ２ -** (wherein * is a bonding site with CO, and ** is Z ２ is a binding site for L ａ２ But -CH ２ - (CH ２ -O-CH ２ ) ｑ２ -CH ２ - (the symbols in the formula have the same meanings as defined above), and L ｂ２ is a bond and L ｃ２ But NR ｇ２ (wherein the symbols are as defined above), an oxygen atom, or a sulfur atom).

[0116] In the embodiment of (A2-1), L ａ２ is C １－６ In one embodiment, L represents an alkylene group. ａ２ is preferably C ２－４ In the embodiment of (A2-1), L is an alkylene group. ｃ２ represents a divalent cyclic amino group. ｃ２ is preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group. ｃ２is more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, and particularly preferably piperazine-1,4-diyl.

[0117] The "divalent cyclic amino group" is L in formula (I-2). ｂ２ and R ｅ２ It binds to the following structure

[0118]

[0119] In the formula, the nitrogen atom is L ｂ２ and W is R ｅ２ Alternatively, the nitrogen atom may be bonded to R ｅ２ and W is L ｂ２ However, the nitrogen atom may be bonded to R ｅ２ and W is L ｂ２ A preferred embodiment is to bind to

[0120] In the embodiment (A2-1), preferred embodiments include the following embodiments (A2-1-1) to (A2-1-2).

[0121] (A2-1-1) L ２ However, *-L ｃ２ -L ｂ２ -L ａ２ -** (wherein * is a bonding site with CO, and ** is Z ２ is a binding site for L ａ２ But C １－６ Alkylene group (preferably C ２－４ alkylene group), and L ｂ２ is a bond and L ｃ２ is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl).

[0122] (A2-1-2) L ２ However, *-L ｃ２ -L ｂ２ -L ａ２-** (wherein * is a bonding site with CO, and ** is Z ２ is a binding site for L ａ２ But C １－６ Alkylene group (preferably C ２－４ alkylene group), and L ｂ２ is —CO—, and L ｃ２ is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl).

[0123] In the embodiment of (A2-2), L ａ２ is -CH ２ - (CH ２ -O-CH ２ ) ｑ２ -CH ２ In one embodiment, q2 is preferably an integer of 1 to 3. In the embodiment (A2-2), L ｃ２ is NR ｇ２ (In the formula, R ｇ２ is a hydrogen atom or C １－３ represents an alkyl group; an oxygen atom or a sulfur atom. ｇ２ is preferably a hydrogen atom. ｃ２ is preferably NR ｇ２ (The symbols in the formula have the same meanings as defined above.) More preferably, it is NH.

[0124] In the embodiment (B2), Z ２ is NR ｆ２ (In the formula, R ｆ２ is a hydrogen atom or C １－３ In one embodiment, R ｆ２ is preferably a hydrogen atom. ２ is preferably NH. In embodiment (B2), L ２ is *-(NH-A ａ２ -CO)ｒ２ -** (wherein r2 NH-A ａ２ Each —CO independently represents an amino acid residue, and r2 represents an integer of 1 to 3. In one embodiment, r2 NH-A ａ２ -CO is preferably a glycine residue. In one embodiment, r2 is preferably 1. In one embodiment, L ２ is preferably a glycine residue.

[0125] R ｅ２ is C １－６ represents an alkyl-carbonyl group. ｅ２ is preferably an acetyl group. Alternatively, the group R ｅ２ -L ２ -Z ２ - represents a hydrogen atom.

[0126] L ３ is ***-(NH-A ｂ２ -CO) ｓ２ -**** (wherein *** represents a bonding site with CO, **** represents a bonding site with NH, and s2 NH-A ｂ２ -CO each independently represents an amino acid residue, and s2 represents an integer of 0 to 3. In one embodiment, s2 is preferably 0.

[0127] R is a hydrogen atom or C １－３ represents an alkyl group. In one embodiment, R is preferably a hydrogen atom.

[0128] The chiral C atom in the radiolabeled compound (I-2) may be either S or R. The radiolabeled compound (I-2) has optical isomers based on the chiral C atom, and all optical isomers and mixtures thereof in any ratio are encompassed in the radiolabeled compound (I-2). In one embodiment, the compound (I-2) is represented by the following formula (I'-2):

[0129]

[0130] It is preferred that the steric configuration be represented by the following formula:

[0131] Specific examples of suitable radiolabeled compounds (I-2) include the following:

[0132]

[0133] Compound (I-1) or (I-2) may be in the form of a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.), and ammonium salts when the compound has an acidic functional group; and salts with inorganic acids such as hydrogen chloride, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid when the compound has a basic functional group, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.

[0134] A method for producing the radiolabeled compound (I-1) or (I-2) of the present invention is described below. When the starting compound is a salt, examples of such salts include metal salts (e.g., alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt), ammonium salts, salts with organic bases (e.g., trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine), salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid), and salts with organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid).

[0135] The radiolabeled compound (I-1) can be produced by a method comprising the following step 1:

[0136]

[0137] [Each symbol in the formula has the same meaning as defined above.]

[0138] Y １ is a boryl group (-B(OH) ２ ) or an ester group thereof. １is preferably a boryl group (—B(OH) ２ ) or a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group (a pinacol ester group).

[0139] Step 1 comprises reacting a boronic acid compound (II-1) with a boronic acid compound (II-2) in water in the presence of a reagent selected from an alkali metal iodide, an alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br to obtain a radiolabeled compound (I-1).

[0140] The boronic acid compound (II-1) is a novel compound, and preferred specific examples thereof include the following:

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] The boronic acid compound (II-1) can be produced by the method described below. Since the reaction in this step is carried out in water, the boronic acid compound (II-1) may be in the free form or in the form of a salt, as long as it is soluble in water. Alternatively, it may be used by dissolving it in a weakly basic aqueous solution such as an aqueous sodium bicarbonate solution.

[0148] Examples of alkali metal iodides include potassium iodide and sodium iodide, with potassium iodide being preferred. Examples of alkali metal bromides include sodium bromide and potassium bromide.

[0149] Suitable combinations of radionuclides and the above reagents include: (1) radionuclides ２１１ At or ２１０ At and the reagent is selected from potassium iodide, sodium bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide; (2) a combination in which the radionuclide is １２３ I, １２４ I, １２５ I or １３１ I and the reagent is selected from N-bromosuccinimide and N-chlorosuccinimide; (3) a combination in which the radionuclide is ７６ Br or ７７ Br and the reagent is N-chlorosuccinimide. The reagents may be used alone or in combination of two or more. The reagents are usually used in the form of an aqueous solution. In a preferred embodiment, the radionuclide is ２１１ At or １３１ I and the reagent is selected from potassium iodide and N-bromosuccinimide. ２１１ At and the reagent is potassium iodide, and １３１ I and the reagent is N-bromosuccinimide.

[0150] The reagent may be used in an amount sufficient to oxidize or reduce the radionuclide, and is usually used in large excess relative to the radionuclide. From the viewpoints of reaction efficiency and economic efficiency, the reagent is used at a concentration of preferably 0.0001 to 0.2 mol / L, more preferably 0.001 to 0.1 mol / L.

[0151] The radionuclide is usually used in the reaction in the form of an aqueous solution. If necessary, an alkaline aqueous solution such as sodium hydroxide or a buffer solution may be added to the aqueous solution for the purpose of stabilizing the radionuclide. ２１１ In the case of At, bismuth is irradiated with helium particles accelerated to 28 MeV in a cyclotron, ２０９ Bi(α, 2n) ２１１ By the nuclear reaction of At２１１ After producing At, the target material ２０９ Bi is heated and melted, ２１１ At is evaporated and collected in a cold trap, and then dissolved in water. ２１１ Prepare At stock solution. If necessary, ２１１ For the purpose of stabilizing At, an alkaline aqueous solution such as sodium hydroxide or a buffer solution may be added. ２１０ In the case of At, bismuth is irradiated with helium particles accelerated to 29 MeV or more in a cyclotron, ２０９ Bi(α, 3n) ２１０ By the nuclear reaction of At ２１０ After producing At, the same operation as above is carried out to obtain ２１０ Prepare an aqueous solution of At. １２３ In the case of I, Na １２３ It is available as an aqueous solution of radioactive nuclides. １２４ In the case of I, tellurium is irradiated with proton particles accelerated by a cyclotron, １２４ Te(p,n) １２４ By the nuclear reaction of I １２４ After producing I, the target material １２４ Te is dissolved, １２４ Prepare a sodium hydroxide solution containing the radionuclide １２５ In the case of I, Na １２５ It is available as an aqueous solution of radioactive nuclides. １３１ In the case of I, Na １３１ It is available as an aqueous solution of radioactive nuclides. ７６ In the case of Br, tellurium is irradiated with proton particles accelerated by a cyclotron, ７６ Se(p,n) ７６ By the nuclear reaction of Br ７６ After producing Br, ７６ Se is dissolved, ７６ Prepare a sodium hydroxide solution of Br. ７７ In the case of Br, tellurium is irradiated with proton particles accelerated by a cyclotron, ７７ Se(p,n) ７７ By the nuclear reaction of Br ７７ After producing Br, ７７Se is dissolved, ７７ Prepare a solution of Br in sodium hydroxide. ２１１ At has a half-life of 7.2 hours. ２１０ At has a half-life of 8.3 hours. １２３ I has a half-life of 13.2 hours, ７６ Since Br has a short half-life of 16 hours, the radionuclide must be used in the reaction immediately after preparation. １２４ I has a half-life of 4.2 days, １２５ I has a half-life of 59.4 days, １３１ I has a half-life of 8.04 days, ７７ Although Br has a relatively long half-life of 57 hours, it is also preferable to use these radionuclides in the reaction promptly after preparation.

[0152] The boronic acid compound (II-1) is usually used in large excess relative to the radionuclide. From the viewpoints of reaction efficiency and economic efficiency, the boronic acid compound (II-1) is used at a concentration of preferably 0.00001 mol / L to 0.5 mol / L, more preferably 0.0001 mol / L to 0.2 mol / L relative to 1 Bq to 1,000 GBq of the radionuclide.

[0153] The reaction is carried out by mixing the boronic acid compound (II-1), the reagent, and the radionuclide, and the order of mixing is not particularly limited. A preferred method is to add an aqueous solution of the radionuclide and then an aqueous solution of the reagent to an aqueous solution of the boronic acid compound (II-1), or a method is to add an aqueous solution of the reagent and then an aqueous solution of the radionuclide to an aqueous solution of the boronic acid compound (II-1), and a more preferred method is to add an aqueous solution of the radionuclide and then an aqueous solution of the reagent to an aqueous solution of the boronic acid compound (II-1).

[0154] The reaction is carried out in water, i.e., in a system that does not contain an organic solvent. The reaction is carried out at 0 to 95°C, preferably 10 to 80°C. The reaction time is 1 minute to 3 hours, preferably 1 minute to 1 hour. The completion of the reaction is confirmed by the disappearance of free radioactive nuclides by thin layer chromatography (TLC) analysis.

[0155] After the reaction is complete, the reaction solution does not contain any organic solvents or toxic reagents, and therefore the radiolabeled compound (I-1) can be immediately formulated into an injection or the like without isolation. The reaction between the boronic acid compound (II-1) and a radionuclide is an electrophilic substitution reaction and / or a nucleophilic substitution reaction. Since the site of introduction of the radionuclide in the boronic acid compound (II-1) is the benzene ring, ２１１ At or ２１０ In the case of At, it can be successfully introduced into the benzene ring.

[0156] Furthermore, if necessary, the radiolabeled compound (I-1) may be purified to remove by-products. This purification is preferably carried out using a solid-phase extraction column. As the solid-phase extraction column, any column commonly used in the art can be used.

[0157] Furthermore, after the above purification, ascorbic acid or an ascorbate may be added to a final concentration of 0.01% to 10%, preferably 0.1% to 5%, which prevents decomposition of the radiolabeled compound (I-1) and allows it to be stored for a long period of time.

[0158] The production method of the present invention can provide radiolabeled compound (I-1) with a high radiochemical yield (RCY) of 60% or more, particularly 80% or more, and especially 90% or more, and can also provide radiolabeled compound (I-1) with a high radiochemical purity (RCP) of 80% or more, particularly 90% or more, and especially 95% or more.

[0159] Moreover, the radiolabeled compound (I-2) can be produced by the method shown in Scheme 2 below.

[0160]

[0161] [Each symbol in the formula has the same meaning as defined above.]

[0162] Y ２ is a boryl group (-B(OH) ２ ) or an ester group thereof. ２ is preferably a boryl group (—B(OH) ２) or a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group (a pinacol ester group).

[0163] Step 2 comprises treating boronic acid compound (II-2) in water in the presence of a reagent selected from alkali metal iodide, alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br to obtain a radiolabeled compound (I-2).

[0164] The boronic acid compound (II-2) is a novel compound, and preferred specific examples thereof include the following:

[0165]

[0166] Boronic acid compound (II-2) can be produced by the method described below. Since the reaction in this step is carried out in water, boronic acid compound (II-2) may be in the free form or in the form of a salt, as long as it is soluble in water. Alternatively, it may be used by dissolving it in a weakly basic aqueous solution such as an aqueous sodium bicarbonate solution.

[0167] Examples of alkali metal iodides include potassium iodide and sodium iodide, with potassium iodide being preferred. Examples of alkali metal bromides include sodium bromide and potassium bromide.

[0168] Suitable combinations of radionuclides and the above reagents include: (1) radionuclides ２１１ At or ２１０ At and the reagent is selected from potassium iodide, sodium bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide; (2) a combination in which the radionuclide is １２３ I, １２４ I, １２５ I or１３１ I and the reagent is selected from N-bromosuccinimide and N-chlorosuccinimide; (3) a combination in which the radionuclide is ７６ Br or ７７ Br and the reagent is N-chlorosuccinimide. The reagents may be used alone or in combination of two or more. The reagents are usually used in the form of an aqueous solution. In a preferred embodiment, the radionuclide is ２１１ At or １３１ I and the reagent is selected from potassium iodide and N-bromosuccinimide. ２１１ At and the reagent is potassium iodide, and １３１ I and the reagent is N-bromosuccinimide.

[0169] The reagent may be used in an amount sufficient to oxidize or reduce the radionuclide, and is usually used in large excess relative to the radionuclide. From the viewpoints of reaction efficiency and economic efficiency, the reagent is used at a concentration of preferably 0.0001 to 0.2 mol / L, more preferably 0.001 to 0.1 mol / L.

[0170] The radionuclide is usually used in the reaction in the form of an aqueous solution. If necessary, an alkaline aqueous solution such as sodium hydroxide or a buffer solution may be added to the aqueous solution for the purpose of stabilizing the radionuclide. ２１１ In the case of At, bismuth is irradiated with helium particles accelerated to 28 MeV in a cyclotron, ２０９ Bi(α, 2n) ２１１ By the nuclear reaction of At ２１１ After producing At, the target material ２０９ Bi is heated and melted, ２１１ At is evaporated and collected in a cold trap, and then dissolved in water. ２１１ Prepare At stock solution. If necessary, ２１１ For the purpose of stabilizing At, an alkaline aqueous solution such as sodium hydroxide or a buffer solution may be added. ２１０In the case of At, bismuth is irradiated with helium particles accelerated to 29 MeV or more in a cyclotron, ２０９ Bi(α, 3n) ２１０ By the nuclear reaction of At ２１０ After producing At, the same operation as above is carried out to obtain ２１０ Prepare an aqueous solution of At. １２３ In the case of I, Na １２３ It is available as an aqueous solution of radioactive nuclides. １２４ In the case of I, tellurium is irradiated with proton particles accelerated by a cyclotron, １２４ Te(p,n) １２４ By the nuclear reaction of I １２４ After producing I, the target material １２４ Te is dissolved, １２４ Prepare a sodium hydroxide solution containing the radionuclide １２５ In the case of I, Na １２５ It is available as an aqueous solution of radioactive nuclides. １３１ In the case of I, Na １３１ It is available as an aqueous solution of radioactive nuclides. ７６ In the case of Br, tellurium is irradiated with proton particles accelerated by a cyclotron, ７６ Se(p,n) ７６ By the nuclear reaction of Br ７６ After producing Br, ７６ Se is dissolved, ７６ Prepare a sodium hydroxide solution of Br. ７７ In the case of Br, tellurium is irradiated with proton particles accelerated by a cyclotron, ７７ Se(p,n) ７７ By the nuclear reaction of Br ７７ After producing Br, ７７ Se is dissolved, ７７ Prepare a solution of Br in sodium hydroxide. ２１１ At has a half-life of 7.2 hours. ２１０ At has a half-life of 8.3 hours. １２３ I has a half-life of 13.2 hours, ７６ Since Br has a short half-life of 16 hours, the radionuclide must be used in the reaction immediately after preparation. １２４I has a half-life of 4.2 days, １２５ I has a half-life of 59.4 days, １３１ I has a half-life of 8.04 days, ７７ Although Br has a relatively long half-life of 57 hours, it is also preferable to use these radionuclides in the reaction promptly after preparation.

[0171] The boronic acid compound (II-2) is usually used in large excess relative to the radionuclide. From the viewpoints of reaction efficiency and economic efficiency, the boronic acid compound (II-2) is used at a concentration of preferably 0.00001 mol / L to 0.5 mol / L, more preferably 0.0001 mol / L to 0.2 mol / L relative to 1 Bq to 1,000 GBq of the radionuclide.

[0172] The reaction is carried out by mixing the boronic acid compound (II-2), the reagent, and the radionuclide, and the order of mixing is not particularly limited. Preferably, an aqueous solution of the radionuclide and then an aqueous solution of the reagent are added to an aqueous solution of the boronic acid compound (II-2), or an aqueous solution of the reagent and then an aqueous solution of the radionuclide are added to an aqueous solution of the boronic acid compound (II-2), and more preferably, an aqueous solution of the radionuclide and then an aqueous solution of the reagent are added to an aqueous solution of the boronic acid compound (II-2).

[0173] The reaction is carried out in water, i.e., in a system that does not contain an organic solvent. The reaction is carried out at 0 to 95°C, preferably 10 to 80°C. The reaction time is 1 minute to 3 hours, preferably 1 minute to 1 hour. The completion of the reaction is confirmed by the disappearance of free radioactive nuclides by thin layer chromatography (TLC) analysis.

[0174] After the reaction is complete, the reaction solution does not contain any organic solvents or toxic reagents, and therefore the radiolabeled compound (I-2) can be immediately formulated into an injection or other preparation without isolation. The reaction between the boronic acid compound (II-2) and a radionuclide is an electrophilic substitution reaction and / or a nucleophilic substitution reaction. Since the site of introduction of the radionuclide in the boronic acid compound (II-2) is the benzene ring, ２１１ At or ２１０ In the case of At, it can be successfully introduced into the benzene ring.

[0175] If necessary, the radiolabeled compound (I-2) may be purified to remove by-products. This purification is preferably carried out using a solid-phase extraction column. As the solid-phase extraction column, any column commonly used in the art can be used.

[0176] Furthermore, after the above purification, ascorbic acid or an ascorbate may be added to a final concentration of 0.01% to 10%, preferably 0.1% to 5%, which prevents decomposition of the radiolabeled compound (I-2) and allows it to be stored for a long period of time.

[0177] The production method of the present invention can provide radiolabeled compound (I-2) with a high radiochemical yield (RCY) of 60% or more, particularly 80% or more, and especially 90% or more, and also with a high radiochemical purity (RCP) of 80% or more, particularly 90% or more, and especially 95% or more.

[0178] The boronic acid compounds (II-1) and (II-2) can be produced by the methods shown in the following schemes 3 to 9.

[0179] In the boronic acid compound (II-1), L １ *-L ｃ１ -L ｂ１ -L ａ１ -** (each symbol in the formula has the same meaning as above) (i.e., L １ *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** and L ｄ１ The boronic acid compound (IIa-1) in which the boronic acid compound (IIa-1) is a bond can be prepared according to the method shown in Scheme 3 below.

[0180]

[0181] (In the formula, P ａ１ represents a protecting group (amino protecting group, hydroxy protecting group, mercapto protecting group), and Hal ａ１ represents a bromine atom or a chlorine atom, and the other symbols are as defined above.) L ｃ１ NRｇ１ (The symbols in the formula are as defined above.) or when it is a divalent cyclic amino group, P ａ１ is an amino-protecting group, preferably a tert-butoxycarbonyl group (Boc group). ｃ１ is an oxygen atom, P ａ１ is a hydroxy protecting group. ｃ１ is a sulfur atom, P ａ１ is a mercapto protecting group. ａ１ is preferably a bromine atom.

[0182] Step 3-1 is a step in which compound (1) is reacted with compound (2) to obtain compound (3). This reaction is carried out in a solvent in the presence of a base. Compound (1) and compound (2) may be commercially available products or may be prepared by a known synthetic method. The amount of compound (2) used is usually 2 to 10 moles, preferably 2 to 5 moles, per mole of compound (1). Examples of the base include inorganic bases such as potassium carbonate and cesium carbonate. The amount of the base used is usually 2 to 20 moles, preferably 4 to 15 moles, per mole of compound (1). Examples of the solvent include N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, and acetonitrile. The reaction is carried out usually at a temperature in the range of 25 to 100°C, preferably 50 to 80°C, for usually 6 to 24 hours, preferably 10 to 24 hours. After completion of the reaction, compound (3) can be obtained by performing a conventional post-treatment and, if necessary, purifying the resulting compound by column chromatography or the like.

[0183] Step 3-2 is a step of converting compound (3) to compound (4). This reaction is carried out by treating with a base in a solvent. For example, the reaction is carried out in a mixed solvent of tetrahydrofuran / 1,4-dioxane / water in the presence of an inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide. Alternatively, the reaction is carried out in methanol in the presence of sodium methoxide. In this case, a methyl ester is obtained, which is then converted to compound (4) by hydrolysis using lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like in a mixed solvent of tetrahydrofuran / 1,4-dioxane / water. The reaction is usually carried out at a temperature in the range of −20 to 40° C., preferably 0 to 30° C., for usually 10 minutes to 24 hours, preferably 0.5 to 2 hours. After completion of the reaction, compound (4) can be obtained by carrying out a typical post-treatment and, if necessary, purifying the ester by column chromatography or the like.

[0184] Step 3-3 is a step of reacting compound (4) with compound (5) to obtain compound (6). ｃ１ NR ｇ１(The symbols in the formula are as defined above.) or a divalent cyclic amino group, the reaction may be carried out in a solvent in the presence of a condensing agent, or in a solvent in the presence of a base after converting compound (4) into a reactive derivative (e.g., acid chloride). Compound (5) may be a commercially available product, or may be produced by a synthetic method known per se. The amount of compound (5) used is usually 1 to 10 moles, preferably 2 to 5 moles, per mole of compound (4). Examples of condensing agents include 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and diisopropylcarbodiimide (DIC). Among these, HATU, EDC, and PyBOP are preferred. The amount of the condensing agent used is usually 1 to 10 moles, preferably 1 to 3 moles, per mole of compound (4). When the reaction is carried out in the presence of a condensing agent, it may be carried out in the presence of a base. Examples of the base include organic bases such as N,N-diisopropylethylamine (DIEA) and triethylamine (TEA). The amount of the base used is usually 1 to 10 moles, preferably 2 to 5 moles, per mole of compound (4). When EDC is used as the condensing agent, the reaction is preferably carried out in the presence of an additive such as 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). The amount of the additive used is usually 1 to 10 moles, preferably 1 to 3 moles, per mole of compound (4). Examples of the solvent include N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), and acetonitrile. The reaction is usually carried out at a temperature in the range of 0 to 60°C, preferably 0 to 30°C, for usually 6 to 72 hours, preferably 6 to 48 hours.After the reaction is completed, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (6).

[0185] Step 3-4 is a step of deprotecting compound (6) to obtain compound (7). The deprotection method is appropriately selected depending on the type of protecting group. For example, P ａ１ When is a tert-butoxycarbonyl group (Boc group), compound (7) can be obtained by treating compound (6) under acidic conditions. Examples of treatments under acidic conditions include acid treatment using trifluoroacetic acid (TFA) or the like. The acid treatment may be carried out in a solvent such as dichloromethane or dichloroethane. After completion of the reaction, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (7).

[0186] Step 3-5 is a step of reacting compound (7) with compound (8) to obtain compound (IIa-1). ｃ１ NR ｇ１ (The symbols in the formula are as defined above.) or a divalent cyclic amino group, this step is carried out in the same manner as in step 3-3. Compound (8) may be a commercially available product or may be produced by a synthetic method known per se. After completion of the reaction, the reaction product is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (IIa-1).

[0187] In the boronic acid compound (II-1), L １ *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein each symbol has the same meaning as above), and L ｄ１ *-(NH-A ａ１ -CO) ｒ１ The boronic acid compound (IIb-1) represented by the formula -*** (each symbol in the formula has the same meaning as defined above) can be produced according to the method shown in the following scheme 4.

[0188]

[0189] (In the formula, P ｂ１represents an amino-protecting group, and the other symbols are as defined above. ｂ１ is preferably a tert-butoxycarbonyl group (Boc group).

[0190] Step 4-1 is a step of reacting compound (7) with compound (9) to obtain compound (10). Compound (9) may be a commercially available product or may be produced by a known synthetic method. For example, L ｃ１ NR ｇ１ (The symbols in the formula are as defined above.) or a divalent cyclic amino group, this step is carried out in the same manner as in step 3-3. After completion of the reaction, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (10).

[0191] Step 4-2 is a step in which compound (10) is deprotected to obtain compound (11). This step is carried out in the same manner as in step 3-4. After completion of the reaction, the compound (11) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0192] Step 4-3 is a step of reacting compound (11) with compound (8) to obtain compound (IIb-1). This step is carried out in the same manner as in step 3-3. After completion of the reaction, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (IIb-1).

[0193] In the boronic acid compound (II-1), L １ *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ -** (wherein each symbol has the same meaning as above), and L ｄ１ *-NH-B ａ１ -O-B ｂ１ The boronic acid compound (IIc-1) represented by —CO-*** (each symbol in the formula has the same meaning as defined above) can be produced according to the method shown in the following scheme 5.

[0194]

[0195] (In the formula, P ｃ１ represents an amino-protecting group, and the other symbols are as defined above. ｃ１ is preferably a tert-butoxycarbonyl group (Boc group).

[0196] Step 5-1 is a step in which compound (7) is reacted with compound (12) to obtain compound (13). This step is carried out by converting compound (12) into an activated ester such as a pentafluorophenyl ester, followed by reaction with compound (7). Compound (12) may be produced by a synthetic method known per se, or it can also be produced by the method described below. In compound (12), the hydroxy group present in the divalent residue derived from an amino sugar or a derivative thereof is preferably protected. Examples of the protecting group include a tert-butyldimethylsilyl group (TBS group) and a benzylidene group (formation of a benzylidene acetal). Conversion to the pentafluorophenyl ester is carried out by reacting compound (12) with pentafluorophenyl trifluoroacetate in a solvent in the presence of a base. The amount of pentafluorophenyl trifluoroacetate used is usually 1 to 10 moles, preferably 2 to 8 moles, per mole of compound (12). Examples of the base include organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine (DIEA). The amount of the base used is usually 1 to 10 moles, preferably 2 to 8 moles, per mole of compound (12). Examples of the solvent include N,N-dimethylformamide (DMF), dichloromethane, and tetrahydrofuran (THF). The reaction is usually carried out at a temperature in the range of −20 to 60°C, preferably 0 to 30°C, for usually 0.5 to 24 hours, preferably 0.5 to 6 hours. After completion of the reaction, the resulting pentafluorophenyl ester is subjected to a reaction with compound (7) after operations such as concentration. The reaction is carried out in a solvent in the presence of a base. The amount of the pentafluorophenyl ester used is usually 1 to 10 moles, preferably 1 to 3 moles, per mole of compound (7). Examples of the base include organic bases such as N,N-diisopropylethylamine (DIEA), triethylamine (TEA), and pyridine. The amount of the base used is usually 1 to 30 mol, preferably 2 to 25 mol, per 1 mol of compound (7). Examples of the solvent include N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and dichloromethane.The reaction is carried out usually at a temperature in the range of −20 to 60° C., preferably in the range of 0 to 30° C., for usually 1 to 48 hours, preferably 1 to 24 hours. After completion of the reaction, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (13).

[0197] Step 5-2 is a step in which compound (13) is deprotected to obtain compound (14). This step is carried out in the same manner as in step 3-4. After completion of the reaction, the compound (14) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0198] Step 5-3 is a step of reacting compound (14) with compound (8) to obtain compound (IIc-1). This step is carried out in the same manner as in step 3-3. After completion of the reaction, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (IIc-1).

[0199] Compound (12) used as a starting material in Scheme 5 can be produced according to the following method.

[0200]

[0201] (The symbols in the formula are as defined above.) Step 5-4 is a step in which compound (15) is reacted with trichloroacetonitrile to obtain compound (16). The reaction is carried out in a solvent in the presence of a base. Compound (15) may be a commercially available product, or may be produced by a synthetic method known per se. In compound (15), the hydroxy group present in the divalent residue derived from an amino sugar or a derivative thereof is preferably protected, and examples of the protecting group include a tert-butyldimethylsilyl group (TBS group) and a benzylidene group (formation of a benzylidene acetal). In addition, in compound (15), P ｃ１is preferably a trichloroethoxycarbonyl group (Troc group). The amount of trichloroacetonitrile used is usually 1 to 20 mol, preferably 5 to 15 mol, per mol of compound (15). Examples of the base include inorganic and organic bases such as cesium carbonate, potassium carbonate, and diazabicycloundecene. The amount of the base used is usually 1 to 10 mol, preferably 1 to 5 mol, per mol of compound (15). Examples of the solvent include dichloromethane, dichloroethane, toluene, and acetonitrile. The reaction is usually carried out at a temperature in the range of −20 to 50° C., preferably 0 to 30° C., for usually 10 minutes to 12 hours, preferably 0.5 to 4 hours. After completion of the reaction, compound (16) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the resulting compound by column chromatography or the like.

[0202] Step 5-5 is a step in which compound (16) is reacted with compound (17) to obtain compound (18). The reaction is carried out in a solvent in the presence of a Lewis acid or a protonic acid. Compound (17) may be commercially available or may be prepared by a known synthetic method. The amount of compound (17) used is usually 0.1 to 10 mol, preferably 0.5 to 5 mol, per mol of compound (16). Examples of Lewis acids or protonic acids include trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, trifluoromethanesulfonic anhydride, boron trifluoride diethyl ether complex, and trifluoromethanesulfonic acid. The amount of Lewis acid or protonic acid used is usually 0.001 to 10 mol, preferably 0.001 to 1 mol, per mol of compound (16). Examples of the solvent include dichloromethane, dichloroethane, tetrahydrofuran (THF), diethyl ether, cyclopentyl methyl ether (CPME), acetonitrile, and toluene. The reaction may be carried out under an argon atmosphere. The reaction may also be carried out in the presence of molecular sieves. The reaction is usually carried out at a temperature in the range of −78 to 50° C., preferably −20 to 30° C., for usually 10 minutes to 24 hours, preferably 0.5 to 4 hours. After completion of the reaction, the reaction mixture is subjected to a typical post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (18).

[0203] Compound (18) is a compound having a protecting group (P ｃ１ For example, the trichloroethoxycarbonyl group (Troc group) may be converted to a tert-butoxycarbonyl group (Boc group) in order to use the compound (12) obtained in the next step as a starting material in Scheme 5.

[0204] Step 5-6 is a step in which compound (18) is subjected to hydrolysis to obtain compound (12). The hydrolysis is carried out according to a conventional method, for example, using lithium hydroxide in a mixed solvent of tetrahydrofuran / 1,4-dioxane / water. After completion of the reaction, the reaction mixture is subjected to a conventional post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (12).

[0205] In the boronic acid compound (II-1), L １ *-(NH-A ｂ１ -CO) ｓ１ The boronic acid compound (IId-1) represented by the formula -** (each symbol in the formula has the same meaning as defined above) can be produced according to the method shown in the following scheme 6.

[0206]

[0207] (In the formula, P ｄ１ represents an amino-protecting group, and the other symbols are as defined above. ｄ１ is preferably a tert-butoxycarbonyl group (Boc group).

[0208] Step 6-1 is a step in which compound (1) is reacted with compound (19) to obtain compound (20). Compound (19) may be a commercially available product or may be produced by a synthetic method known per se. This step is carried out in the same manner as step 3-3. After completion of the reaction, the compound is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (20).

[0209] Step 6-2 is a step of converting compound (20) into compound (21). This step is carried out in the same manner as in step 3-2. After completion of the reaction, the compound (21) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0210] Step 6-3 is a step of reacting compound (21) with compound (5) to obtain compound (22). This step is carried out in the same manner as in step 3-3. After completion of the reaction, the compound (22) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0211] Step 6-4 is a step in which compound (22) is deprotected to obtain compound (23). This step is carried out in the same manner as in step 3-4. After completion of the reaction, the compound (23) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0212] Step 6-5 is a step of reacting compound (23) with compound (8) to obtain compound (IId-1). This step is carried out in the same manner as in step 3-3. After completion of the reaction, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (IId-1).

[0213] In the boronic acid compound (II-2), L ２ *-L ｃ２ -L ｂ２ -L ａ２ The boronic acid compound (IIa-2) represented by the formula -** (each symbol in the formula has the same meaning as defined above) can be produced according to the method shown in the following scheme 7.

[0214]

[0215] (In the formula, P ａ２ represents an amino-protecting group, Resin represents a resin used in peptide synthesis, and other symbols have the same meanings as above. ａ２ is preferably a 9-fluorenylmethyloxycarbonyl group (Fmoc group). Resins used in peptide synthesis represented by "Resin" include resins used in solid-phase synthesis, such as Cl-Trt(2-Cl)-Resin.

[0216] Step 7-1 is a step of deprotecting compound (24) to obtain compound (25). This reaction is carried out according to a conventional method, for example, ａ２When is a 9-fluorenylmethyloxycarbonyl group (Fmoc group), the reaction is carried out using a secondary amine such as piperidine, pyrrolidine, or morpholine in a solvent such as N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone (NMP). Compound (24) can be produced by a synthetic method known per se. After completion of the reaction, the reaction mixture is subjected to a conventional post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (25).

[0217] Step 7-2 is a step in which compound (25) is reacted with compound (26) to obtain compound (27). Compound (26) can be synthesized by a method similar to that in Scheme 3. Alternatively, it can also be produced by the method described below. This step is carried out in the same manner as in Step 3-3. After completion of the reaction, the compound is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (27).

[0218] Step 7-3 is a step in which compound (27) is subjected to resin removal to obtain compound (28). The resin removal method is appropriately selected depending on the type of resin. For example, when the resin is Cl-Trt(2-Cl)-Resin, the resin is removed by treatment with a hexafluoro-2-propanol (HFIP) / chloroform (TCM) solution. After the reaction is completed, the removed resin is removed, followed by a typical post-treatment, and if necessary, purification by column chromatography or the like to obtain compound (28).

[0219] Step 7-4 is a step of reacting compound (28) with compound (29) to obtain compound (IIa-2). This reaction is carried out by converting compound (28) to an activated ester such as pentafluorophenyl ester, and then reacting it with compound (29). The conversion to the pentafluorophenyl ester is carried out by reacting compound (28) with pentafluorophenyl trifluoroacetate in a solvent in the presence of a condensing agent. The amount of pentafluorophenyl trifluoroacetate used is usually 1 to 10 mol, preferably 1 to 5 mol, per mol of compound (28). Examples of condensing agents include dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide (DIC). The amount of condensing agent used is usually 1 to 10 mol, preferably 1 to 5 mol, per mol of compound (28). Examples of solvents include tetrahydrofuran (THF), N,N-dimethylformamide (DMF), chloroform, acetonitrile, and dichloromethane. The reaction is generally carried out at a temperature in the range of −20 to 50° C., preferably 0 to 30° C., for generally 1 to 48 hours, preferably 1 to 24 hours. After completion of the reaction, operations such as concentration are performed, and then the resulting pentafluorophenyl ester is reacted with compound (29). Compound (29) may be a commercially available product, or may be produced by a synthetic method known per se. This reaction is carried out in the same manner as in the reaction of pentafluorophenyl ester with compound (7) described in step 5-1, except that the base, solvent, etc. are not limited to those used in step 5-1. After completion of the reaction, the reaction is carried out in the usual manner, and if necessary, purified by column chromatography or the like to obtain compound (IIa-2).

[0220] In the compound (26) used as a starting material in Scheme 7, L ｃ２ The compound (26') in which is a divalent cyclic diamino group (piperazine-1,4-diyl, etc.) can also be produced according to the following method.

[0221]

[0222] (In the formula, P ｂ２ represents an amino-protecting group, and the other symbols are as defined above.ｂ２ is preferably a tert-butoxycarbonyl group (Boc group).

[0223] Step 7-5 is a step in which compound (1) is reacted with compound (30) to obtain compound (31). Compound (30) may be a commercially available product or may be produced by a synthetic method known per se. This step is carried out in the same manner as step 3-1. After completion of the reaction, the compound (31) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0224] Step 7-6 is a step in which compound (31) is reacted with compound (32) to obtain compound (33). This reaction is carried out in a solvent in the presence of sodium iodide. Compound (32) may be commercially available or may be prepared by a known synthetic method. The amount of compound (32) used is usually 1 to 10 moles, preferably 1 to 5 moles, per mole of compound (31). The amount of sodium iodide used is usually 1 to 10 moles, preferably 1 to 5 moles, per mole of compound (31). Examples of solvents include N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and acetonitrile. The reaction is carried out usually at a temperature in the range of 0 to 80°C, preferably 20 to 60°C, for usually 1 to 48 hours, preferably 4 to 30 hours. After completion of the reaction, compound (33) can be obtained by carrying out a typical post-treatment and, if necessary, purifying the reaction by column chromatography or the like.

[0225] In step 7-7, compound (33) is deprotected and acylated (R ｅ２ The deprotection is carried out in the same manner as in step 3-4. The acylation is carried out by subjecting the deprotected product to the introduction of R ｅ２The reaction is carried out by reacting the compound (33) with an acylating agent corresponding to the above. Examples of the acylating agent include acetic anhydride and acetyl chloride. The amount of the acylating agent used is usually 1 to 10 moles, preferably 1 to 5 moles, per mole of compound (33). Examples of the base include pyridine, triethylamine (TEA), and N,N-diisopropylethylamine (DIEA). The amount of the base used is usually 1 to 20 moles, preferably 1 to 10 moles, per mole of compound (33). Alternatively, the base is added as a solvent. Examples of the solvent include N,N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), pyridine, and triethylamine. The reaction is usually carried out at a temperature in the range of −20 to 60°C, preferably 0 to 30°C, for usually 0.5 to 24 hours, preferably 0.5 to 12 hours. After completion of the reaction, compound (26′) can be obtained by carrying out a typical post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0226] In the boronic acid compound (II-2), L ２ *-L ｃ２ -L ｂ２ -L ａ２ The boronic acid compound (IIa-2) represented by the formula -** (each symbol in the formula has the same meaning as defined above) can also be produced according to the method shown in the following scheme 8.

[0227]

[0228] (The symbols in the formula are as defined above.)

[0229] Step 8-1 is a step in which compound (34) is reacted with compound (29) to obtain compound (35). Compound (34) may be a commercially available product or may be produced by a synthetic method known per se. This step is carried out in the same manner as in step 7-4. After completion of the reaction, the compound (35) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0230] Step 8-2 is a step in which compound (35) is deprotected to obtain compound (36). This step is carried out in the same manner as in step 3-3. After completion of the reaction, the compound (36) can be obtained by carrying out a usual post-treatment and, if necessary, purifying the compound by column chromatography or the like.

[0231] Step 8-3 is a step of reacting compound (36) with compound (26) to obtain compound (IIa-2). This step is carried out in the same manner as in step 3-3. After completion of the reaction, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (IIa-2).

[0232] In the boronic acid compound (II-2), L ２ *-(NH-A ａ２ -CO) ｒ２ The boronic acid compound (IIb-2) represented by the formula -** (each symbol in the formula has the same meaning as defined above) can be produced according to the method shown in the following scheme 9.

[0233]

[0234] (The symbols in the formula are as defined above.)

[0235] Step 9-1 is a step in which compound (36) is reacted with compound (37) to obtain compound (IIa-2). Compound (37) can be synthesized by a method similar to that in Scheme 6. Alternatively, it can also be produced by the method described below. This step is carried out in the same manner as in Step 3-3. After completion of the reaction, the compound is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (IIb-2).

[0236] Compound (37) used as a starting material in Scheme 9 can be prepared according to the following method.

[0237]

[0238] (In the formula, P ｃ２ represents an amino-protecting group, and the other symbols are as defined above. ｃ２is preferably a tert-butoxycarbonyl group (Boc group). In step 9-2, compound (38) is deprotected and acylated (R ｅ２ (introduction of ) to obtain compound (37). Compound (38) can be produced by a method similar to that in Scheme 6. This step is carried out by a method similar to that in step 7-7. After completion of the reaction, the reaction mixture is subjected to a usual post-treatment, and if necessary, purified by column chromatography or the like to obtain compound (37).

[0239] The reaction conditions such as solvents and reaction temperatures in each step of the production method of the present invention described above will be described in detail as representative examples in the synthesis examples and working examples described below, but are not necessarily limited thereto, and can be appropriately selected by a person skilled in the art based on general knowledge in organic synthesis.

[0240] The radiolabeled compounds (I-1) and (I-2) thus produced (hereinafter collectively referred to as compound (I)) specifically bind to fibroblast activation protein α (FAPα) and accumulate in cancer-associated fibroblasts (CAFs). They destroy the stroma by emitting α-particles, damaging the cells. In addition, since cancer cells themselves may express FAPα, simultaneous damage to both the stroma and cancer cells can exert a more potent therapeutic effect. As such, radiolabeled compound (I) targets cells expressing FAPα, and thus radiolabeled compound (I) containing a therapeutically effective radionuclide can be useful in the treatment of tumors or cancers containing cancer stroma expressing FAPα (also referred to herein as "tumors or cancers expressing FAPα"). Therapeutically effective radionuclides include: ２１１ At, ２１０ At, １３１ I, １２５ I and ７７Br. In addition, since the radiolabeled compound (I) targets cells expressing FAPα, the radiolabeled compound (I) containing an imaging-effective radionuclide can image tumors or cancers expressing FAPα, and thus may be useful for diagnosis. Examples of imaging-effective radionuclides include: ２１１ At, １３１ I, １２４ I, １２３ I, ７７ Br and ７６ Br is an example. ２１１ At, １３１ I, １２４ I, １２３ I, ７７ Br and ７６ Compound (I) radiolabeled with a radionuclide selected from Br is utilized for imaging by positron emission tomography (PET) or single photon emission tomography (SPECT).

[0241] Tumors or cancers that express FAPα include solid cancers such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colon cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, and liver cancer. Therefore, radiolabeled Compound (I) is effective for the treatment and imaging of these solid cancers, particularly pancreatic cancer. The dosage of radiolabeled Compound (I) used for therapeutic or diagnostic purposes is generally determined by the radionuclide used, the patient's body weight, age, sex, treatment site / diagnosis site, etc. For example, when a human is the subject, ２１１ The effective dose of Compound (I) radiolabeled with At is approximately 100 MBq to 900 MBq per dose.

[0242] The radiolabeled Compound (I) is usually mixed with a pharmaceutically acceptable carrier and used as a pharmaceutical composition. A pharmaceutically acceptable carrier refers to a biocompatible solution that has sufficient consideration given to sterility, pH, isotonicity, stability, etc., and can include any and all solvents, diluents (including sterile saline, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection, and other aqueous buffer solutions), dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, etc. The pharmaceutically acceptable carrier can also include stabilizers, preservatives, antioxidants, or other additives known to those skilled in the art.

[0243] The dosage form of the pharmaceutical composition is not particularly limited, and it can be prepared as a pharmaceutical composition for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, or solutions, or as a pharmaceutical composition for parenteral administration in the form of injections for intravenous, intramuscular, or subcutaneous administration, infusions, transdermal or transmucosal agents, nasal drops, inhalants, or suppositories. These preparations can be prepared according to conventional methods. Liquid preparations for oral or injectable administration are preferred. Such liquid preparations are prepared by dissolving radiolabeled Compound (I) in water, but may also be dissolved in physiological saline or glucose solution as needed, and buffers and preservatives may also be added. As mentioned above, the liquid preparations may further contain a reducing agent such as ascorbic acid. In particular, to produce an injection, the active ingredient may be dissolved in distilled water for injection, if necessary, together with a pH adjuster such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc., and an isotonic agent such as sodium chloride or glucose, and then sterile filtered and filled into an ampule, or mannitol, dextrin, cyclodextrin, gelatin, etc. may be added, followed by vacuum freeze-drying to produce an injection that is dissolved before use. Alternatively, the active ingredient may be emulsified in water with lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. to produce an emulsion for injection.

[0244] The half-life of the radionuclide contained in the radiolabeled compound (I) is ２１１ At 7.2 hours, ２１０At 8.3 hours, １３１ I is 8.04 days, １２５ I is 59.4 days, １２４ I is 4.2 days, １２３ I is 13.2 hours, ７７ Br 57 hours, ７６ Since the Br is short, 16 hours, it is desirable to prepare the pharmaceutical composition immediately before administration to a subject so that it contains the amount of radiolabeled Compound (I) required for administration.

[0245] The present invention will be further explained in detail by the following synthesis examples, examples and test examples, but these are merely examples and do not limit the present invention, and can be modified within the scope of the present invention.

[0246] Synthesis Example 1: Synthesis of Compound 7 (Borono(C1)-Pip-6Qui-FAPI(F))

[0247]

[0248] (1) Synthesis of Compound 4: Under an argon atmosphere, N,N-dimethylformamide (1.1 mL), potassium carbonate (76.3 mg, 552 μmol), and 4-(3-bromopropyl)-1-piperazinecarboxylic acid 1,1-dimethylethyl ester (51.8 mg, 168.6 μmol) were added to commercially available compound 1 (14.9 mg, 55.2 μmol) and stirred at 60 °C for 12 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate and washed with saturated brine. The resulting organic layer was dried over sodium sulfate and filtered to remove the sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crudely purified by silica gel column chromatography to obtain compound 2 as a yellow solid. Methanol (1.0 mL) and sodium methoxide (8.4 μL, 5.7 M, 47.7 μmol) dissolved in methanol were added to the resulting compound 2 under an argon atmosphere and stirred at room temperature for 40 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, which was then extracted with ethyl acetate and washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate and filtered to remove the sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was roughly purified by silica gel column chromatography to obtain compound 3 as a yellow solid. Under an argon atmosphere, a tetrahydrofuran / 1,4-dioxane / water (4 / 2 / 1) mixed solvent (1.4 mL) and lithium hydroxide monohydrate (17.8 mg, 424 μmol) were added to the resulting compound 3 and stirred at room temperature for 40 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, which was extracted with chloroform and washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate and filtered to remove the sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 4 as a yellow solid (15.7 mg, yield: 68% for all three steps). 1H-NMR (DMSO-D6) δ: 8.88 (d, J = 4.3 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 4.3 Hz, 1H), 7.50 (dd, J = 9.2, 2.5 Hz, 1H), 4.22 (t, J = 5.7 Hz, 2H), 4.03 (s, 2H), 3.52 (s, 2H), 3.15-3.04 (br m, 6H), 2.25-2.20 (m, 2H), 1.43 (s, 9H).

[0249] (2) Synthesis of Compound 7: Under an argon atmosphere, N,N-dimethylformamide (7.5 mL), HATU (34.0 mg, 90.0 μmol), and N,N-diisopropylethylamine (54.6 μL, 313 μmol) were added to compound 4 (31.0 mg, 74.6 μmol) and stirred at room temperature for 5 minutes. (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile (42.3 mg, 224 μmol) was then added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and then dried in vacuo to obtain compound 5 as a yellow solid. Dichloromethane (1.9 mL) was added to the resulting compound 5 and cooled to 0 °C. After cooling, trifluoroacetic acid (475 μL) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and then dried in vacuo to obtain compound 6 as a white solid. To the resulting compound 6, N,N-dimethylformamide (1.0 mL), HATU (14.0 mg, 36.8 μmol), and N,N-diisopropylethylamine (20.0 μL, 115 μmol) were added under an argon atmosphere and stirred at room temperature for 5 minutes. Then, 4-(carboxymethyl)phenylboronic acid (8.0 mg, 44.5 μmol) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain 0.6 mg of compound 7 as a white solid (yield: 1% for all four steps).

[0250] Synthesis Example 2: Synthesis of Compound 13 (Borono(C1)-PEG2-6Qui-FAPI(F))

[0251]

[0252] (1) Synthesis of Compound 8: Under an argon atmosphere, N,N-dimethylformamide (18.3 mL), potassium carbonate (1.26 g, 9.15 mmol), and tert-butyl N-[2-(2-bromoethoxy)ethyl]carbamate (574 μL, 2.74 mmol) were added to commercially available compound 1 (247 mg, 915 μmol) and stirred at 60 °C for 21 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate and washed with saturated brine. The resulting organic layer was dried over sodium sulfate and then filtered to remove the sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 8 (416.6 mg, 90% yield) as a yellow oil. 1 H-NMR (CDCl3) δ: 8.76 (d, J = 4.0 Hz, 1H), 8.11 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 5.47 (br d, J = 10.0 Hz, 2H), 4.48 (s, 2H), 4.18 (s, 2H), 3.81 (s, 2H), 3.77 (s, 2H), 3.57-3.56 (m, 4H), 3.31 (s, 4H), 1.38 (s, 9H), 1.35 (s, 9H).

[0253] (2) Synthesis of Compound 9. Compound 8 (301 mg, 534 μmol) was added with methanol (10.7 mL) and sodium methoxide (19.7 mg, 534 μmol) and stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, which was extracted with ethyl acetate and washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate and then filtered to remove the sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 187.3 mg (93% yield) of compound 9 as a yellow oil. 1H-NMR (CDCl3) δ: 8.75 (t, J = 2.1 Hz, 1H), 8.16 (t, J = 2.5 Hz, 1H), 7.97 (dt, J = 9.2, 2.1 Hz, 1H), 7.81-7.79 (m, 1H), 7.36 (dt, J = 9.2, 2.4 Hz, 1H), 5.18 (br s, 1H), 4.20 (t, J = 4.4 Hz, 2H), 3.92 (s, 3H), 3.81 (dd, J = 5.2, 3.7 Hz, 2H), 3.56 (t, J = 4.4 Hz, 2H), 3.29 (d, J = 4.3 Hz, 2H), 1.35 (s, 9H).

[0254] (3) Synthesis of Compound 10. Compound 9 (32.5 mg, 83.2 μmol) was added to a tetrahydrofuran / 1,4-dioxane / water (4 / 2 / 1) mixed solvent (2.8 mL) and lithium hydroxide monohydrate (34.9 mg, 832 μmol) and stirred at room temperature for 40 minutes. A 0.5 N aqueous solution of hydrogen chloride was added to the reaction solution, which was then extracted with dichloromethane and washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate and then filtered to remove the sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to quantitatively obtain compound 10. 1 H-NMR (DMSO-D6) δ: 8.86 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 4.4 Hz, 1H), 7.52 (dd, J = 9.2, 2.9 Hz, 1H), 6.77 (br s, 1H), 4.23 (t, J = 4.4 Hz, 2H), 3.81 (t, J = 4.4 Hz, 2H), 3.49 (t, J = 6.0 Hz, 2H), 3.11 (q, J = 5.8 Hz, 2H), 1.36 (s, 9H).

[0255] (4) Synthesis of Compound 12: Under an argon atmosphere, N,N-dimethylformamide (8.3 mL), HATU (47.5 mg, 125 μmol), and N,N-diisopropylethylamine (29.0 μL, 116 μmol) were added to compound 10 (31.3 mg, 83.2 μmol) and stirred at room temperature for 5 minutes. (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile (47.3 mg, 250 μmol) was then added and stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure and then dried in vacuo to obtain compound 11 as a yellow solid. Dichloromethane (2.1 mL) was added to the resulting compound 11 and cooled to 0 °C. After cooling, trifluoroacetic acid (525 μL) was added and stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain 32.4 mg of compound 12 as a white solid (yield: 87% for both steps). 1 H-NMR (DMSO-D6) δ: 8.83 (d, J = 4.4 Hz, 1H), 8.01 (d, J = 9.3 Hz, 1H), 7.88 (d, J = 2.7 Hz, 1H), 7.84 (br s, 2H), 7.53 (d, J = 4.4 Hz, 1H), 7.49 (dd, J = 9.2, 2.8 Hz, 1H), 5.14 (dd, J = 9.3, 2.8 Hz, 1H), 4.32 (t, J = 4.4 Hz, 3H), 4.24 (d, J = 6.0 Hz, 2H), 4.20-4.10 (br m, 1H), 3.89 (t, J = 4.2 Hz, 2H), 3.69 (dd, J = 9.8, 4.4 Hz, 2H), 3.04-2.99 (m, 2H), 2.97-2.83 (m, 2H).

[0256] (5) Synthesis of Compound 13: Under an argon atmosphere, compound 12 (2.8 mg, 6.3 μmol) was added with N,N-dimethylformamide (1.0 mL), HATU (14.0 mg, 36.8 μmol), and N,N-diisopropylethylamine (20.0 μL, 115 μmol) and stirred at room temperature for 5 minutes. 4-(carboxymethyl)phenylboronic acid (8.0 mg, 44.5 μmol) was then added and stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure, and the residue was purified by high-performance liquid chromatography to quantitatively obtain compound 13 as a white solid. 1 H-NMR (DMSO-D6) δ: 8.81 (d, J = 4.5 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.92 (s, 2H), 7.89 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 4.2 Hz, 1H), 7.47 (dd, J = 9.3, 2.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 5.14 (d, J = 6.8 Hz, 1H), 4.33-4.31 (m, 1H), 4.28 (d, J = 3.8 Hz, 2H), 4.24 (t, J = 6.5 Hz, 2H), 4.17-4.11 (m, 1H), 3.82 (t, J = 4.3 Hz, 2H), 3.50 (t, J = 5.8 Hz, 2H), 3.40 (s, 2H), 3.24 (t, J = 5.6 Hz, 2H), 2.91-2.88 (m, 1H), 2.82-2.80 (br m, 1H).

[0257] Synthesis Example 3: Synthesis of Compound 19 (Borono(C1)-Gly(1)-8Qui-FAPI(F))

[0258]

[0259] (1) Synthesis of Compound 16: Under an argon atmosphere, N-(tert-butoxycarbonyl)glycine (55.9 mg, 319 μmol) was added with N,N-dimethylformamide (5.3 mL), HATU (121 mg, 319 μmol), and N,N-diisopropylethylamine (66.6 μL, 382 μmol) and stirred at room temperature for 5 minutes. Then, commercially available compound 14 (10.0 mg, 53.1 μmol) was added and stirred at room temperature for 23 hours. The reaction solution was concentrated under reduced pressure and then dried in vacuo to obtain compound 15 as a yellow solid. Tetrahydrofuran / 1,4-dioxane / water (4 / 2 / 1) mixed solvent (5.3 mL) and potassium carbonate (73.4 mg, 531 μmol) were added to the resulting compound 15 and stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, which was extracted with dichloromethane and washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain 11.8 mg of compound 16 as a white solid (64% yield for both steps). 1 H-NMR (CD3OD) δ: 8.96 (d, J = 4.3 Hz, 1H), 8.73 (d, J = 7.7 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 4.3 Hz, 1H), 7.65 (t, J = 8.3 Hz, 1H), 3.97 (s, 2H), 1.53 (s, 9H).

[0260] (2) Synthesis of Compound 18: Under an argon atmosphere, N,N-dimethylformamide (1.0 mL), HATU (11.0 mg, 28.8 μmol), and N,N-diisopropylethylamine (21.4 μL, 123 μmol) were added to compound 16 (4.0 mg, 9.6 μmol) and stirred at room temperature for 5 minutes. (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile (19.5 mg, 103 μmol) was then added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and then dried in vacuo to obtain compound 17 as a yellow solid. Dichloromethane (3.4 mL) was added to the resulting compound 17 and cooled to 0 °C. After cooling, trifluoroacetic acid (855 μL) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain 7.5 mg of compound 18 as a yellow solid (yield: 53% for both steps). 1 H-NMR (CD3OD) δ: 8.97 (d, J = 4.3 Hz, 1H), 8.70 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 4.3 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 5.15 (dd, J = 9.4, 2.8 Hz, 1H), 4.31 (dd, J = 39.5, 16.9 Hz, 2H), 4.28-4.21 (m, 1H), 4.19-4.10 (m, 1H), 4.13 (s, 2H), 3.07-3.02 (br m, 1H), 2.93-2.91 (br m, 1H), 2.81-2.79 (br m, 1H).

[0261] (3) Synthesis of Compound 19: Under an argon atmosphere, 4-(carboxymethyl)phenylboronic acid (5.2 mg, 28.8 μmol) was added to N,N-dimethylformamide (1.0 mL), HATU (11.0 mg, 28.8 μmol), and N,N-diisopropylethylamine (6.0 μL, 34.6 μmol) and stirred at room temperature for 5 minutes. Compound 18 (2.8 mg, 6.3 μmol) was then added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain 3.9 mg (70% yield) of compound 19 as a white solid. 1 H-NMR (DMSO-D6) δ: 10.39 (s, 1H), 9.14 (t, J = 5.9 Hz, 1H), 8.98 (d, J = 4.2 Hz, 1H), 8.72 (t, J = 5.8 Hz, 1H), 8.67 (d, J = 7.4 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.96 (s, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.66 (dd, J = 11.4, 6.1 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 5.17 (dd, J = 9.4, 2.2Hz, 1H), 4.34-4.30 (m, 1H), 4.24 (ddd, J = 31.7, 17.0, 5.8 Hz, 2H), 4.18-4.12 (m, 1H), 4.06 (d, J = 5.9 Hz, 2H), 3.63 (s, 2H), 2.94-2.89 (br m, 1H), 2.82 (t, J = 13.9 Hz, 1H). LRMS (ESI-Q-TOF) calcd for C 27 H 25 BF2N6O6

[0262] Synthesis Example 4 Synthesis of Compound 29 (Borono(C0)-GlcN-Pip-6Qui-FAPI(F))

[0263]

[0264] (1) Synthesis of Compound 22: Under an argon atmosphere, known compound 20 (4.6 g, 8.26 mmol) was added with dichloromethane (160 mL), trichloroacetonitrile (6.6 mL, 82.6 mmol), and cesium carbonate (5.38 g, 16.5 mmol) and stirred at room temperature for 40 minutes. The mixture was then filtered through Celite using dichloromethane. The solvent was removed under reduced pressure, and the residue was crudely purified by silica gel column chromatography to obtain 4.6 g of compound 21 as a white amorphous solid. Under an argon atmosphere, dichloromethane (138 mL), molecular sieves 4A, and methyl 4-hydroxybutyrate (2.3 mL, 20.7 mmol) were added to the resulting compound 21 and cooled to 0 °C. After cooling, trimethylsilyl trifluoromethanesulfonate (125 μL, 804 μmol) was added and stirred at 0 °C for 20 minutes. After warming to room temperature, triethylamine was added to the reaction solution, which was then extracted with ethyl acetate and washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate and filtered to remove the sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.2 g of compound 22 as a white amorphous solid (59% yield for both steps). 1H-NMR (CDCl3) δ: 7.44 (d, J = 7.0 Hz, 2H), 7.31 (d, J = 7.2 Hz, 3H), 5.75 (d, J = 8.3 Hz, 1H), 5.37 (s, 1H), 4.70 (dd, J = 19.3, 11.9 Hz, 2H), 4.52 (d, J = 8.2 Hz, 1H), 4.26 (dd, J = 10.0, 4.2 Hz, 1H), 3.90 (t, J = 8.9 Hz, 1H), 3.87-3.82 (m, 1H), 3.70 (t, J = 10.1 Hz, 1H), 3.63 (s, 3H), 3.49 (dt, J = 11.8, 4.9 Hz, 1H), 3.43 (t, J = 9.0 Hz, 2H), 3.38-3.33 (m, 1H), 2.39-2.36 (m, 2H), 1.88-1.82 (m, 2H), 0.81 (s, 9H), 0.03 (s, 3H), -0.03 (s, 3H).

[0265] (2) Synthesis of Compound 23. Water was added to zinc (1.5 g) and the mixture was stirred with ultrasound for 30 minutes. Then, a 2% aqueous solution of copper sulfate was added and washed with water. The zinc-copper couple was removed by filtration. Under an argon atmosphere, tetrahydrofuran (38 mL), acetic acid (AcOH, 38 mL), cesium carbonate (5.38 g, 16.5 mmol), and the zinc-copper couple were added to compound 22 (500 mg, 761 μmol) and stirred at room temperature for 2 hours. The mixture was then filtered through Celite using ethyl acetate. The filtrate was azeotroped with toluene, and the residue was added with saturated aqueous sodium bicarbonate. It was extracted with ethyl acetate and washed with water and saturated brine. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to quantitatively obtain compound 23 as a colorless amorphous solid. 1H-NMR (CDCl3) δ: 7.48-7.46 (m, 2H), 7.37-7.35 (m, 3H), 5.49 (s, 1H), 4.34 (dd, J = 7.9, 1.4 Hz, 1H), 4.29 (dd, J = 10.5, 4.7 Hz, 1H), 3.94 (dt, J = 11.3, 4.9 Hz, 1H), 3.77 (t, J = 10.1 Hz, 1H), 3.70-3.68 (m, 1H), 3.68 (s, 3H), 3.58 (dt, J = 11.7, 4.8 Hz, 1H), 3.47 (q, J = 7.8 Hz, 1H), 3.44-3.40 (m, 1H), 2.84 (t, J = 8.6 Hz, 1H), 2.44 (td, J = 7.4, 2.1 Hz, 2H), 1.99-1.93 (m, 2H), 0.85 (s, 9H), 0.09 (s, 3H), -0.02 (s, 3H).

[0266] (3) Synthesis of Compound 25. Compound 23 (328.5 mg, 682 mmol) was mixed with dichloromethane (68.2 mL), 2,6-lutidine (219.7 μL, 2.05 mmol), and di-tert-butyl dicarbonate (2.0 mL, 6.82 mmol) and stirred at room temperature for two nights. A saturated aqueous solution of ammonium chloride was added to the reaction solution, which was extracted with dichloromethane and washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate and filtered to remove the sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was roughly purified by silica gel column chromatography to obtain compound 24 as a white amorphous solid. A tetrahydrofuran / methanol / water (3 / 2 / 2) mixed solvent (70 mL) and lithium hydroxide monohydrate (171.6 mg, 4.10 mmol) were added to the resulting compound 24 and stirred at room temperature overnight. The reaction solution was added with 0.5 N aqueous hydrogen chloride solution until the pH reached approximately 3, extracted with dichloromethane, and washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate and then filtered to remove the sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 303.6 mg of compound 25 as a white amorphous solid (78% yield for both steps). 1H-NMR (CD3OD) δ: 7.46 (dd, J = 6.6, 2.9 Hz, 2H), 7.33 (dd, J = 6.4, 2.6 Hz, 3H), 6.73 (d, J = 9.7 Hz, 1H), 5.51 (s, 1H), 4.43 (d, J = 8.4 Hz, 1H), 4.24 (dd, J = 10.3, 4.9 Hz, 1H), 3.87 (dt, J = 11.0, 5.0 Hz, 1H), 3.78 (t, J = 9.2 Hz, 1H), 3.76 (t, J = 10.1 Hz, 1H), 3.53 (dt, J = 11.6, 4.9 Hz, 1H), 3.45 (q, J = 9.7 Hz, 2H), 3.40-3.39 (br m, 1H), 2.46-2.35 (m, 2H), 1.86-1.81 (m, 2H), 1.45 (s, 9H), 0.84 (s, 9H), 0.06 (s, 3H), -0.03 (s, 3H).

[0267] (4) Synthesis of Compound 29. Compound 25 (5.8 mg, 10.3 μmol) was mixed with N,N-dimethylformamide (1.0 mL), pyridine (4.2 μL, 51.5 μmol), and pentafluorophenyl trifluoroacetate (8.8 μL, 51.5 μmol) and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and then dried in vacuo to give compound 26 as a white solid. N,N-dimethylformamide (1.0 mL), compound 6 (10.3 μmol), and N,N-diisopropylethylamine (34.0 μL, 146 μmol) were added to the resulting compound 26 and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was crudely purified by preparative thin-layer chromatography to give compound 27 as a white solid. Dichloromethane (1.0 mL) and water (100 μL) were added to the resulting compound 27 and cooled to 0 °C. After cooling, trifluoroacetic acid (100 μL) was added and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was roughly purified by high-performance liquid chromatography to obtain compound 28 as a white solid. Under an argon atmosphere, 4-carboxyphenylboronic acid (16.3 mg, 98.1 μmol) was added to N,N-dimethylformamide (1.0 mL), HATU (37.3 mg, 98.1 μmol), and N,N-diisopropylethylamine (51.2 μL, 294 μmol) and stirred at room temperature for 5 minutes. Compound 28 was then added and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain compound 29 as a white solid (3.1 mg, 35% yield over 4 steps). HRMS (ESI-LTQ-orbitrap) calculation for C 41 H 51 BF2N7O 12 H (M + H) + 882.3651, found: 882.3657

[0268] Synthesis Example 5 Synthesis of Compound 32 (Borono(C0)-GlcN-Pip-6Qui-FAPI(H))

[0269]

[0270] Compound 25 (2.9 mg, 5.09 μmol), synthesized by a method similar to that of Synthesis Example 4, was added with N,N-dimethylformamide (510 μL), pyridine (2.1 μL, 25.5 μmol), and pentafluorophenyl trifluoroacetate (4.3 μL, 25.5 μmol) and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and then dried in vacuo to obtain compound 26 as a white solid. N,N-dimethylformamide (1.0 mL), compound 37 (5.09 μmol, synthesized in Reference Example 1 below), and N,N-diisopropylethylamine (4.3 μL, 24.4 μmol) were added to the resulting compound 26 and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was roughly purified by preparative thin-layer chromatography to obtain compound 30 as a white solid. To the resulting compound 30, dichloromethane (500 μL) and water (50 μL) were added and cooled to 0 °C. After cooling, trifluoroacetic acid (50 μL) was added and stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was roughly purified by high-performance liquid chromatography to obtain compound 31 as a white solid. Under an argon atmosphere, 4-carboxyphenylboronic acid (10.1 mg, 61.1 μmol) was added with N,N-dimethylformamide (1.0 mL), HATU (23.2 mg, 61.6 μmol), and N,N-diisopropylethylamine (31.9 μL, 183 μmol) and stirred at room temperature for 5 minutes. Then, the resulting compound 31 was added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain compound 32 as a white solid (2.9 mg, 67% yield for 4 steps). HRMS (ESI-orbitrap) calculation for C 41 H 53 BN7O 12 (M + H) + 846.3840, found: 846.3844

[0271] Synthesis Example 6 Synthesis of Compound 35 (Borono(C1)-GlcN-PEG-6Qui-FAPI(F))

[0272]

[0273] Compound 25 (10.0 mg, 17.8 μmol), synthesized by a method similar to that described in Synthesis Example 4, was added with N,N-dimethylformamide (1.8 mL), pyridine (7.1 μL, 88.1 μmol), and pentafluorophenyl trifluoroacetate (15.0 μL, 88.1 μmol) and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and then dried in vacuo to obtain compound 26 as a white solid. N,N-dimethylformamide (800 μL), compound 12 (7.9 mg, 17.6 μmol), and N,N-diisopropylethylamine (84.5 μL, 14.7 μmol) were added to the resulting compound 26 and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and then dried in vacuo to obtain compound 33 as a white solid. Dichloromethane (1.6 mL) and water (160 μL) were added to the resulting compound 33 and cooled to 0 °C. After cooling, trifluoroacetic acid (160 μL) was added and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain compound 34 as a white solid. Under an argon atmosphere, 4-(carboxymethyl)phenylboronic acid (2.0 mg, 11.2 μmol) was added to N,N-dimethylformamide (500 μL), HATU (4.3 mg, 11.2 μmol), and N,N-diisopropylethylamine (2.4 μL, 13.5 μmol) and stirred at room temperature for 5 minutes. Compound 34 was then added and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain compound 35 as a white solid (3.6 mg, 24% yield, 4 steps). LRMS (ESI-Q-TOF) calculation for C 39 H 48 BN6O 13 (M + H) + 857.33, found: 857.33

[0274] Reference Example 1 Synthesis of Compound 37

[0275]

[0276] (1) Synthesis of Compound 36: Under an argon atmosphere, N,N-dimethylformamide (1.0 mL), HATU (4.2 mg, 11.1 μmol), and N,N-diisopropylethylamine (1.9 μL, 11.1 μmol) were added to compound 4 (3.8 mg, 9.23 μmol), synthesized by a method similar to that described in Synthesis Example 1, and the mixture was stirred at room temperature for 5 minutes. (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile (10.2 mg, 27.8 μmol) was then added and the mixture was stirred at room temperature for two nights. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.8 mg (55% yield) of compound 36 as a white solid.

[0277] (2) Synthesis of Compound 37 Dichloromethane (130 μL) was added to Compound 36 and cooled to 0°C. After cooling, trifluoroacetic acid (33 μL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then dried in vacuo to obtain Compound 37 as a white solid (TFA salt). The entire amount of the obtained Compound 37 was used in the condensation with Compound 26 in Synthesis Example 5.

[0278] Synthesis Example 7 Synthesis of Compound 39 (Borono(C1)-PEG2-6Qui-FAPI(H))

[0279]

[0280] (1) Synthesis of Compound 10. Compound 1 (1.1 g, 4.1 mmol) was dissolved in DMF (20 mL), potassium carbonate (5.7 g, 41 mmol) was added, and 1,1-dimethylethyl N-[2-(2-bromoethoxy)ethyl]carbamate (3.9 g, 15 mmol) was added dropwise. The reaction mixture was stirred at 60 °C for 2 hours, and then insoluble materials were removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in 20 mL of 60% aqueous acetonitrile. 5 M aqueous sodium hydroxide solution (4.1 mL, 21 mmol) was added and stirred for 1.5 hours. The mixture was then neutralized to pH 4 with AcOH under ice cooling, and the solvent was evaporated under reduced pressure. The precipitate was suspended in DMF (40 mL), water was added, and the precipitate was collected by filtration. It was washed with water and diethyl ether, and dried to give compound 10 (1.17 g, 75%).

[0281] (2) Synthesis of Compound 38: (S)-1-(2-(tert-butoxycarbonylamino)acetyl)-pyrrolidine-2-carbonitrile (440 mg, 1.7 mmol) was dissolved in cold TFA and stirred for 1 hour. The solvent was then evaporated under reduced pressure. The resulting (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile TFA salt (1.7 mmol) was dissolved in NMP (10 mL) and neutralized with TEA. Compound 10 (0.62 g, 1.7 mmol), HOAt (0.24 g, 1.7 mmol), and water (1 mL) were added, and EDC (0.6 mL, 3.3 mmol) was added dropwise under ice cooling. After stirring at room temperature for 3.5 hours, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was evaporated under reduced pressure. The resulting residue was dissolved in 30% aqueous AcOH and purified by reversed-phase HPLC to give Compound 38 (0.43 g, 51%).

[0282] (3) Synthesis of Compound 39. Compound 38 (0.23 g, 0.45 mmol) was dissolved in cold TFA and stirred for 30 minutes. The solvent was then evaporated under reduced pressure. The resulting residue was dissolved in DMF (2 mL) and neutralized with TEA. 4-(Carboxymethyl)phenylboronic acid pinacol ester (89 mg, 0.50 mmol), HOAt (67 mg, 0.50 mmol), and water (0.2 mL) were added, followed by dropwise addition of EDC (0.11 mL, 0.63 mmol) under ice cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 0.1% TFA in water and purified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to give compound 39 (0.24 g, 93%) as a lyophilized powder. HPLC purity: 99.8%, ESI-MS MH+: 574.3 (theoretical value: 574.2).

[0283] Synthesis Example 8 Synthesis of Compound 42 (Borono(C1)-PEG4-6Qui-FAPI(H))

[0284]

[0285] (1) Synthesis of Compound 40. Compound 1 (0.32 g, 1.2 mmol) was dissolved in DMF (5 mL), potassium carbonate (1.6 g, 12 mmol) was added, and 1-(tert-butoxycarbonylamino)-3,6,9-trioxaundecanyl-11-bromide (1.3 g, 3.6 mmol) was added dropwise. The reaction mixture was stirred at 65°C for 4 hours, and then insoluble materials were removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in 60% acetonitrile (10 mL). 5 M aqueous sodium hydroxide solution (1.2 mL, 6.0 mmol) was added and stirred at room temperature for 30 minutes. The mixture was then neutralized with AcOH under ice cooling, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in a small amount of chloroform, and hexane was added to solidify it. The solid was collected by filtration and dried to obtain Compound 40 (0.55 g, 99%).

[0286] (2) Synthesis of Compound 41: (S)-1-(2-(tert-butoxycarbonylamino)acetyl)-pyrrolidine-2-carbonitrile (301 mg, 1.2 mmol) was dissolved in cold TFA and stirred for 40 minutes. The solvent was evaporated under reduced pressure. The resulting (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile TFA salt was dissolved in DMF (9 mL) and neutralized with TEA. Compound 40 (0.55 g, 1.2 mmol), HOAt (0.18 g, 1.3 mmol), and water (1 mL) were added, and EDC (0.24 mL, 1.3 mmol) was added dropwise under ice cooling. After stirring at room temperature for 1.5 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in 10% aqueous AcOH and purified by reverse-phase HPLC. The fractions containing the target product were lyophilized to give compound 41 as a lyophilized powder (0.56 g, 78%).

[0287] (3) Synthesis of Compound 42. Compound 41 (0.21 g, 0.35 mmol) was dissolved in TFA (5 mL) and stirred for 1 hour. The solvent was removed under reduced pressure. The resulting residue was dissolved in DMF (2 mL) and neutralized with TEA. 4-(carboxymethyl)phenylboronic acid pinacol ester (0.10 g, 0.39 mmol), HOAt (52 mg, 0.39 mmol), and water (0.2 mL) were added. EDC (69 μL, 0.39 mmol) was added dropwise under cooling to -78 °C and stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the mixture was dissolved in 2 mL of 20% aqueous AcOH and stirred at room temperature for 17 hours. The reaction mixture was diluted with water and purified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to give compound 42 (0.14 g, 61%) as a lyophilized powder. HPLC purity: 99.7%, ESI-MS MH+: 662.3 (theoretical value: 662.3)

[0288] Synthesis Example 9 Synthesis of Compound 44 (Borono(C1)-Pip-6Qui-FAPI(H))

[0289]

[0290] (1) Synthesis of Compound 37: (S)-1-(2-(tert-butoxycarbonylamino)acetyl)-pyrrolidine-2-carbonitrile (0.16 g, 0.66 mmol) was dissolved in 95% TFA / acetonitrile (8.4 mL) and stirred for 40 minutes. The solvent was evaporated under reduced pressure, and the residue was dissolved in water and lyophilized. The resulting (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile TFA salt was dissolved in 90% DMF (6 mL) and neutralized with TEA. Compound 4 (0.35 g, 0.66 mmol) and HOAt (99 mg, 0.73 mmol) were added, and EDC (0.13 mL, 0.73 mmol) was added dropwise under ice cooling. After stirring at room temperature for 1.5 hours, the solvent was evaporated under reduced pressure to give Compound 43. This was dissolved in 98% TFA / acetonitrile (20 mL) and stirred for 30 minutes. The solvent was removed under reduced pressure, and diisopropyl ether was added to solidify the product, which was then filtered. The filtered product was dissolved in water and purified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to give compound 37 (TFA salt, 0.21 g, 48%).

[0291] (2) Synthesis of Compound 44. Compound 37 (0.20 g, 0.30 mmol) was dissolved in 90% DMF (6 mL) and neutralized with TEA. 4-(carboxymethyl)phenylboronic acid pinacol ester (75 mg, 0.29 mmol) and HOAt (39 mg, 0.29 mmol) were added. EDC (58 μL, 0.32 mmol) was added dropwise under ice cooling and stirred at room temperature for 1 hour. The reaction mixture was concentrated and then diluted with 0.1% TFA / 30% AcOH (7 mL) and stirred at 40°C for 1.5 hours. The reaction mixture was purified by reverse-phase HPLC, and the fraction containing the desired product was lyophilized to give compound 44 (0.15 g, 69%) as a lyophilized powder. HPLC purity: 99.3%, ESI-MS MH+: 613.3 (theoretical value: 613.3).

[0292] Synthesis Example 10: Synthesis of Compound 49 (Borono(C1)-Pip-8Qui-FAPI(H))

[0293]

[0294] (1) Synthesis of Compound 46. Compound 45 (0.50 g, 2.6 mmol) was dissolved in DMF (20 mL), potassium carbonate (4.4 g, 32 mmol) was added, and 1-bromo-3-chloropropane (0.91 mL, 9.3 mmol) was added dropwise. The reaction mixture was stirred at 65 °C for 1.5 hours, and then insoluble materials were removed by filtration. The filtrate was evaporated under reduced pressure. The resulting residue was dissolved in 50% MeCN (50 mL). 5 M aqueous sodium hydroxide solution (2.6 mL, 13 mmol) was added under ice cooling. The mixture was stirred for 2 hours, neutralized with AcOH, and the solvent was evaporated under reduced pressure. The resulting precipitate was collected by filtration, washed with water, and dried to give compound 46 (0.49 g, 70%).

[0295] (2) Synthesis of Compound 47. Compound 46 (0.49 g, 1.8 mmol), 1-(tert-butoxycarbonyl)piperazine (1.8 g, 9.8 mmol), and sodium iodide (1.5 g, 10 mmol) were dissolved in DMF (25 mL) and stirred at 55 °C for 20 hours. The solvent was then evaporated under reduced pressure. The resulting residue was diluted with 50% aqueous AcOH and purified by reversed-phase HPLC. The fraction containing the desired product was lyophilized to give Compound 47 (0.79 g, 81%).

[0296] (3) Synthesis of Compound 48: (S)-1-(2-(tert-butoxycarbonylamino)acetyl)-pyrrolidine-2-carbonitrile (0.17 g, 0.66 mmol) was dissolved in 95% TFA / acetonitrile (8 mL) and stirred for 40 minutes. The solvent was then evaporated under reduced pressure. The residue was dissolved in water and lyophilized. The resulting (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile TFA salt was dissolved in 90% DMF (10 mL) and neutralized with DIEA. Compound 47 (0.35 g, 0.66 mmol) and HOAt (99 mg, 0.73 mmol) were added, and EDC (0.13 mL, 0.73 mmol) was added dropwise under ice cooling. The mixture was stirred at room temperature for 1.5 hours, and the solvent was then evaporated under reduced pressure. The resulting residue was dissolved in 97% TFA / acetonitrile (15 mL) and stirred for 1 hour. The solvent was then evaporated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration. The filtrate was dissolved in water and purified by reverse-phase HPLC. The fraction containing the target product was lyophilized to give compound 48 (0.26 g, 59%).

[0297] (4) Synthesis of Compound 49. Compound 48 (0.26 g, 0.39 mmol) was dissolved in 90% DMF (10 mL) and neutralized with TEA. 4-(carboxymethyl)phenylboronic acid pinacol ester (92 mg, 0.35 mmol) and HOAt (53 mg, 0.39 mmol) were added to the solution. EDC (79 μL, 0.43 mmol) was added dropwise under ice cooling and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the mixture was diluted with 2.5% TFA / 15% AcOH (60 mL) and stirred at 40 °C for 1.5 hours. The reaction mixture was purified by reverse-phase HPLC, and the fraction containing the desired product was lyophilized to give compound 49 (0.14 g, 50%) as a lyophilized powder. HPLC purity: 99.9%, ESI-MS MH+: 613.3 (theoretical value: 613.3).

[0298] Synthesis Example 11 Synthesis of Compound 51 (Borono(C0)-Pip-6Qui-FAPI(H))

[0299]

[0300] (1) Synthesis of Compound 50. Compound 1 (4.3 g, 16 mmol) was dissolved in DMF (70 mL), potassium carbonate (27 g, 0.19 mol) was added, and 1-bromo-3-chloropropane (5.5 mL, 56 mmol) was added dropwise. The reaction mixture was stirred at 60 °C for 2 hours, after which the insoluble material was removed by filtration and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in 100 mL of 60% aqueous acetonitrile, and 5 M aqueous sodium hydroxide (16 mL, 80 mmol) was added. The mixture was stirred for 30 minutes, neutralized with AcOH under ice cooling, and the solvent was evaporated under reduced pressure. The precipitate was collected by filtration, washed with water, and dried to give compound 50 (3.1 g, 72%).

[0301] (2) Synthesis of Compound 4. Compound 50 (1.4 g, 5.1 mmol), 1-(tert-butoxycarbonyl)piperazine (5.0 g, 27 mmol), and sodium iodide (4.1 g, 27 mmol) were dissolved in DMF (50 mL) and stirred at 55 °C for 23 hours. The solvent was then evaporated under reduced pressure. The resulting residue was diluted with 30% aqueous AcOH and purified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to give compound 4 (2.1 g, 77%).

[0302] (3) Synthesis of Compound 37. Compound 4 (0.47 g, 0.89 mmol), HOAt (0.12 g, 0.89 mmol), and DIEA (0.31 mL, 1.8 mmol) were dissolved in DMF (7 mL), followed by the addition of HATU (0.32 g, 0.84 mmol) and stirring for 10 min. To the reaction mixture, (S)-1-(2-(tert-butoxycarbonylamino)acetyl)-pyrrolidine-2-carbonitrile (0.24 g, 0.95 mmol) was dissolved in TFA. After stirring for 30 min, the solvent was evaporated under reduced pressure to give (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile TFA salt. After stirring at room temperature for 1 h, the solvent was evaporated under reduced pressure, and the resulting crude product was dissolved in 30 mL of TFA. After stirring for 30 minutes, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to solidify the residue, which was then filtered. The filtered residue was dissolved in 0.1% TFA / 1% acetonitrile and purified by reverse-phase HPLC. The fractions containing the desired product were lyophilized to give compound 37 (TFA salt, 0.36 g, 60%).

[0303] (4) Synthesis of Compound 51. Compound 37 (0.31 g, 0.46 mmol), 4-carboxyphenylboronic acid (72 mg, 0.43 mmol), and PyAOP (0.24 g, 0.46 mmol) were dissolved in 3 mL of DMF, and then DIEA (0.28 mL, 1.6 mmol) was added. After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure. The resulting residue was diluted with 20% aqueous AcOH and purified by reversed-phase HPLC. The fraction containing the target product was lyophilized to give compound 51 (0.25 g, 76%). HPLC purity: 99.9%, ESI-MS MH+: 598.4 (theoretical value: 598.5).

[0304] Synthesis Example 12: Synthesis of Compound 53 (Qui-Gly-Pro-(B)Phe)

[0305]

[0306] (1) Synthesis of Compound 52 Solid-phase peptide synthesis (SPPS) was performed as follows. Cl-Trt(2-Cl)-Resin (1.2 g, 2.1 mmol) was mixed with 15 mL of a chloroform solution of Fmoc-Pro·HO (0.53 g, 1.5 mmol) and DIEA (0.71 mL, 4.2 mmol) and stirred at room temperature for 1.5 hours. The resin was washed with 20 mL of a TCM / MeOH / DIEA (17 / 2 / 1) solution and then with TCM. The peptide chain was extended by deprotection of Fmoc-Gly and 4-quinolinecarboxylic acid with 20% piperidine / NMP, followed by condensation with PyAOP-DIEA. 20% HFIP / TCM solution was added to the resulting protected peptide resin and stirred at room temperature for 1 hour. The resin was then filtered off. The solvent was evaporated under reduced pressure, and diethyl ether was added to solidify the residue. The precipitate was collected by filtration and dried to obtain Compound 52 (0.33 g, 47%).

[0307] (2) Synthesis of Compound 53. Compound 52 (0.16 g, 0.51 mmol) and pentafluorophenol (0.11 g, 0.61 mmol) were dissolved in THF, and DCC (87 μL, 0.53 mmol) was added dropwise under ice cooling. The mixture was then stirred at room temperature for 3 hours. After adding AcOH, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting residue was washed with hexane to obtain the activated ester (0.27 g). The activated ester (0.24 g) was dissolved in DMF (4 mL), and a suspension of 4-borono-L-phenylalanine (0.10 g, 0.48 mmol) and 40% aqueous tetrabutylammonium hydroxide (0.14 μL, 0.42 mmol) was added dropwise under ice cooling. After stirring at room temperature for 18 hours, water and TFA were added to the reaction mixture, which was then purified by reverse-phase HPLC. The fractions containing the target product were lyophilized to give compound 53 as a lyophilized powder (80 mg, 30%). HPLC purity: 99.5%, ESI-MS MH+: 519.2 (theoretical value: 519.2).

[0308] Synthesis Example 13: Synthesis of Compound 57 (Ac-Pip-6Qui-Gly-Pro-(B)Phe)

[0309]

[0310] (1) Synthesis of Compound 54. Compound 4 (0.5 g, 0.78 mmol), synthesized by a method similar to that in Synthesis Example 11, was dissolved in TFA (30 mL). After stirring for 1 hour, the solvent was evaporated under reduced pressure. 4.5 N hydrochloric acid / dioxane (0.55 mL, 2.5 mmol) was added to the residue, followed by the addition of diethyl ether to solidify, which was then filtered and dried. The resulting powder was dissolved in a mixture of DMF (15 mL), pyridine (15 mL), and water (3 mL). Acetic anhydride (0.18 mL, 1.9 mmol) was added and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure, followed by the addition of diethyl ether to solidify, which was then filtered. The resulting powder was dissolved in 0.5% TFA / 25% acetonitrile in water and lyophilized. The lyophilized product was dissolved in 0.1% TFA in water and purified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to give Compound 54 (0.45 g, 97%).

[0311] (2) Synthesis of Compound 56. Compound 55 (0.14 g, 0.5 mmol) and pentafluorophenol (97 mg, 0.53 mmol) were dissolved in THF (10 mL), and DIC (82 μL, 0.53 mmol) was added and stirred for 2 hours. The reaction mixture was neutralized with AcOH, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMF (10 mL), and 4-borono-L-phenylalanine (0.10 g, 0.5 mmol) and 40% aqueous tetrabutylammonium hydroxide (0.29 mL, 0.45 mmol) were added and stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in TFA and stirred for 1 hour. The reaction mixture was concentrated, solidified with diethyl ether, and collected by filtration. The resulting powder was dissolved in 0.1% TFA in water and purified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to give compound 56 (0.11 g, 46%).

[0312] (3) Synthesis of Compound 57. Compound 54 (72 mg, 0.12 mmol) was dissolved in DMF (3 mL), and PyAOP (76 mg, 0.15 mmol) and DIEA (78 μL, 0.46 mmol) were added and stirred for 10 min. Compound 56 (0.11 g, 0.23 mmol) dissolved in 2% aqueous DMF (3 mL) was added to the solution and stirred for 1 h. The solvent was evaporated under reduced pressure, and the residue was solidified with diethyl ether and collected by filtration. The resulting powder was dissolved in 1% TFA in water and purified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to give compound 57 (55 mg, 49%). HPLC purity: 99.3%, ESI-MS MH+: 703.3 (theoretical value: 703.3).

[0313] Synthesis Example 14 Synthesis of Compound 61 (Borono(C1)-Pip-amide-6Qui-FAPI(H))

[0314]

[0315] (1) Synthesis of Compound 58. Commercially available compound 1 (1.0 g, 5.3 mmol) and 3-bromopropionic acid (2.8 g, 19 mmol) were dissolved in DMF (10 mL). Under ice cooling, sodium hydride (60%, dispersed in liquid paraffin, 1.9 g, 48 mmol) was added. After stirring for 2 hours, 3-bromopropionic acid (2.8 g, 19 mmol) and sodium hydride (60%, dispersed in liquid paraffin, 1.9 g, 48 mmol) were added. After stirring for 2 hours, the reaction mixture was neutralized with AcOH, diluted with 50% aqueous AcOH (100 mL), and purified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to give compound 58 (0.37 g, 26%).

[0316] (2) Synthesis of Compound 59. 1-(tert-Butoxycarbonyl)piperazine (0.43 g, 2.3 mmol), compound 58 (0.60 g, 2.3 mmol), and HOBt (0.37 g, 2.8 mmol) were dissolved in DMF (5 mL), and DIC (0.43 mL, 0.28 mmol) was added dropwise under ice cooling. After stirring at room temperature for 2 hours, AcOH was added, and the solvent was evaporated under reduced pressure. The residue was dissolved in 50% aqueous AcOH and purified by reverse-phase HPLC. The fraction containing the target product was neutralized with saturated aqueous sodium bicarbonate, and the acetonitrile was concentrated. Ethyl acetate was added to the resulting aqueous solution, and 0.1 N hydrochloric acid was added. The organic layer was extracted, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound 59 (0.68 g, 69%).

[0317] (3) Synthesis of Compound 60 (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile TFA salt (0.79 mmol), obtained by a method similar to that used in the synthesis of Compound 38 in Synthesis Example 7, was dissolved in 90% DMF (8 mL) and neutralized with DIEA. Compound 59 (0.34 g, 0.79 mmol) and HOAt (0.12 g, 0.87 mmol) were added, and EDC (0.16 mL, 0.87 mmol) was added dropwise under ice cooling. After stirring at room temperature for 1.5 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in 50% AcOH (25 mL) and purified by reverse-phase HPLC. The fraction containing the target product was lyophilized to give Compound 60 (0.31 g, 70%).

[0318] (4) Synthesis of Compound 61. Compound 60 (0.15 g, 0.27 mmol) was dissolved in 4.5 mL of 95% TFA / acetonitrile and stirred for 60 minutes. The solvent was removed under reduced pressure, and the resulting residue was dissolved in 90% DMF (2.7 mL) and neutralized with DIEA. 4-(carboxymethyl)phenylboronic acid pinacol ester (70 mg, 0.27 mmol) and HOAt (40 mg, 0.29 mmol) were added, and EDC (54 μL, 0.29 mmol) was added dropwise under ice cooling. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 30% aqueous AcOH (5 mL) and stirred overnight. The reaction mixture was purified by reverse-phase HPLC, and the fraction containing the desired product was lyophilized. The resulting powder was dissolved in 10% aqueous acetonitrile and repurified by reverse-phase HPLC. The fraction containing the desired product was lyophilized to obtain Compound 61 (79 mg, 48%). HPLC purity: 99.4%, ESI-MS [M+H] + : 627.3 (theoretical value: 627.3)

[0319] Synthesis Example 15 Synthesis of Compound 62 (Borono(C2)-Pip-6Qui-FAPI(H))

[0320]

[0321] Compound 37 (TFA salt, 0.30 g, 0.45 mmol), synthesized from compound 4 in a similar manner to Reference Example 1, was dissolved in 10 mL of 90% DMF water and neutralized with TEA. 4-(2-carboxyethyl)phenylboronic acid (87 mg, 0.45 mmol) and HOAt (61 mg, 0.45 mmol) were added, and EDC (90 μL, 0.49 mmol) was added dropwise under ice cooling. The mixture was stirred at room temperature for 3.5 hours. The solvent from the reaction mixture was evaporated under reduced pressure, and the residue was dissolved in 30% aqueous AcOH (20 mL) and purified by reverse-phase HPLC. The fraction containing the target product was lyophilized. The resulting powder was dissolved in 0.1% aqueous TFA and re-purified by reverse-phase HPLC. The fraction containing the target product was lyophilized to obtain the target product (81 mg, 29%). HPLC purity: 99.4%, ESI-MS [M+H] + : 627.3 (theoretical value: 627.3)

[0322] The Borono-FAPI derivative synthesized in the synthesis example can be synthesized by the following basic procedure: 211 The procedure is outlined in Figure 1. A 2 mL polypropylene (PP) tube was charged with 0.1 or 1% Borono-FAPI derivative (1 μg, 10 μg, or 100 μg), 7% Meylon solution (10 μL), water (90 μL), and 211 Aqueous At solution (0.5-10 MBq, 1-10 μL) and 0.1 M potassium iodide (KI) solution (30 μL) were added and heated at 50°C or 80°C for 45 minutes. The reaction mixture was then passed through a solid-phase extraction cartridge (Oasis HLB, Waters) and retained. The HLB cartridge was washed with 1.0 mL of water (fraction E1). The target compounds were then eluted by passing 0.5 mL of 40% ethanol solution and 0.5 mL of 100% ethanol through the cartridge (fractions E2 and E3). 1-2 μL of the reaction mixture and fraction E2 (or E3) were analyzed by thin-layer chromatography (TLC) to determine the radiochemical yield (RCY, %) and radiochemical purity (RCP, %), respectively. The radiochemical yield was calculated using the following formula: Radiochemical yield (%) = (radioactivity of target compound in thin plate / total radioactivity in thin plate) x 100. The specific radioactivity for each Borono-FAPI derivative is as follows: 211 The At labeling method, the chemical structure of the product, and the quality analysis results (TLC) are shown.

[0323] Example 1 211 Synthesis of At(C1)-Pip-6Qui-FAPI(F) / PIP(1,F)

[0324]

[0325] 10 μL (mass 10 μg) of a 0.1% aqueous solution of Compound 7 (Borono(C1)-Pip-6Qui-FAPI(F)) synthesized in Synthesis Example 1, 10 μL of 7% Meylon, 90 μL of water, 2112 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 91.0% and the RCP was 99.9%. The TLC results of the reaction mixture are shown in Figure 2.

[0326] Example 2 211 Synthesis of At(C1)-Pip-6Qui-FAPI(H) / PIP(1,H)

[0327]

[0328] 1 μL or 10 μL (mass 1 μg or 10 μg) of a 0.1% aqueous solution of Compound 44 (Borono(C1)-Pip-6Qui-FAPI(H)) synthesized in Synthesis Example 9, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 14.1% with 1 μg of starting material, and 98.0% and 99.9% with 10 μg of starting material. The TLC results of the reaction mixture are shown in Figure 3.

[0329] Example 3 211 Synthesis of At(C1)-Pip-8Qui-FAPI(H) / PIP(1,H)-8Qui

[0330]

[0331] 10 μL (mass 10 μg) of a 0.1% aqueous solution of Compound 49 (Borono(C1)-Pip-8Qui-FAPI(H)) synthesized in Synthesis Example 10, 10 μL of 7% Meylon, 90 μL of water, 211 4 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 91.8% and the RCP was 99.8%. The TLC results of the reaction mixture are shown in Figure 4.

[0332] Example 4 211 Synthesis of At(C0)-Pip-6Qui-FAPI(H) / PIP(0,H)

[0333]

[0334] 1 μL of a 0.1% aqueous solution or 10 μL of a 1.0% aqueous solution (mass 1 μg or 100 μg) of Compound 51 (Borono(C0)-Pip-6Qui-FAPI(H)) synthesized in Synthesis Example 11, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. When the starting material mass was 1 μg, the RCY was 1.6%, and when the starting material mass was 100 μg, the RCY was 77.8% and the RCP was 91.7%. The TLC results of the reaction mixture are shown in Figure 5.

[0335] Example 5 211 Synthesis of At(C1)-PEG2-6Qui-FAPI(F) / PEG(1,F)

[0336]

[0337] 10 μL (mass 10 μg) of a 0.1% aqueous solution of Compound 13 (Borono(C1)-PEG2-6Qui-FAPI(F)) synthesized in Synthesis Example 2, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 98.0% and the RCP was 99.9%. The TLC results of the reaction mixture are shown in Figure 6.

[0338] Example 6 211 Synthesis of At(C1)-PEG2-6Qui-FAPI(H) / PEG(1,H)

[0339]

[0340] 1 μL or 10 μL (mass 1 μg or 10 μg) of a 0.1% aqueous solution of Compound 39 (Borono(C1)-PEG2-6Qui-FAPI(H)) synthesized in Synthesis Example 7, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 58.7% when 1 μg of starting material was used, and 98.8% and 99.5% when 10 μg of starting material was used. The TLC results of the reaction mixture are shown in Figure 7.

[0341] Example 7 211Synthesis of At(C1)-PEG4-6Qui-FAPI(H) / PEG4(1,H)

[0342]

[0343] 10 μL (mass 10 μg) of a 0.1% aqueous solution of Compound 42 (Borono(C1)-PEG4-6Qui-FAPI(H)) synthesized in Synthesis Example 8, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 98.7% and the RCP was 99.9%. The TLC results of the reaction mixture are shown in Figure 8.

[0344] Example 8 211 Synthesis of At(C1)-Gly(1)-8Qui-FAPI(F) / Gly(1,F)

[0345]

[0346] 10 μL (mass 10 μg) of a 0.1% aqueous solution of Compound 19 (Borono(C1)-Gly(1)-8Qui-FAPI(F)) synthesized in Synthesis Example 3, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 50°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 95.7% and the RCP was 97.4%. The TLC results of the reaction mixture are shown in Figure 9.

[0347] Example 9 211Synthesis of At(C0)-GlcN-Pip-6Qui-FAPI(F) / GlcN-PIP(0,F)

[0348]

[0349] 10 μL (mass 10 μg) of a 0.1% aqueous solution of Compound 29 (Borono(C0)-GlcN-Pip-6Qui-FAPI(F)) synthesized in Synthesis Example 4, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 70.3% and the RCP was 90.9%. The TLC results of the reaction mixture are shown in Figure 10.

[0350] Example 10 211 Synthesis of At(C0)-GlcN-Pip-6Qui-FAPI(H) / GlcN-PIP(0,H)

[0351]

[0352] 10 μL (mass 10 μg or 100 μg) of 0.1% or 1.0% aqueous solution of Compound 32 (Borono(C0)-GlcN-Pip-6Qui-FAPI(H)) synthesized in Synthesis Example 5, 10 μL of 7% Meylon, 90 μL of water, 2112 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. When 10 μg of starting material was used, the RCY was 55.9%, and when 100 μg of starting material was used, the RCY was 62.0% and the RCP was 70.4%. The TLC results of the reaction mixture are shown in Figure 11.

[0353] Example 11 211 Synthesis of At(C1)-GlcN-PEG-6Qui-FAPI(F) / GlcN-PEG(1,F)

[0354]

[0355] 10 μL (mass 10 μg) of a 0.1% aqueous solution of Compound 35 (Borono(C1)-GlcN-PEG-6Qui-FAPI(F)) synthesized in Synthesis Example 6, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 97.2% and the RCP was 99.9%. The TLC results of the reaction mixture are shown in Figure 12.

[0356] Example 12 Qui-Gly-Pro-( 211 Synthesis of At)Phe / Qui-Phe

[0357]

[0358] 1 μL or 10 μL (mass 1 μg or 10 μg) of 0.1% aqueous solution of Compound 53 (Qui-Gly-Pro(B)Phe) synthesized in Synthesis Example 12, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E2. The RCY was 96.3% when 1 μg of starting material was used, and 98.6% when 10 μg of starting material was used. The TLC results of the reaction solution are shown in Figure 13.

[0359] Example 13 Ac-Pip-6Qui-Gly-Pro-( 211 Synthesis of At)Phe / Ac-PIP

[0360]

[0361] 10 μL (mass 10 μg) of 0.1% aqueous solution of compound 57 (Ac-Pip-6Qui-Gly-Pro-(B)Phe) synthesized in Synthesis Example 13, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E2. The RCY was 95.7% and the RCP was 99.2%. The TLC results of the reaction mixture are shown in Figure 14.

[0362] Example 14 211 Synthesis of At(C1)-Pip-amide-6Qui-FAPI(H) / PIP-amide(1,H)

[0363]

[0364] 10 μL of 0.1% aqueous solution (mass 10 μg) of compound 61 (Borono(C1)-Pip-amide-6Qui-FAPI(H)) synthesized in Synthesis Example 14, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 97.1% and the RCP was 97.7%. The TLC results of the reaction mixture are shown in Figure 15.

[0365] Example 15 211 Synthesis of At(C2)-Pip-6Qui-FAPI(H) / PIP(2,H)

[0366]

[0367] 10 μL (mass 10 μg) of 0.1% aqueous solution of compound 62 (Borono(C2)-Pip-6Qui-FAPI(H)) synthesized in Synthesis Example 15, 10 μL of 7% Meylon, 90 μL of water, 211 2 μL of At solution and 30 μL of 0.1 M potassium iodide solution were added to a polypropylene (PP) tube. This solution was heated at 80°C for 45 minutes and then passed through an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through the same HLB cartridge. The target compound was eluted in fraction E3. The RCY was 98.1% and the RCP was 98.2%. The TLC results of the reaction mixture are shown in Figure 16.

[0368] Table 1 summarizes the RCY% and RCP% of the radiolabeled compounds obtained in the examples. For Examples 1-11, 14, and 15, the parenthesized C0, C1, and C2 indicate the alkylene chain length between the phenyl group bearing the borono group and the carbonyl group. When the alkylene chain length was 1 or 2 (Examples 1-3, 5-8, 11, 14, and 15), a high reaction yield of RCY >90% was obtained with 10 μg of starting material. On the other hand, when the alkylene chain length was 0 (Examples 4, 9, and 10), the reaction yield was low, failing to reach 90% even with 100 μg of starting material (Examples 4 and 10). Furthermore, in these cases, the purity after purification was low (RCP <92%), and the stability of the product was also poor. These findings demonstrate that in the synthesis of radiolabeled compound (I-1) from boronic acid compound (II-1), the alkylene chain length affects the reaction yield, and that a carbon number of 1 or more is preferred to achieve a reaction yield of 90% or greater.

[0369]

[0370] Example 16 131 Synthesis of I(C1)-Pip-6Qui-FAPI(H)

[0371]

[0372] In this example, 211 According to the basic procedure for At labeling 131 I-labeling was performed. 1 mg of Compound 44 (Borono(C1)-Pip-6Qui-FAPI(H)) synthesized in Synthesis Example 9, 80 μL of water, 13130 μL of I-NaI aqueous solution and 30 μL of 0.4% N-bromosuccinimide were added to a PP tube. This solution was heated at 80°C for 30 minutes, and then 10 μL of 4% ascorbic acid was added to the reaction mixture. The reaction mixture was then allowed to stand at room temperature for 15 minutes. The reaction mixture was then loaded onto an Oasis HLB cartridge. After washing with 1 mL of water (fraction E1), 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were loaded onto the cartridge. The target compound was eluted in fraction E3. The RCY was 50.0% and the RCP was 94.6%. The TLC results of the reaction mixture and eluate are shown in Figure 17. Borono(C1)-Pip-6Qui-FAPI(H) were also found to be useful for the synthesis of iodine derivatives.

[0373] Test Example 1 211 Uptake of At-labeled FAPI derivatives into FAPα / 293 cells. Human embryonic kidney 293 (HEK293) cells and the same cells transfected with the human fibroblast activation protein (FAPα) gene (FAPα / 293) were used as FAPα-negative and FAPα-positive cells, respectively. Each cell was plated at 2x10 cells per well in a 24-well plate. 4 Each was seeded and cultured for two days. 211Eight At-labeled FAPI derivatives (Gly(1,F) (Example 8), PEG(1,F) (Example 5), PIP(1,F) (Example 1), PIP(1,H)-8Qui (Example 3), Ac-PIP (Example 13), PEG4(1,H) (Example 7), GlcN-PEG(1,F) (Example 11), and PEG(1,H) (Example 6)) were added to each cell line and incubated for 30 minutes. The supernatant was then aspirated, and the cells were lysed with 0.1 N sodium hydroxide solution. The intracellular radioactivity was measured using a gamma counter. Radioactivity counts were normalized per unit protein (counts / μg protein). The results are shown in Figure 18. The three compounds with the highest uptake into FAPα-positive cells were PIP(1,F) > PIP(1,H)-8Qui > PEG(1,H). Furthermore, both compounds were found to be specifically taken up by FAPα, as they were more highly taken up by FAPα-positive cells than by FAPα-negative cells.

[0374] Test Example 2 211 Uptake of At-labeled FAPI derivatives into FAPα / A549 or FAPα / MDA-MB-231 cells. Human non-small cell lung cancer cell line (A549), human triple-negative (absence of all three hormone receptors: estrogen receptor, progesterone receptor, and HER2 protein) breast cancer cell line (MDA-MB-231), and the same cells transfected with the human fibroblast activation protein (FAPα) gene (FAPα / A549, FAPα / MDA-MB-231) were used in the experiments as cancer cells with low FAPα expression and cancer cells with high FAPα expression (mimicking the formation of advanced tissue), respectively. Each cell was plated at 2 × 10 4 Each was seeded and cultured for two days. 211Two At-labeled FAPI derivatives (PIP(1,H) (Example 1) and PIP-amide(1,H) (Example 14)) were added to each cell line and incubated for 30 minutes. The supernatant was then removed by aspiration and washed with PBS(-). The cells were then lysed with 0.1 N sodium hydroxide solution, and intracellular radioactivity was measured using a gamma counter. Radioactivity counts were normalized per unit protein (counts / μg protein). Enhanced FAPα expression was confirmed to increase uptake, with PIP(1,H) demonstrating slightly superior uptake compared to PIP-amide(1,H). The extent of competitive inhibition was also confirmed by adding the corresponding unlabeled compounds. It was found that FAPα expression was suppressed to low levels. Considering the results of PIP(1,F) and other compounds in Test Example 1, where uptake in human embryonic kidney-derived cells (HEK293) was at most 20 counts / μg protein, cancer cells can be said to internalize more FAPI derivatives than non-cancerous cells. The results are shown in FIGS. 19(a) and (b).

[0375] Test Example 3: Tumor growth inhibitory effect in mice transplanted with human pancreatic cancer Human pancreatic cancer cells (PANC-1) 1x10 7 The mice were subcutaneously administered with the drug to nude mice (male, 6 weeks old) to create mice bearing pancreatic cancer. 211 At(C1)-Pip-6Qui-FAPI(H) (PIP(1,H), Example 2) or 211 At(C1)-PEG2-6Qui-FAPI(H) (PEG(1,H), Example 6) was intravenously administered at 1 MBq per mouse (N=4). A control group (Control (Saline)) was administered physiological saline (N=4). The tumor size and body weight of the mice were measured over a 3-week period. The results are shown in Figure 20. The PIP(1,H) and PEG(1,H)-administered groups exhibited tumor growth inhibitory effects compared to the control group. Since the weight changes in both groups were comparable to those in the control group, the toxicity of these agents was considered low.

[0376] According to the present invention, it is possible to provide a radiolabeled compound that specifically binds to FAPα and is effective in the treatment and diagnosis of tumors or cancers that express FAPα, for example, the treatment and diagnosis of solid cancers (particularly pancreatic cancer) such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, and liver cancer, with a lower risk of prolonged side effects.

[0377] This application is based on Japanese Patent Application No. 2022-026194 filed on February 22, 2022, the contents of which are incorporated in their entirety herein.

Claims

1. ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ a radioactive moiety comprising an aryl group substituted with a radionuclide selected from: A physiologically active moiety having affinity for fibroblast activation protein α (FAPα). , a conjugate comprising:

2. The biologically active moiety having affinity for fibroblast activation protein alpha has the following formula: 【Chemistry 1】 The conjugate of claim 1, comprising a structure represented by:

3. The radioactive part is ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ aryl-C substituted with a radionuclide selected from Br; １－３ The conjugate of claim 1 , comprising an alkyl group.

4. A radiolabeled compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 [In the formula, X １ teeth, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Ar 1 is C ６－１４ represents an aryl group; p1 R ａ１ and R ｂ１ are each independently a hydrogen atom or C １－６ represents an alkyl group; m1 R ｃ１ are each independently C １－６ represents an alkyl group or a hydroxy group; n1 R ｄ１ each independently represents a halogen atom; Z １ is an oxygen atom, a sulfur atom, or NR ｆ１ (In the formula, R ｆ１ is a hydrogen atom or C １－３ represents an alkyl group; L １ teeth, (1) *-L ｄ１ -8 ｃ１ -8 ｂ１ -8 ａ１ -** (In the formula, * indicates the binding site with CO, ** is Z １ indicates the binding site with L ａ１ teeth, (i) C １－６ an alkylene group, or (ii) -CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (wherein q1 represents an integer of 0 to 5). indicates, L ｂ１ represents a bond or —CO—, L ｃ１ teeth, (i) NR ｇ１ (In the formula, R ｇ１ is a hydrogen atom or C １－３ represents an alkyl group.) (ii) a divalent cyclic amino group, (iii) an oxygen atom, or (iv) sulfur atom indicates, L ｄ１ teeth, (i) combination; (ii) *-(NH-A ａ１ -CO) ｒ１ -*** (wherein r1 NH-A ａ１ -CO each independently represents an amino acid residue, r1 represents an integer of 1 to 3, * represents a bonding site with CO, and *** represents L ｃ１ ), or (iii) *-NH-B ａ１ -O-B ｂ１ -CO-*** (in the formula, -NH-B ａ１ -O- represents a divalent residue derived from an amino sugar or a derivative thereof, and B ｂ１ is C １－６ represents an alkylene group, * represents a bonding site with CO, and *** represents L ｃ１ The binding site is shown.) Indicates.) or a linker represented by (2) *-(NH-A ｂ１ -CO ｓ１ -** (In the formula, * indicates the binding site with CO, ** is Z １ indicates the binding site with s1 NH-A ｂ１ each —CO independently represents an amino acid residue; s1 represents an integer of 1 to 3. A linker represented by the formula: p1 represents an integer of 1 to 3; m1 represents an integer of 0 to 3; n1 represents an integer of 0 to 3.

5. Z １ is an oxygen atom or a sulfur atom, and L １ However, *-L ｄ１ -L ｃ１ -L ｂ１ -L ａ１ 5. The compound according to claim 4, wherein the linker is represented by -** (each symbol in the formula has the same meaning as in claim 4), or a pharmaceutically acceptable salt thereof.

6. Z １ But NR ｆ１ (The symbols in the formula have the same meanings as in claim 4.) L １ However, *-(NH-A ｂ１ -CO) ｓ１ 5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the linker is represented by -** (the symbols in the formula have the same meanings as in claim 4).

7. L １ が、*-L ｄ１ -8 ｃ１ -8 ｂ１ -8 ａ１ -** (In the formula, * is the binding site with CO, ** is Z １ is the binding site for L ａ１ But C １－６ is an alkylene group, L ｂ１ is a bond or —CO—, L ｃ１ is a divalent cyclic amino group, and L ｄ１ but, (i) combination; (ii) *-(NH-A ａ１ -CO) ｒ１ -*** (each symbol in the formula has the same meaning as in claim 4), or (iii) *-NH-B ａ１ -O-B ｂ１ -CO-*** (each symbol in the formula has the same meaning as in claim 4) It is.) 6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the linker is represented by the following formula:

8. L ｃ１ 5. The compound according to claim 4, wherein the divalent cyclic amino group represented by the formula: is a divalent 3- to 8-membered cyclic diamino group, or a pharmaceutically acceptable salt thereof.

9. L １ が、*-L ｄ１ -8 ｃ１ -8 ｂ１ -8 ａ１ -** (In the formula, * is the binding site with CO, ** is Z １ is the binding site for L ａ１ But -CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (the symbols in the formula have the same meanings as in claim 4), L ｂ１ is a bond, L ｃ１ But NR ｇ１ (The symbols in the formula have the same meanings as in claim 4), an oxygen atom or a sulfur atom, and L ｄ１ is a bond.) 6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the linker is represented by the following formula:

10. 5. The compound of claim 4, wherein s1 is 1, or a pharmaceutically acceptable salt thereof.

11. A radiolabeled compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof: 【Transformation 3】 [In the formula, X ２ teeth, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Ar ２ is C ６－１４ represents an aryl group; p2 R ａ２ and R ｂ２ are each independently a hydrogen atom or C １－６ represents an alkyl group; m2 R ｃ２ are each independently C １－６ represents an alkyl group or a hydroxy group; n2 R ｄ２ each independently represents a halogen atom; Z ２ is an oxygen atom, a sulfur atom, or NR ｆ２ (In the formula, R ｆ２ is a hydrogen atom or C １－３ represents an alkyl group; L ２ teeth, (1) *-L ｃ２ -8 ｂ２ -8 ａ２ -** (In the formula, * indicates R ｅ２ indicates the binding site with ** is Z ２ indicates the binding site with L ａ２ teeth, (i) C １－６ an alkylene group, or (ii) -CH ２ - (CH ２ -O-CH ２ ) ｑ２ -CH ２ - (wherein q2 represents an integer of 0 to 5). indicates, L ｂ２ represents a bond or —CO—, L ｃ２ teeth, (i) NR ｇ２ (In the formula, R ｇ２ is a hydrogen atom or C １－３ represents an alkyl group.) (ii) a divalent cyclic amino group, (iii) an oxygen atom, or (iv) sulfur atom Indicates.) or a linker represented by (2) *-(NH-A ａ２ -CO ｒ２ -** (In the formula, * indicates R ｅ２ indicates the binding site with ** is Z ２ indicates the binding site with r2 NH-A ａ２ each —CO independently represents an amino acid residue; r2 represents an integer of 1 to 3. A linker represented by the formula: R ｅ２ is C １－６ represents an alkyl-carbonyl group; Alternatively, the group R ｅ２ -L ２ -Z ２ - represents a hydrogen atom; L ３ は、***-(NH-A ｂ２ -CO) ｓ２ -**** (In the formula, *** indicates the binding site with CO, **** indicates the binding site with NH, s2 NH-A ｂ２ each —CO independently represents an amino acid residue; s2 represents an integer of 0 to 3. A linker represented by the formula: R is a hydrogen atom or C １－３ represents an alkyl group; p2 represents an integer of 0 to 3; m2 represents an integer of 0 to 3; n2 represents an integer of 0 to 3.

12. Z ２ is an oxygen atom or a sulfur atom, and L ２ However, *-L ｃ２ -L ｂ２ -L ａ２ 12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the linker is represented by -** (each symbol in the formula has the same meaning as in claim 11).

13. Z ２ But NR ｆ２ (The symbols in the formula have the same meanings as in claim 11.) L ２ However, *-(NH-A ａ２ -CO) ｒ２ 12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the linker is represented by -** (each symbol in the formula has the same meaning as in claim 11).

14. 12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein p2 is an integer of 1 to 3.

15. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein s2 is 0.

16. A pharmaceutical composition comprising the compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A therapeutic agent for a tumor or cancer expressing fibroblast activation protein α (FAPα), comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

18. The therapeutic agent according to claim 17, wherein the tumor or cancer expressing fibroblast activating protein alpha is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colon cancer, neuroendocrine tumor, thyroid cancer, uterine cancer or liver cancer.

19. 16. The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for use in treating a tumor or cancer that expresses fibroblast activation protein α (FAPα).

20. 20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein the tumor or cancer expressing fibroblast activator protein alpha is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colon cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, or liver cancer.

21. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for a tumor or cancer expressing fibroblast activation protein α (FAPα).

22. The use of claim 21, wherein the tumor or cancer expressing fibroblast activating protein alpha is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colon cancer, neuroendocrine tumor, thyroid cancer, uterine cancer or liver cancer.

23. A compound represented by formula (II-1) or a salt thereof: 【Chemistry 4】 [In the formula, Y １ is a boryl group (-B(OH) ２ ) or an ester group thereof; Ar 1 is C ６－１４ represents an aryl group; p1 R ａ１ and R ｂ１ are each independently a hydrogen atom or C １－６ represents an alkyl group; m1 R ｃ１ are each independently C １－６ represents an alkyl group or a hydroxy group; n1 R ｄ１ each independently represents a halogen atom; Z １ is an oxygen atom, a sulfur atom, or NR ｆ１ (In the formula, R ｆ１ is a hydrogen atom or C １－３ represents an alkyl group; L １ teeth, (1) *-L ｄ１ -8 ｃ１ -8 ｂ１ -8 ａ１ -** (In the formula, * indicates the binding site with CO, ** is Z １ indicates the binding site with L ａ１ teeth, (i) C １－６ an alkylene group, or (ii) -CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (wherein q1 represents an integer of 0 to 5). indicates, L ｂ１ represents a bond or —CO—, L ｃ１ teeth, (i) NR ｇ１ (In the formula, R ｇ１ is a hydrogen atom or C １－３ represents an alkyl group.) (ii) a divalent cyclic amino group, (iii) an oxygen atom, or (iv) sulfur atom indicates, L ｄ１ teeth, (i) combination; (ii) *-(NH-A ａ１ -CO) ｒ１ -*** (wherein r1 NH-A ａ１ -CO each independently represents an amino acid residue, r1 represents an integer of 1 to 3, * represents a bonding site with CO, and *** represents L ｃ１ ), or (iii) *-NH-B ａ１ -O-B ｂ１ -CO-*** (in the formula, -NH-B ａ１ -O- represents a divalent residue derived from an amino sugar or a derivative thereof, and B ｂ１ is C １－６ represents an alkylene group, * represents a bonding site with CO, and *** represents L ｃ１ The binding site is shown.) Indicates.) or a linker represented by (2) *-(NH-A ｂ１ -CO ｓ１ -** (In the formula, * indicates the binding site with CO, ** is Z １ indicates the binding site with s1 NH-A ｂ１ each —CO independently represents an amino acid residue; s1 represents an integer of 1 to 3. A linker represented by the formula: p1 represents an integer of 1 to 3; m1 represents an integer of 0 to 3; n1 represents an integer of 0 to 3.

24. A compound represented by formula (II-2) or a salt thereof: 【Transformation 5】 [In the formula, Y ２ is a boryl group (-B(OH) ２ ) or an ester group thereof; Ar ２ is C ６－１４ represents an aryl group; p2 R ａ２ and R ｂ２ are each independently a hydrogen atom or C １－６ represents an alkyl group; m2 R ｃ２ are each independently C １－６ represents an alkyl group or a hydroxy group; n2 R ｄ２ each independently represents a halogen atom; Z ２ is an oxygen atom, a sulfur atom, or NR ｆ２ (In the formula, R ｆ２ is a hydrogen atom or C １－３ represents an alkyl group; L ２ teeth, (1) *-L ｃ２ -8 ｂ２ -8 ａ２ -** (In the formula, * indicates R ｅ２ indicates the binding site with ** is Z ２ indicates the binding site with L ａ２ teeth, (i) C １－６ an alkylene group, or (ii) -CH ２ - (CH ２ -O-CH ２ ) ｑ２ -CH ２ - (wherein q2 represents an integer of 0 to 5). indicates, L ｂ２ represents a bond or —CO—, L ｃ２ teeth, (i) NR ｇ２ (In the formula, R ｇ２ is a hydrogen atom or C １－３ represents an alkyl group.) (ii) a divalent cyclic amino group, (iii) an oxygen atom, or (iv) sulfur atom Indicates.) or a linker represented by (2) *-(NH-A ａ２ -CO ｒ２ -** (In the formula, * indicates R ｅ２ indicates the binding site with ** is Z ２ indicates the binding site with r2 NH-A ａ２ each —CO independently represents an amino acid residue; r2 represents an integer of 1 to 3. A linker represented by the formula: R ｅ２ is C １－６ represents an alkyl-carbonyl group; Alternatively, the group R ｅ２ -L ２ -Z ２ - represents a hydrogen atom; L ３ は、***-(NH-A ｂ２ -CO) ｓ２ -**** (In the formula, *** indicates the binding site with CO, **** indicates the binding site with NH, s2 NH-A ｂ２ each —CO independently represents an amino acid residue; s2 represents an integer of 0 to 3. A linker represented by the formula: R is a hydrogen atom or C １－３ represents an alkyl group; p2 represents an integer of 0 to 3; m2 represents an integer of 0 to 3; n2 represents an integer of 0 to 3.

25. A method for producing a radiolabeled compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the steps of: 【Transformation 6】 [In the formula, X １ teeth, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Y １ is a boryl group (-B(OH) ２ ) or an ester group thereof; Ar 1 is C ６－１４ represents an aryl group; p1 R ａ１ and R ｂ１ are each independently a hydrogen atom or C １－６ represents an alkyl group; m1 R ｃ１ are each independently C １－６ represents an alkyl group or a hydroxy group; n1 R ｄ１ each independently represents a halogen atom; Z １ is an oxygen atom, a sulfur atom, or NR ｆ１ (In the formula, R ｆ１ is a hydrogen atom or C １－３ represents an alkyl group; L １ teeth, (1) *-L ｄ１ -8 ｃ１ -8 ｂ１ -8 ａ１ -** (In the formula, * indicates the binding site with CO, ** is Z １ indicates the binding site with L ａ１ teeth, (i) C １－６ an alkylene group, or (ii) -CH ２ - (CH ２ -O-CH ２ ) ｑ１ -CH ２ - (wherein q1 represents an integer of 0 to 5). indicates, L ｂ１ represents a bond or —CO—, L ｃ１ teeth, (i) NR ｇ１ (In the formula, R ｇ１ is a hydrogen atom or C １－３ represents an alkyl group.) (ii) a divalent cyclic amino group, (iii) an oxygen atom, or (iv) sulfur atom indicates, L ｄ１ teeth, (i) combination; (ii) *-(NH-A ａ１ -CO) ｒ１ -*** (wherein r1 NH-A ａ１ -CO each independently represents an amino acid residue, r1 represents an integer of 1 to 3, * represents a bonding site with CO, and *** represents L ｃ１ ), or (iii) *-NH-B ａ１ -O-B ｂ１ -CO-*** (in the formula, -NH-B ａ１ -O- represents a divalent residue derived from an amino sugar or a derivative thereof, and B ｂ１ is C １－６ represents an alkylene group, * represents a bonding site with CO, and *** represents L ｃ１ The binding site is shown.) Indicates.) or a linker represented by (2) *-(NH-A ｂ１ -CO ｓ１ -** (In the formula, * indicates the binding site with CO, ** is Z １ indicates the binding site with s1 NH-A ｂ１ each —CO independently represents an amino acid residue; s1 represents an integer of 1 to 3. A linker represented by the formula: p1 represents an integer of 1 to 3; m1 represents an integer of 0 to 3; n1 represents an integer of 0 to 3. Step 1: A compound represented by formula (II-1) or a salt thereof is reacted in water in the presence of a reagent selected from an alkali metal iodide, an alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br to obtain a radiolabeled compound of formula (I-1) or a pharmaceutically acceptable salt thereof.

26. A method for producing a radiolabeled compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof, comprising the steps of: 【Transformation 7】 [In the formula, X ２ teeth, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br; Y ２ is a boryl group (-B(OH) ２ ) or an ester group thereof; Ar ２ is C ６－１４ represents an aryl group; p2 R ａ２ and R ｂ２ are each independently a hydrogen atom or C １－６ represents an alkyl group; m2 R ｃ２ are each independently C １－６ represents an alkyl group or a hydroxy group; n2 R ｄ２ each independently represents a halogen atom; Z ２ is an oxygen atom, a sulfur atom, or NR ｆ２ (In the formula, R ｆ２ is a hydrogen atom or C １－３ represents an alkyl group; L ２ teeth, (1) *-L ｃ２ -8 ｂ２ -8 ａ２ -** (In the formula, * indicates R ｅ２ indicates the binding site with ** is Z ２ indicates the binding site with L ａ２ teeth, (i) C １－６ an alkylene group, or (ii) -CH ２ - (CH ２ -O-CH ２ ) ｑ２ -CH ２ - (wherein q2 represents an integer of 0 to 5). indicates, L ｂ２ represents a bond or —CO—, L ｃ２ teeth, (i) NR ｇ２ (In the formula, R ｇ２ is a hydrogen atom or C １－３ represents an alkyl group.) (ii) a divalent cyclic amino group, (iii) an oxygen atom, or (iv) sulfur atom Indicates.) or a linker represented by (2) *-(NH-A ａ２ -CO ｒ２ -** (In the formula, * indicates R ｅ２ indicates the binding site with ** is Z ２ indicates the binding site with r2 NH-A ａ２ each —CO independently represents an amino acid residue; r2 represents an integer of 1 to 3. A linker represented by the formula: R ｅ２ is C １－６ represents an alkyl-carbonyl group; Alternatively, the group R ｅ２ -L ２ -Z ２ - represents a hydrogen atom; L ３ は、***-(NH-A ｂ２ -CO) ｓ２ -**** (In the formula, *** indicates the binding site with CO, **** indicates the binding site with NH, s2 NH-A ｂ２ each —CO independently represents an amino acid residue; s2 represents an integer of 0 to 3. A linker represented by the formula: R is a hydrogen atom or C １－３ represents an alkyl group; p2 represents an integer of 0 to 3; m2 represents an integer of 0 to 3; n2 represents an integer of 0 to 3. Step 2: The compound represented by formula (II-2) or a salt thereof is reacted in water in the presence of a reagent selected from an alkali metal iodide, an alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ Br to obtain a radiolabeled compound of formula (I-2) or a pharmaceutically acceptable salt thereof.

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