WO2015152128A1

WO2015152128A1 - Amino acid precursor, amino acid, and production method for amino acid, and pet diagnostic tracer using amino acid

Info

Publication number: WO2015152128A1
Application number: PCT/JP2015/059862
Authority: WO
Inventors: 憲一郎山本; 和也児玉; 有未笹野; ウィリアムユーワンヒューム; 桂司八塩; 聡野崎
Original assignee: 長瀬産業株式会社; 独立行政法人理化学研究所
Priority date: 2014-03-31
Filing date: 2015-03-30
Publication date: 2015-10-08
Also published as: JPWO2015152128A1

Abstract

Disclosed is an amino acid that can be prevented from being incorporated into normal cells and selectively incorporated into tumor cells, even when used in a PET diagnostic tracer. Also disclosed are an amino acid precursor, a production method for the amino acid, and a PET diagnostic tracer that uses the amino acid. The amino acid of the present invention is represented by formula (II). The amino acid of the present invention is, for example, useful as a PET diagnostic tracer or as a building block for a pharmaceutical intermediate.

Description

Amino acid precursor, amino acid and method for producing the same, and PET diagnostic tracer using the amino acid

The present invention relates to an amino acid precursor, an amino acid, a production method thereof, and a PET diagnostic tracer using the amino acid.

For example, new diagnostic methods such as positron emission tomography (PET) have been developed for diagnostic imaging using means such as X-ray, MRI, CT scan, etc. It is coming.

In such PET diagnosis currently utilizing glucose metabolism ^[18 F] - fluoro-deoxy-glucose ^([18 F] -FDG) is used as a tracer (Non-Patent Document 1).

However, this [ ¹⁸ F] -FDG is taken into cells by a glucose transporter like glucose, but remains in the cells without being further metabolized by being phosphorylated by hexokinase in the cells. For this reason, in tumor diagnosis by PET, tumor cells are described as a positive image because glucose metabolism is enhanced and uptake is increased compared to normal cells, and in areas where glucose metabolism is active such as the brain It has been pointed out that it is not suitable for diagnosis (Non-Patent Document 2). [ ¹⁸ F] -FDG has a property of accumulating in inflamed tissues (Non-patent Document 3), and it may be difficult to distinguish between tumor tissues and inflamed tissues in cancer diagnosis.

Thus, instead of [ ¹⁸ F] -FDG, which makes it difficult to diagnose brain tumors, in recent years, PET diagnostic agents focusing on amino acid transporters rather than glucose metabolic systems have been developed. As a PET diagnostic agent focusing on amino acid transporters, L-methyl-11C-methionine (L- [ ¹¹ C] MET) is mainly used in clinical studies (Non-patent Document 4).

However, L- [ ¹¹ C] MET is a natural amino acid and has the property of being taken up by normal cells. For this reason, it has been pointed out that in PET diagnosis using L- [ ¹¹ C] MET, the background increases and it is difficult to obtain sufficient detection sensitivity. In addition, since the physicochemical half-life of ¹¹ C is as short as about 20 minutes, it is pointed out that the time from manufacture to use must be performed in a very short time, and the time margin at the PET diagnosis site is not sufficient. Yes.

Furthermore, it is considered that such amino acids and their precursors can be used for other pharmaceutical raw materials. Therefore, in addition to the PET diagnostic tracer, it is desired to provide amino acids and precursors thereof that can be used for various pharmaceutical applications.

An object of the present invention is to solve the above-mentioned problems. The object of the present invention is to suppress uptake into normal cells and to be selective for tumor cells even when used in a PET diagnostic tracer. It is to provide an amino acid and a precursor thereof, and a production method thereof.

The present invention is a compound represented by the following formula (I):

here,
R ¹ is
C ₁ -C ₅ alkyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C ₂ -C ₅ alkenyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C ₂ -C ₅ alkynyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C ₁ -C ₅ alkyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An oxy group;
C ₂ -C ₈ alkoxy optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An alkyloxy group;
C ₂ -C ₅ alkenyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An oxy group; or C ₃ optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability ~ _{C 5} alkynyloxy group;
And
R ² and R ³ are each independently
Hydrogen atom;
A C ₁ -C ₈ alkyl group which may form a branch or a ring and may be substituted with a halogen atom;
A C ₁ -C ₅ alkyl group, a C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, a C ₁ -C ₅ alkyloxy group, or a benzyl group optionally substituted with a halogen atom; or a protecting group;
And
X ¹ and X ² are each independently a group selected from the group consisting of a hydrogen atom and a halogen atom, and Y may contain a radioisotope and may form a branch or a ring A good C ₁ -C ₃ alkyl group.

In one embodiment, the compound represented by the above formula (I) is represented by the following formula (I ′):

It is represented by

In one embodiment, in Formula (I) above, R ¹ is
A C ₁ -C ₅ alkyl group optionally substituted with a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₂ -C ₅ alkenyl group optionally substituted by a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₂ -C ₅ alkynyl group optionally substituted with a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₁ -C ₅ alkyloxy group optionally substituted with a radioisotope ¹⁸ F and optionally having a branch or ring;
A C ₂ -C ₈ alkoxyalkyloxy group optionally substituted by a radioisotope ¹⁸ F, optionally having a branch or ring;
Substituted with a radioactive isotope ^{18 F,} which may have a branched or cyclic C _{2 ~} C ₅ alkenyloxy group; or substituted with a radioactive isotope ^{18 F,} may be branched or cyclic A C ₃ -C ₅ alkynyloxy group;
It is.

In one embodiment, in Formula (I) above, R ¹ is
A C ₁ -C ₅ alkyl group which may be branched or ring-substituted with a functional group capable of leaving;
Replaced with a functional group having a leaving Hanareno, which may have a branched or cyclic C _{2 ~} C ₅ alkenyl group;
A C ₂ -C ₅ alkynyl group optionally substituted with a functional group having a leaving ability, which may be branched or ringed;
A C ₁ -C ₅ alkyloxy group optionally having a branch or ring, substituted with a functional group having a leaving ability;
A C ₂ -C ₈ alkoxyalkyloxy group which may be branched or ring-substituted with a functional group capable of leaving;
A C ₂ -C ₅ alkenyloxy group optionally substituted with a functional group having a leaving ability, or a branched or ring substituted with a functional group having a leaving ability; An optionally substituted C ₃ -C ₅ alkynyloxy group;
It is.

The present invention also provides a compound represented by the following formula (II):

here,
R ¹ is
A C ₁ -C ₅ alkyl group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C ₂ -C ₅ alkenyl group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C ₂ -C ₅ alkynyl group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C ₁ -C ₅ alkyloxy group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C ₂ -C ₈ alkoxyalkyloxy group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C ₂ -C ₅ alkenyloxy group optionally substituted with a halogen atom which may be a radioisotope; or a halogen atom which may be a radioisotope; A C ₃ -C ₅ alkynyloxy group which may have a branch or a ring;
And
X ¹ and X ² are each independently a group selected from the group consisting of a hydrogen atom and a halogen atom, and Y may contain a radioisotope and may form a branch or a ring A good C ₁ -C ₃ alkyl group.

In one embodiment, the compound represented by the above formula (II) has the following formula (II ′):

It is represented by

In one embodiment, in Formula (II) above, R ¹ is
A C ₁ -C ₅ alkyl group optionally substituted with a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₂ -C ₅ alkenyl group optionally substituted by a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₂ -C ₅ alkynyl group optionally substituted with a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₁ -C ₅ alkyloxy group optionally substituted with a radioisotope ¹⁸ F and optionally having a branch or ring;
A C ₂ -C ₈ alkoxyalkyloxy group optionally substituted by a radioisotope ¹⁸ F, optionally having a branch or ring;
Substituted with a radioactive isotope ^{18 F,} which may have a branched or cyclic C _{2 ~} C ₅ alkenyloxy group; or substituted with a radioactive isotope ^{18 F,} may be branched or cyclic A C ₃ -C ₅ alkynyloxy group;
It is.

In one embodiment, in Formula (II) above, Y is a C ₁ -C ₃ alkyl group that contains the radioisotope ¹¹ C and may form a branch or ring.

The present invention also provides a method for producing a compound represented by the above formula (II),
It is a method including the process of hydrolyzing the compound represented by the said formula (I).

In one embodiment, the hydrolysis step is performed under acidic conditions.

The present invention also provides a compound represented by the above formula (II), wherein R ¹ is
A C ₁ -C ₅ alkyl group optionally substituted with a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₂ -C ₅ alkenyl group optionally substituted by a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₂ -C ₅ alkynyl group optionally substituted with a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₁ -C ₅ alkyloxy group optionally substituted with a radioisotope ¹⁸ F and optionally having a branch or ring;
A C ₂ -C ₈ alkoxyalkyloxy group optionally substituted by a radioisotope ¹⁸ F, optionally having a branch or ring;
Substituted with a radioactive isotope ^{18 F,} which may have a branched or cyclic C _{2 ~} C ₅ alkenyloxy group; or substituted with a radioactive isotope ^{18 F,} may be branched or cyclic A C ₃ -C ₅ alkynyloxy group;
This is a PET diagnostic tracer containing a compound.

According to the present invention, it is possible to provide an amino acid and a precursor thereof, and a method for producing them, in which uptake into normal cells is suppressed and can be selectively taken up into tumor cells. The compound of the present invention can function, for example, as an amino acid transporter not involved in the glucose metabolism system, and when used as a PET diagnostic tracer, it can be avoided because the detection sensitivity is impaired due to an increase in background. Furthermore, since the compound of the present invention can incorporate, for example, any radioisotope into its structure, it can provide a compound having a relatively long physicochemical half-life. Thereby, sufficient use time can be provided when using as a PET diagnostic tracer.

FIG. 9 is a graph showing the evaluation of the function as a PET tracer for mice using the compounds of Examples 19 to 21 and Comparative Examples 1 to 4 performed in Example 22, respectively, and the tumor part of the mice after administration It is a graph which shows the change of the accumulation | aggregation degree of each compound in. FIG. 7 is a graph showing the evaluation of the function as a PET tracer for mice using the compounds of Examples 19 to 21 and Comparative Examples 1 to 4 performed in Example 22, respectively, and the bladder portion of the mice after administration It is a graph which shows the change of the accumulation | aggregation degree of each compound in.

The terms used in this specification are defined below.

The term “an alkyl group of C ₁ to C _n which may form a branch or a ring” (where n is an integer) is any linear alkyl group having 1 to n carbon atoms, 3 to n carbon atoms It includes any branched alkyl group and any cyclic alkyl group having 3 to n carbon atoms. For example, arbitrary linear alkyl groups having 1 to 5 carbon atoms include methyl, ethyl, n-propyl, n-butyl, and n-pentyl, and as arbitrary branched alkyl groups having 3 to 5 carbon atoms, Includes isopropyl, isobutyl, tert-butyl, isopentyl and the like, and examples of the cyclic alkyl group having 3 to 5 carbon atoms include cyclopropyl, cyclopentyl and the like.

Further, for example, the term “having a branch or a ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability” may be included. The “C ₁ -C _n alkyl group” (where n is an integer) means that at least one hydrogen atom constituting the C ₁ -C _n alkyl group which may have the above-mentioned branch or ring is a halogen atom and / or Alternatively, it refers to a C ₁ -C _n alkyl group which may be substituted with a functional group having a leaving ability. Examples of halogen atoms constituting the alkyl group include natural isotope fluorine atoms ( ¹⁹ F), chlorine atoms ( ³⁵ Cl, ³⁷ Cl), bromine atoms ( ⁷⁹ Br, ⁸¹ Br), and iodine atoms ( ¹²⁷ I), and radioisotope fluorine atoms ( ¹⁸ F), chlorine atoms ( ³⁶ Cl, ³⁸ Cl), bromine atoms ( ⁷⁷ Br, ^{80 m} Br, ⁸⁰ Br, ⁸² Br), and iodine atoms ( ¹²³ I, ¹²⁴ I ¹³¹ I), and examples of the functional group having a leaving ability include a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, a fluorosulfonate group, and the like.

Still further, for example, the term “C ₁ -C _n alkyl group optionally containing a radioisotope and optionally having a branch or a ring” (where n is an integer) has the above-mentioned branch or ring. at least one carbon atom constituting also good C _{1 ~} C _n alkyl group has may be a carbon atom of a radioactive isotope ^{(11 C),} refers to a C 1 _~ C _n alkyl group.

The term “C ₂ -C _n alkenyl group which may form a branch or a ring” (where n is an integer) refers to any straight chain alkenyl group having 2 to n carbon atoms, 3 to n carbon atoms. It includes any branched alkenyl group and any cyclic alkenyl group having 3 to n carbon atoms. For example, as an arbitrary linear alkenyl group having 2 to 5 carbon atoms, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl Examples of the branched alkenyl group having 3 to 5 carbon atoms include isopropenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl -2-propenyl and the like, and examples of the cyclic alkenyl group having 3 to 5 carbon atoms include cyclobutenyl, cyclopentenyl and the like.

Further, for example, the term “having a branch or a ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability” may be included. “C ₂ -C _n alkenyl group” (where n is an integer) means that at least one hydrogen atom constituting the C ₂ -C _n alkenyl group optionally having a branch or a ring is a halogen atom and / or Alternatively, it refers to a C ₂ -C _n alkenyl group which may be substituted with a functional group having a leaving ability. Examples of halogen atoms constituting the alkenyl group include natural isotope fluorine atoms ( ¹⁹ F), chlorine atoms ( ³⁵ Cl, ³⁷ Cl), bromine atoms ( ⁷⁹ Br, ⁸¹ Br), and iodine atoms ( ¹²⁷ I), and radioisotope fluorine atoms ( ¹⁸ F), chlorine atoms ( ³⁶ Cl, ³⁸ Cl), bromine atoms ( ⁷⁷ Br, ^{80 m} Br, ⁸⁰ Br, ⁸² Br), and iodine atoms ( ¹²³ I, ¹²⁴ I ¹³¹ I), and examples of the functional group having a leaving ability include a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, a fluorosulfonate group, and the like.

The term “C ₂ -C _n alkynyl group which may form a branch or a ring” (where n is an integer) refers to any straight chain alkynyl group having 2 to n carbon atoms, 3 to n carbon atoms It includes any branched alkynyl group and any cyclic alkynyl group having 3 to n carbon atoms. For example, the arbitrary linear alkynyl group having 2 to 5 carbon atoms includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, etc. Examples of the branched alkynyl group include 1-methyl-2-propynyl, and examples of the cyclic alkynyl group having 3 to 5 carbon atoms include cyclopropylethynyl and cyclobutylethynyl.

Further, for example, the term “having a branch or a ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability” may be included. The “C ₂ -C _n alkynyl group” (where n is an integer) means that at least one hydrogen atom constituting the C ₂ -C _n alkynyl group optionally having a branch or a ring is a halogen atom and / Alternatively, it refers to a C ₂ -C _n alkynyl group which may be substituted with a functional group having a leaving ability. Examples of halogen atoms constituting the alkynyl group include natural isotope fluorine atoms ( ¹⁹ F), chlorine atoms ( ³⁵ Cl, ³⁷ Cl), bromine atoms ( ⁷⁹ Br, ⁸¹ Br), and iodine atoms ( ¹²⁷ I), and radioisotope fluorine atoms ( ¹⁸ F), chlorine atoms ( ³⁶ Cl, ³⁸ Cl), bromine atoms ( ⁷⁷ Br, ^{80 m} Br, ⁸⁰ Br, ⁸² Br), and iodine atoms ( ¹²³ I, ¹²⁴ I ¹³¹ I), and examples of the functional group having a leaving ability include a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, a fluorosulfonate group, and the like.

The term “C ₁ -C _n alkyloxy group which may form a branch or a ring” (where n is an integer) refers to any linear alkyloxy group having 1 to n carbon atoms, 3 to n includes any branched-chain alkyloxy group and any cyclic alkyloxy group having 3 to n carbon atoms. For example, the arbitrary linear alkyl group having 1 to 5 carbon atoms includes methoxy, ethoxy, n-propoxy, n-butoxy, and n-pentyloxy, and any branched alkyloxy group having 3 to 5 carbon atoms. As examples thereof, isopropoxy, isobutyroxy, tert-butyroxy, isopentyloxy and the like can be mentioned, and examples of the cyclic alkyloxy group having 3 to 5 carbon atoms include cyclobutoxy, cyclopentyloxy and the like.

Further, for example, the term “having a branch or a ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability” may be included. “C ₁ -C _n alkyloxy group” (where n is an integer) means that at least one hydrogen atom constituting the C ₁ -C _n alkyloxy group which may have the above-mentioned branched or ring is a halogen atom. And / or a C ₁ -C _n alkyloxy group which may be substituted by a functional group having a leaving ability. Examples of halogen atoms constituting the alkyloxy group include natural isotope fluorine atoms ( ¹⁹ F), chlorine atoms ( ³⁵ Cl, ³⁷ Cl), bromine atoms ( ⁷⁹ Br, ⁸¹ Br), and iodine atoms ( ¹²⁷ I), and the radioisotope fluorine atom ( ¹⁸ F), chlorine atom ( ³⁶ Cl, ³⁸ Cl), bromine atom ( ⁷⁷ Br, ^{80 m} Br, ⁸⁰ Br, ⁸² Br), and iodine atom ( ¹²³ I, ¹²⁴ I, ¹³¹ I), and examples of the functional group having a leaving ability include a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, and a fluorosulfonate group. .

The term “C ₂ -C _n alkoxyalkyloxy group which may form a branch or a ring” (where n is an integer) refers to any linear alkoxyalkyloxy group having 2 to n carbon atoms, carbon number Including any branched alkoxyalkyloxy group having 3 to n and any cyclic alkoxyalkyloxy group having 4 to n carbon atoms, the carbon number represents the total number of carbon atoms in the alkoxyalkyloxy group. For example, any linear alkoxyalkyloxy group having 2 to 5 carbon atoms includes methoxymethyloxy, ethoxymethyloxy, n-propoxymethyloxy, n-butoxymethyloxy, methoxyethyloxy, ethoxyethyloxy, n- Propoxyethyloxy, methoxypropyloxy, ethoxypropyloxy, etc. are mentioned, and arbitrary branched alkoxyalkyloxy groups having 3 to 5 carbon atoms include isopropoxymethyloxy, isopropoxyethyloxy, etc. Examples of the optional cyclic alkoxyalkyloxy group of 4 to 5 include cyclobutoxymethyloxy and the like.

Further, for example, the term “having a branch or a ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability” may be included. “C ₂ -C _n alkoxyalkyloxy group” (where n is an integer) represents at least one hydrogen atom constituting the C ₂ -C _n alkoxyalkyloxy group which may have the above-mentioned branch or ring, A C ₂ -C _n alkoxyalkyloxy group which may be substituted with a halogen atom and / or a functional group having a leaving ability. Examples of halogen atoms constituting the alkoxyalkyloxy group include natural isotope fluorine atom ( ¹⁹ F), chlorine atom ( ³⁵ Cl, ³⁷ Cl), bromine atom ( ⁷⁹ Br, ⁸¹ Br), and iodine atom ( ¹²⁷ I), and the radioisotope fluorine atom ( ¹⁸ F), chlorine atom ( ³⁶ Cl, ³⁸ Cl), bromine atom ( ⁷⁷ Br, ^{80 m} Br, ⁸⁰ Br, ⁸² Br), and iodine atom ( ¹²³ I, ¹²⁴ I, ¹³¹ I), and examples of the functional group having a leaving ability include a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, and a fluorosulfonate group. Be

The term “C ₂ -C _n alkenyloxy group which may form a branch or a ring” (where n is an integer) refers to any straight chain alkenyloxy group having 2 to n carbon atoms, 3 to n includes any branched-chain alkenyloxy group and any cyclic alkenyloxy group having 3 to n carbon atoms. For example, any linear alkenyloxy group having 2 to 5 carbon atoms includes ethenyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3- Examples of the branched alkenyloxy group having 3 to 5 carbon atoms include isopropenyloxy, 1-methyl-1-propenyloxy, 1-methyl-2-propenyloxy, and the like. 2-methyl-1-propenyloxy, 2-methyl-2-propenyloxy and the like, and examples of the cyclic alkenyloxy group having 3 to 5 carbon atoms include cyclobutenyloxy, cyclopentenyloxy and the like. .

Further, for example, the term “having a branch or a ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability” may be included. “C ₂ -C _n alkenyloxy group” (where n is an integer) is a group in which at least one hydrogen atom constituting the C ₂ -C _n alkenyloxy group optionally having a branch or ring is a halogen atom And / or a C ₂ -C _n alkenyloxy group which may be substituted by a functional group having a leaving ability. Examples of halogen atoms constituting the alkenyloxy group include natural isotope fluorine atoms ( ¹⁹ F), chlorine atoms ( ³⁵ Cl, ³⁷ Cl), bromine atoms ( ⁷⁹ Br, ⁸¹ Br), and iodine atoms ( ¹²⁷ I), and the radioisotope fluorine atom ( ¹⁸ F), chlorine atom ( ³⁶ Cl, ³⁸ Cl), bromine atom ( ⁷⁷ Br, ^{80 m} Br, ⁸⁰ Br, ⁸² Br), and iodine atom ( ¹²³ I, ¹²⁴ I, ¹³¹ I), and examples of the functional group having a leaving ability include a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, and a fluorosulfonate group. .

The term “C ₃ -C _n alkynyloxy group which may form a branch or a ring” (where n is an integer) refers to any straight chain alkynyloxy group having 3 to n carbon atoms, 4 to Including any branched alkynyloxy group of n and any cyclic alkynyloxy group having 4 to n carbon atoms. For example, the arbitrary linear alkynyloxy group having 3 to 5 carbon atoms includes 2-propynyloxy, 3-butynyloxy, 2-butynyloxy, 2-pentynyloxy, etc., and any branched chain having 4 to 5 carbon atoms. Examples of the chain alkynyloxy group include 1-methyl-2-propynyloxy, and examples of the cyclic alkynyloxy group having 4 to 5 carbon atoms include cyclopropylethynyloxy and cyclobutylethynyloxy.

Further, for example, the term “having a branch or a ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability” may be included. “C ₂ -C _n alkynyloxy group” (where n is an integer) represents a halogen atom in which at least one hydrogen atom constituting the C ₂ -C _n alkynyloxy group which may have a branched or ring structure is a halogen atom And / or a C ₂ -C _n alkynyloxy group which may be substituted by a functional group having a leaving ability. Examples of the halogen atom constituting the alkynyloxy group include a fluorine atom ( ¹⁹ F), a chlorine atom ( ³⁵ Cl, ³⁷ Cl), a bromine atom ( ⁷⁹ Br, ⁸¹ Br), and an iodine atom ( ¹²⁷ I), and the radioisotope fluorine atom ( ¹⁸ F), chlorine atom ( ³⁶ Cl, ³⁸ Cl), bromine atom ( ⁷⁷ Br, ^{80 m} Br, ⁸⁰ Br, ⁸² Br), and iodine atom ( ¹²³ I, ¹²⁴ I, ¹³¹ I), and examples of the functional group having a leaving ability include a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, and a fluorosulfonate group. .

The term “protecting group” is a group provided to prevent the amino group from being involved in a reaction occurring at any other position of the molecular structure with respect to the binding portion of the amino group in a given molecular structure. A group that can be bonded to an amino group known in the art. Examples of “protecting groups” include aryloxycarbonyl groups such as t-butoxycarbonyl (BOC), triphenylmethyl, alkoxycarbonyl, and benzyloxycarbonyl.

Examples of the term “aryl group” include phenyl, naphthyl, anthryl, phenanthryl and the like.

Examples of the term “heteroaryl group” include pyridyl, pyrrolyl, imidazolyl, benzoxazolyl, furyl, indolyl, benzothiophen-2-yl, thienyl, oxazolyl, thiazolyl, 3,4-methylenedioxyphenyl, 3, 4-Ethylenedioxyphenyl and tetrazolyl.

Examples of the term “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Hereinafter, the present invention will be described in detail.

(Amino acid precursor)
The amino acid precursor of the present invention can be represented by the following formula (I):

(here,
R ¹ is
C ₁ -C ₅ alkyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C ₂ -C ₅ alkenyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C ₂ -C ₅ alkynyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C ₁ -C ₅ alkyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An oxy group;
C ₂ -C ₈ alkoxy optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An alkyloxy group;
C ₂ -C ₅ alkenyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An oxy group; or C ₃ optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability ~ _{C 5} alkynyloxy group;
And
R ² and R ³ are each independently
Hydrogen atom;
A C ₁ -C ₈ alkyl group which may form a branch or a ring and may be substituted with a halogen atom;
A C ₁ -C ₅ alkyl group, a C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, a C ₁ -C ₅ alkyloxy group, or a benzyl group optionally substituted with a halogen atom; or a protecting group;
And
X ¹ and X ² are each independently a group selected from the group consisting of a hydrogen atom and a halogen atom, and Y may contain a radioisotope and may form a branch or a ring Good C ₁ -C ₃ alkyl group).

The compound represented by the above formula (I) is not necessarily limited, but includes, for example, each compound represented by the following formula.

(Here, R ¹ , R ² , R ³ , X ¹ , X ² , and Y each independently represent the same group as defined above).

Furthermore, in the present invention, the compound represented by the above formula (I) is represented by the following formula (I ′):

(Here, R ¹ , R ² , R ³ , X ¹ , X ² , and Y each independently represent a group similar to the group defined above). Preferably it is. The amino acid precursor of the formula (I ′) having such a structure can be converted into, for example, an amino acid that can be used in a PET diagnostic tracer as described later.

(Method for producing amino acid precursor)
The compound (amino acid precursor) represented by the above formula (I) can be synthesized by various methods.

For example, the compound represented by the formula (I) of the present invention is a compound represented by the following formula (III):

Together with an optically active phase transfer catalyst in a medium and in the presence of an inorganic base, the following formula (IV):

It can manufacture by alkylating with the compound represented by these.

here,
In formulas (III) and (IV), R ¹ , R ² , X ¹ , X ² , and Y each independently represent the same group as defined above, and A ¹ and A ² are , Each independently
(i) a hydrogen atom; or (ii) aryl group, where the aryl group is branched C ₁ may be substituted in good and halogen atoms have _~ C ₄ alkyl group,
A C ₁ -C ₅ alkoxy group which may be branched and optionally substituted with a halogen atom,
A halogen atom, a C ₁ -C ₄ alkyl group that may be branched and substituted with a halogen atom, a cyano group, —NR ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ are each independently , A hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with a halogen atom), a nitro group, a carbamoyl group, an N— (C ₁ -C ₄ alkyl) carbamoyl group, N, N— A di (C ₁ -C ₄ alkyl) carbamoyl group, or —NHCOR ¹² (wherein R ¹² is a C ₁ -C ₄ alkyl group which may be branched and optionally substituted with a halogen atom); An optionally substituted aryl group,
A cyano group,
-NR ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ are each independently a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with a halogen atom),
Nitro group,
An aryl group optionally substituted with at least one group selected from the group consisting of a hydroxyl group and a halogen atom (except when both A ¹ and A ² are hydrogen atoms), and Z ¹ Is a functional group having a leaving ability (for example, a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, or a fluorosulfonate group).

The compound of the above formula (III) and the compound of the formula (IV) are known per se, and can be easily synthesized or obtained by those skilled in the art.

The optically active phase transfer catalyst that can be used in the alkylation reaction is not particularly limited, and a phase transfer catalyst known to those skilled in the art can be used. Examples of the optically active phase transfer catalyst include Marukaka catalyst (registered trademark) (manufactured by Nagase Sangyo Co., Ltd.).

Furthermore, the amount of the optically active phase transfer catalyst that can be used in the alkylation reaction is not particularly limited, and any amount can be set by those skilled in the art.

The medium that can be used for the alkylation reaction is not necessarily limited, but examples thereof include benzene, toluene, xylene, mesitylene, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, cyclopentyl methyl ether, and methyl t. -Butyl ether, as well as combinations thereof. Alternatively, the medium may be a two-phase medium of water and a medium that does not mix with water. The amount of medium used can be set arbitrarily by those skilled in the art.

Examples of inorganic bases that can be used in the alkylation reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, rubidium hydroxide, cesium hydroxide, and combinations thereof. Any amount of the inorganic base can be set by those skilled in the art.

In the above alkylation reaction, other reaction conditions can be arbitrarily set by those skilled in the art.

Alternatively, the compound represented by the formula (I) of the present invention has the following formula (V):

In a medium and in the presence of an inorganic base, the following formula (VI):

It can manufacture by making it react.

here,
In formulas (V) and (VI), R ¹ , R ² , R ³ , X ¹ , X ² , and Y each independently represent the same group as defined above, and Z ¹ is , A functional group having a leaving ability (for example, a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, or a fluorosulfonate group).

The compound of the above formula (V) and the compound of the formula (VI) are known per se and can be easily synthesized or obtained by those skilled in the art.

The medium that can be used for the reaction between the compound of formula (V) and the compound of formula (VI) is not necessarily limited. For example, benzene, toluene, xylene, mesitylene, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetic acid Examples include ethyl, isopropyl acetate, cyclopentyl methyl ether, and methyl t-butyl ether, and combinations thereof. The amount of medium used can be set arbitrarily by those skilled in the art.

Examples of inorganic bases that can be used in the reaction of the compound of formula (V) and the compound of formula (VI) include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, rubidium hydroxide, and cesium hydroxide. As well as combinations thereof. Any amount of the inorganic base can be set by those skilled in the art.

In the reaction between the compound of formula (V) and the compound of formula (VI), other reaction conditions can also be arbitrarily set by those skilled in the art.

Alternatively, the compound represented by the formula (I) of the present invention has the following formula (III):

A compound represented by the following formula (VII) in the medium and in the presence of an inorganic base together with an optically active phase transfer catalyst:

It can manufacture by alkylating with the compound represented by these.

here,
In formulas (III) and (VII), R ¹ , R ² , X ¹ , Y, A ¹ and A ² each independently represent a group similar to the group defined above, and Z ¹ is A functional group having a leaving ability (for example, a tosylate group, a mesylate group, a nonafluorobutanesulfonate group, a trifluoromethanesulfonate group, or a fluorosulfonate group).

Like the compound of the above formula (III), the compound of the formula (VII) is also known per se and can be easily synthesized or obtained by those skilled in the art.

Thus, the amino acid precursor represented by the formula (I) of the present invention can be produced.

(amino acid)
The amino acids of the invention can be represented by the following formula (II):

(Here, R ¹ , X ¹ , X ² , and Y each independently represent the same group as defined above).

Furthermore, in the present invention, the compound represented by the above formula (II) is represented by the following formula (II ′):

(Here, R ¹ , X ¹ , X ² , and Y each independently represent a group similar to the group defined above), and preferably has a three-dimensional structure. The amino acid of the formula (II ′) having such a structure can effectively function as an active ingredient of a PET diagnostic tracer as described later, for example.

(Amino acid production method)
The amino acid represented by the formula (II) of the present invention can be produced, for example, by hydrolyzing the amino acid precursor represented by the formula (I) of the present invention.

The reaction conditions that can be used for the hydrolysis are not particularly limited, and hydrolysis conditions that can be generally used in amino acid production can be arbitrarily selected by those skilled in the art.

In this way, the amino acid represented by the formula (II) of the present invention can be produced.

(PET diagnostic tracer)
The PET diagnostic tracer of the present invention contains an amino acid represented by the above formula (II).

In particular, among the amino acids represented by the above formula (II), the following formula (II ′):

(Here, R ¹ , X ¹ , X ² , and Y each independently represent a group similar to the group defined above), and preferably has a three-dimensional structure. Further, in the above formula (II) or formula (II ′), R ¹ is
A C ₁ -C ₅ alkyl group optionally substituted with a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₂ -C ₅ alkenyl group optionally substituted by a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₂ -C ₅ alkynyl group optionally substituted with a radioisotope ¹⁸ F, optionally having a branch or ring;
A C ₁ -C ₅ alkyloxy group optionally substituted with a radioisotope ¹⁸ F and optionally having a branch or ring;
A C ₂ -C ₈ alkoxyalkyloxy group optionally substituted by a radioisotope ¹⁸ F, optionally having a branch or ring;
Substituted with a radioactive isotope ^{18 F,} which may have a branched or cyclic C _{2 ~} C ₅ alkenyloxy group; or substituted with a radioactive isotope ^{18 F,} may be branched or cyclic A C ₃ -C ₅ alkynyloxy group;
R ¹ is more preferably a C ₁ -C ₅ alkyloxy group substituted with the radioactive isotope ¹⁸ F and optionally having a branch or a ring.

In the tracer of the present invention, the amino acid of the above formula (II) can be used as it is, but ascorbic acid or the like may be added together if necessary. The addition amount in that case is not particularly limited, and a person skilled in the art can set an arbitrary amount ratio.

Since the physicochemical half-life of the radioisotope is about 110 minutes, the tracer of the present invention is administered, for example, intravenously to a subject requiring diagnosis immediately after the production of the amino acid of the above formula (II). Can be administered. The dose is not necessarily limited, and any dose can be selected by those skilled in the art.

The scan time in PET diagnosis after administration is not particularly limited, and any scan time can be selected by those skilled in the art. The method and apparatus used for PET diagnosis are not particularly limited, and those known to those skilled in the art can be employed.

Thus, PET diagnosis can be performed using the compound represented by the formula (II) of the present invention. The compound of the present invention is inhibited from being taken up by normal cells and can be selectively taken up by tumor cells. Furthermore, the compounds of the present invention are amino acid transporters that are not involved in the glucose metabolism system and may include radioisotopes having a relatively long physicochemical half-life. For this reason, in PET diagnosis, the time restriction at the time of diagnosis than before is eased, and the conventional disadvantage that the background increases can be improved.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

In the following examples, unless otherwise specified, the measurement was performed under the following conditions: ¹ H NMR spectrum was JEOL JUM-FX400 NMR apparatus manufactured by JEOL Ltd. (400 MHz for ¹ H NMR). ) At room temperature and calibrated using SiMe ₄ (δ = 0 ppm) as an internal standard unless otherwise indicated. The following abbreviations were used to express multiplicity: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad.

Reference Example 1: Synthesis of (S) -N-tert-butoxycarbonyl-α-methyl- (3-hydroxy-4-iodo) phenylalanine tert-butyl ester

3-Hydroxy-4-iodobenzoic acid was methyl esterified in the presence of a sulfuric acid catalyst and then reacted with chloromethyl methyl ether in the presence of potassium carbonate to protect the phenolic hydroxyl group with a methoxymethyl group. This was reduced with diisobutylaluminum hydride in a solvent of tetrahydrofuran, and the resulting alcohol was brominated via methanesulfonylation to obtain 3-methoxymethoxy-4-iodobenzylbromide. This is reacted with N-benzylidenealanine tert-butyl ester in the presence of (R) -Maruoka catalyst (registered trademark; manufactured by Nagase Sangyo Co., Ltd .; (CAS: 887938-70-7)), using an aqueous citric acid solution. N-benzylidene was deprotected to synthesize (S) -α-methyl- (3-methoxymethoxy-4-iodo) phenylalanine tert-butyl ester.

This was deprotected by adding 6N aqueous hydrochloric acid solution in methanol solvent and stirring, and reacted with di-tert-butyl dicarbonate in tetrahydrofuran solvent to give (S) -N-tert-butoxycarbonyl. -Α-Methyl- (3-hydroxy-4-iodo) phenylalanine tert-butyl ester was obtained.

Example 1: Synthesis of (S) -N-tert-butoxycarbonyl-α-methyl- {3- (2-tosyloxyethoxy) -4-iodo} phenylalanine tert-butyl ester

To (S) -N-tert-butoxycarbonyl-α-methyl- (3-hydroxy-4-iodo) phenylalanine tert-butyl ester (2.86 g, 6 mmol) synthesized in Reference Example 1, acetonitrile 29 mL, 1, 2, -Bistosyloxyethane (6.67 g, 18 mmol) and potassium carbonate (1.66 g, 12 mmol) were added and stirred for 15 hours under heating to reflux. To this, 30 mL of ethyl acetate and 30 mL of water were added for liquid separation, and the organic layer was concentrated. To the concentrated residue, 30 mL of MTBE was added and stirred for 1 hour, and then the insoluble matter was filtered off. The filtrate was concentrated and purified by silica gel column chromatography, and (S) -N-tert-butoxycarbonyl-α-methyl- {3- (2-tosyloxyethoxy) -4-iodo} phenylalanine tert-butyl ester ( 2.27 g, 61% yield).

The NMR spectrum of the obtained compound was as follows.

Reference Example 2: Synthesis of (S) -N-benzylidene-α-methyl- {3- (2-fluoroethoxy) -4-iodo} phenylalanine tert-butyl ester

Methyl 3-hydroxy-4-iodobenzoate was reacted with 1-fluoro-2-tosyloxyethane in the presence of potassium carbonate and reduced with diisobutylaluminum hydride in a tetrahydrofuran solvent. The resulting alcohol was then brominated with phosphorus tribromide to synthesize 3- (2-fluoroethoxy) -4-iodobenzyl bromide.

Example 2: Synthesis of (S) -α-methyl- {3- (2-fluoroethoxy) -4-iodo} phenylalanine tert-butyl ester

3- (2-Fluoroethoxy) -4-iodobenzyl bromide (7.98 g, 20 mmol) was added to (R) -Maruka catalyst (registered trademark; manufactured by Nagase Sangyo Co., Ltd .; (CAS: 887938-70-7)) ( 74.9 mg, 0.1 mmol), N-benzylidenealanine tert-butyl ester (5.60 g, 24 mmol), and 40 mL of toluene were added, and 80% aqueous cesium hydroxide solution (22.5 g, 120 mmol) was added under ice cooling. And stirred for 13 hours under ice-cooling. Subsequently, 40 mL of water and 40 mL of ethyl acetate are added thereto for liquid separation, the organic layer is concentrated, and (S) -N-benzylidene-α-methyl- {3- (2-fluoroethoxy) -4- Iodo} phenylalanine tert-butyl ester was obtained.

Next, 40 mL of tetrahydrofuran and 30 mL of 2N hydrochloric acid aqueous solution were added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution was decompressed and tetrahydrofuran was distilled off, and then 50 mL of MTBE was added. The organic layer was separated, the aqueous layer was washed twice with 20 mL of MTBE, and 10 mL of 8N aqueous sodium hydroxide and 50 mL of MTBE were added to the aqueous layer, respectively. The aqueous layer was separated, the organic layer was washed with 50 mL of water, the organic layer was concentrated under reduced pressure, and (S) -α-methyl- {3- (2-fluoroethoxy) -4-iodo} phenylalanine tert-butyl ester A crude product of 7.28 g was obtained. This crude product was purified by silica gel column chromatography to obtain (S) -α-methyl- {3- (2-fluoroethoxy) -4-iodo} phenylalanine tert-butyl ester (5.84 g, yield 69%). Obtained.

The NMR spectrum of the obtained compound was as follows.

Example 3: Synthesis of (S) -α-methyl- {3- (2-fluoroethoxy) -4-iodo} phenylalanine

To (S) -α-methyl- {3- (2-fluoroethoxy) -4-iodo} phenylalanine tert-butyl ester (5.50 g, 13 mmol) obtained in Example 2, 20 mL of 4N hydrochloric acid aqueous solution was added. And stirred at 80 ° C. for 10 hours. The reaction mixture was cooled to room temperature, and 1N aqueous sodium hydroxide solution was added until the pH reached 6-7. The precipitated crystals were collected by filtration and washed 3 times with 5.5 mL of water. The obtained white crystals were dried in warm air at 40 ° C. to obtain the desired (S) -α-methyl- {3- (2-fluoroethoxy) -4-iodo} phenylalanine (2.54 g, yield 53%). Obtained.

The NMR spectrum of the obtained compound was as follows.

Reference Example 3: Synthesis of (S) -α-methyl- {4- (2-fluoroethoxy)} phenylalanine tert-butyl ester

(S) -α-methyl-tyrosine is methylesterified with thionyl chloride and reacted with di-tert-butyl dicarbonate in tetrahydrofuran in the presence of triethylamine to give (S) -N-tert-butoxycarbonyl-α -Methyl-tyrosine methyl ester was obtained. This is reacted with 1-fluoro-2-tosyloxyethane in the presence of potassium carbonate to give (S) -N-tert-butoxycarbonyl-α-methyl- {4- (2-fluoroethyl) } Phenylalanine methyl ester was obtained.

Example 4: Synthesis of (S) -α-methyl- {4- (2-fluoroethoxy)} phenylalanine tert-butyl ester

To (S) -N-tert-butoxycarbonyl-α-methyl- {4- (2-fluoroethyl)} phenylalanine methyl ester (124 mg, 0.35 mmol) obtained in Reference Example 3, 2 mL of acetonitrile was added. A solution was prepared and N-iodosuccinimide (95 mg, 0.42 mmol) was added and stirred at room temperature for 4 days, then at 60 ° C. for 8 hours. 20 mL of ethyl acetate and 10 mL of saturated aqueous sodium sulfite solution were added, the aqueous layer was separated, the organic layer was concentrated under reduced pressure, and (S) -N-tert-butoxycarbonyl-α-methyl- {3-iodo-4- ( 2-Fluoroethyl)} phenylalanine methyl ester (135 mg, 80% yield) was obtained.

The NMR spectrum of the obtained compound was as follows.

(Example 5: Synthesis of (S) -α-methyl- {3-iodo-4- (2-fluoroethoxy)} phenylalanine)

The (S) -N-tert-butoxycarbonyl-α-methyl- {3-iodo-4- (2-fluoroethyl)} phenylalanine methyl ester (72 mg, 0.15 mmol) obtained in Example 4 was added to 1 mL of methanol. And 1.5 mL of 1N aqueous potassium hydroxide solution were added, and the mixture was stirred at room temperature for 8 days. After confirming disappearance of the raw material by TLC, methanol was distilled off under reduced pressure, and 3 mL of 1N aqueous hydrochloric acid solution and 5 mL of MTBE were added and separated. The organic layer was concentrated to give (S) -N-tert-butoxycarbonyl-α-methyl- {3-iodo-4- (2-fluoroethyl)} phenylalanine. 1 mL of methanol and 1.2 mL of concentrated hydrochloric acid were added thereto, and the mixture was stirred at 80 ° C. for 16 hours. The reaction solution is diluted by adding 5 mL of water and 3 mL of acetonitrile, and then subjected to preparative purification by HPLC to obtain the target (S) -α-methyl- {3-iodo-4- (2-fluoroethoxy)} phenylalanine. (6.0 mg, 9% yield).

The NMR spectrum of the obtained compound was as follows.

(Example 6: Synthesis of (S) -α-methyl- {3-bromo-4- (2-fluoroethoxy)} phenylalanine)

(S) -N-tert-butoxycarbonyl-α-methyl- {3-bromo-4- (2-fluoroethyl)} phenylalanine methyl ester was synthesized according to Example 4, and this was prepared according to Example 5. Synthesis is carried out, and (S) -α-methyl- {3- is synthesized via (S) -N-tert-butoxycarbonyl-α-methyl- {3-iodo-4- (2-fluoroethyl)} phenylalanine. Bromo-4- (2-fluoroethoxy)} phenylalanine (18.6 mg) was obtained.

The NMR spectrum of the obtained compound was as follows.

(Example 7: Synthesis of (S) -α-methyl- {3- (2-fluoroethoxy)} phenylalanine)

According to Reference Example 3, (S) -N-tert-butoxycarbonyl-α-methyl- {3- (2-fluoroethoxy)} phenylalanine ethyl ester was synthesized, which was synthesized according to Example 5 (S) Synthesized via —N-tert-butoxycarbonyl-α-methyl- {3- (2-fluoroethoxy)} phenylalanine and purified by crystallization instead of HPLC preparative purification to give (S) -α -Methyl- {3- (2-fluoroethoxy)} phenylalanine (45 mg) was obtained.

The NMR spectrum of the obtained compound was as follows.

(Example 8: Synthesis of (S) -α-methyl- {3- (2-fluoroethoxy) -4-bromo} phenylalanine)

(S) -N-tert-butoxycarbonyl-α-methyl- {3- (2-fluoroethoxy)} phenylalanine ethyl ester is brominated with N-bromosuccinimide according to Example 6 to give (S) -N -Tert-Butoxycarbonyl-α-methyl- {3- (2-fluoroethoxy) -4-bromo} phenylalanine ethyl ester was synthesized and subsequently subjected to ester hydrolysis reaction and deprotection reaction under acidic conditions Purification by crystallization gave (S) -α-methyl- {3- (2-fluoroethoxy) -4-bromo} phenylalanine (81 mg).

The NMR spectrum of the obtained compound was as follows.

(Example 9: Synthesis of (S) -α-methyl- {3- (2-fluoroethoxy) -4-bromo} phenylalanine)

By synthesizing 3- (2-fluoroethoxy) -5-bromobenzyl bromide according to Reference Example 2, and subjecting it to a reaction using Maruoka catalyst (registered trademark) according to Example 2, (S ) -Α-methyl- {3- (2-fluoroethyl) -5-bromo} phenylalanine tert-butyl ester was obtained, and further tert-butyl ester was removed using concentrated hydrochloric acid instead of the 4N aqueous hydrochloric acid solution of Example 3. After purification by HPLC fractionation, (S) -α-methyl- {3- (2-fluoroethyl) -5-bromo)} phenylalanine (43 mg) was obtained.

The NMR spectrum of the obtained compound was as follows.

Reference Example 4: Synthesis of 3-iodo-4- (2-fluoroethyl) benzyl bromide

4-Vinylbenzoic acid was methyl esterified with methyl iodide under basic conditions, and the vinyl group was converted to a hydroxyethyl group by hydroboration and hydroxylation. Next, the hydroxyl group is fluorinated with N, N-diethylaminosulfur trifluoride, the ester is reduced with diisobutylaluminum hydride in tetrahydrofuran solvent, and the resulting benzyl alcohol is reacted with phosphorus tribromide in chloroform. To give 3-iodo-4- (2-fluoroethyl) benzyl bromide.

(Example 10: Synthesis of (S) -α-methyl- {3-iodo-4- (2-fluoroethyl)} phenylalanine)

3-Iodo-4- (2-fluoroethyl) benzyl bromide (0.17 g, 0.5 mmol) obtained in Reference Example 4 was added to (R) -Marukaka catalyst (registered trademark; manufactured by Nagase Sangyo Co., Ltd.) (CAS : 887938-70-7)) (2.2 mg, 3 μmol), N-benzylidenealanine tert-butyl ester (0.18 g, 0.75 mmol), and 2 mL of toluene were added, and 80% hydroxylation was performed under ice cooling. A cesium aqueous solution (1.1 g, 6 mmol) was added, and the mixture was stirred for 20 hours under ice cooling. 10 mL of water and 10 mL of ethyl acetate were added thereto for liquid separation, the organic layer was concentrated, and (S) -N-benzylidene-α-methyl- {3-iodo-4- (2-fluoroethyl) as a residue } Phenylalanine tert-butyl ester was obtained as a crude product (0.45 g). To this were added 10 mL of tetrahydrofuran and 5 mL of 1N aqueous hydrochloric acid, and the mixture was stirred at room temperature for 3 hours. The reaction solution was decompressed, tetrahydrofuran was distilled off, and 10 mL of water and 10 mL of MTBE were added thereto. The organic layer was separated, the aqueous layer was washed twice with 10 mL of MTBE, and 1 mL of 8N aqueous sodium hydroxide and 20 mL of MTBE were added to the aqueous layer, respectively. The aqueous layer was separated, the organic layer was washed with 10 mL of water, the organic layer was concentrated under reduced pressure, and (S) -α-methyl- {3-iodo-4- (2-fluoroethyl)} phenylalanine tert-butyl ester Crude product (0.16 g) was obtained.

This was synthesized according to Example 3 using 95% aqueous trifluoroacetic acid instead of 4N aqueous hydrochloric acid, followed by HPLC preparative purification instead of crystallization purification, and (S) -α-methyl- {3-Iodo-4- (2-fluoroethyl)} phenylalanine (90 mg) was obtained.

The NMR spectrum of the obtained compound was as follows.

(Example 11: Synthesis of (S) -α-methyl- {4-iodo-3- (2-fluoroethyl)} phenylalanine)

Using 4-iodo-3- (2-fluoroethyl) benzyl bromide (0.17 g, 0.5 mmol) obtained according to Reference Example 4 and using Marukaka catalyst (registered trademark) in the same manner as in Example 10. The product was subjected to deprotection reaction, deprotection reaction, and purified by HPLC fractionation to obtain (S) -α-methyl- {4-iodo-3- (2-fluoroethyl)} phenylalanine (21 mg).

The NMR spectrum of the obtained compound was as follows.

(Reference Example 5: Synthesis of 3-iodo-1,4-bisbromomethylbenzene)

3-Bromoterephthalic acid was reacted with copper iodide in a pyridine solvent to replace bromine with iodine to obtain 3-iodoterephthalic acid. This 3-iodoterephthalic acid was reduced with a borane dimethyl sulfide complex in a tetrahydrofuran solvent at 0 ° C. to obtain 3-iodo-1,4-bishydroxymethylbenzene.

Further, this 3-iodo-1,4-bishydroxymethylbenzene was brominated with chloroform tribromide in chloroform to synthesize 3-iodo-1,4-bisbromomethylbenzene.

(Example 12: Synthesis of (S) -α-methyl- (3-iodo-4-fluoromethyl) phenylalanine)

To the 3-iodo-1,4-bishydroxymethylbenzene (0.51 g, 1.3 mmol) obtained in Reference Example 5, (R) -Marukaka catalyst (registered trademark; manufactured by Nagase Sangyo Co., Ltd.) (CAS: 887938) -70-7)) (4.5 mg, 6 μmol), N-benzylidenealanine tert-butyl ester (0.28 g, 1.2 mmol), and 6 mL of toluene were added, and an 80% aqueous cesium hydroxide solution was added under ice cooling. (1.8 g, 9.6 mmol) was added and stirred at 0 ° C. for 30 hours. 10 mL of water and 10 mL of ethyl acetate were added and separated, and the organic layer was concentrated to obtain 0.72 g of residue. This residue was dissolved in 10 mL of tetrahydrofuran, 10 mL of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride was added, and the mixture was stirred for 38 hours under reflux with heating. After cooling to room temperature, tetrahydrofuran was distilled off under reduced pressure, and 20 mL of water and 20 mL of MTBE were added and separated. The organic layer was washed 3 times with 20 mL of water, the organic layer was concentrated, and a crude product of (S) -N-benzylidene-α-methyl- (3-iodo-4-fluoromethyl) phenylalanine tert-butyl ester (0. 45 g) was obtained. To this residue, 3 mL of MTBE and 3 mL of 5N aqueous hydrochloric acid were added, and the mixture was stirred at room temperature for 24 hours. The layers were separated, the aqueous layer was washed twice with 3 mL of MTBE, the aqueous layer was warmed to 60 ° C., and stirred at 60 ° C. for 5 hours. Then, it was cooled to room temperature, and the reaction solution was washed twice with 5 mL of MTBE. The aqueous layer is diluted with 5 mL of water and 3 mL of acetonitrile, and subjected to preparative purification by HPLC to obtain the desired (S) -α-methyl- (3-iodo-4-fluoromethyl) phenylalanine (8. 8 mg) was obtained.

The NMR spectrum of the obtained compound was as follows.

(Example 13: Synthesis of (S) -α-methyl- (4-iodo-3-fluoromethyl) phenylalanine)

4-Iodo-1,3-dimethylbenzene was subjected to radial bromination with N-bromosuccinimide in a cyclohexane solvent to obtain 4-iodo-1,3-bisbromomethylbenzene. This 4-iodo-1,3-bisbromomethylbenzene (0.51 g, 1.3 mmol) was subjected to the reaction by Maruoka catalyst (registered trademark) in the same manner as in Example 12, and the fluorination reaction and desorption at the benzyl position were performed. A protection reaction was performed, and the desired (S) -α-methyl- (4-iodo-3-fluoromethyl) phenylalanine (9.2 mg) was obtained by preparative purification by HPLC.

The NMR spectrum of the obtained compound was as follows.

Reference Example 6 Synthesis of 2-iodo-3- (2-fluoroethyl) benzyl bromide

2-Iodo-phenylacetic acid was reduced with borane dimethyl sulfide complex in a tetrahydrofuran solvent to obtain 2- (2-iodophenyl) ethanol. This was reacted with bis (2-methoxyethyl) aminosulfur trifluoride in a chloroform solvent to fluorinate to obtain 2- (2-fluoroethyl) iodobenzene. This 2- (2-fluoroethyl) iodobenzene was reacted with paraformaldehyde in 47% bromic acid to carry out bromomethylation to obtain 2-bromo-3- (2-fluoroethyl) benzyl bromide.

(Example 14: Synthesis of (S) -α-methyl- {2-iodo-3- (2-fluoroethyl)} phenylalanine)

2-Iodo-3- (2-fluoroethyl) benzyl bromide (0.17 g, 0.5 mmol) obtained in Reference Example 6 was subjected to a reaction with Maruka catalyst (registered trademark) in the same manner as in Example 10. The obtained (S) -N-benzylidene-α-methyl- {2-iodo-3- (2-fluoroethyl)} phenylalanine tert-butyl ester is treated with a 1N aqueous hydrochloric acid solution at room temperature to remove the benzylidene moiety. A protective reaction was carried out, followed by a tert-butyl reaction by heating to 60 ° C. in a 4N aqueous hydrochloric acid solution, and the resulting reaction solution was fractionated and purified by HPLC to obtain (S) -α-methyl- {2-Iodo-3- (2-fluoroethyl)} phenylalanine (28.9 mg) was obtained.

The NMR spectrum of the obtained compound was as follows.

Example 15 Synthesis of (S) -α-methyl-3-fluoromethoxyphenylalanine

According to Example 7, (S) -N-tert-butoxycarbonyl-α-methyl-3-hydroxyphenylalanine ethyl ester (48 mg, 0.15 mmol) was fluoromethylated with bromofluoromethane to give (S)- N-tert-butoxycarbonyl-α-methyl- (3-fluoromethoxy) phenylalanine ethyl ester was obtained. Subsequently, this was hydrolyzed with an aqueous sodium hydroxide solution, subjected to deprotection under acidic conditions, and then subjected to preparative purification by HPLC to obtain (S) -α-methyl-3-fluoromethoxyphenylalanine (0.9 mg )

The NMR spectrum of the obtained compound was as follows.

(Example 16: Synthesis of (S) -α-methyl-4-fluoromethoxyphenylalanine)

According to Reference Example 3, (S) -α-methyltyrosine methyl ester was protected with a benzyloxycarbonyl group, and fluoromethylation of the phenol moiety with fluoromethyltosyl was carried out to obtain (S) -N-benzyl. Oxycarbonyl-α-methyl-4-fluoromethoxyphenylalanine methyl ester was obtained. This was subjected to ester hydrolysis according to Example 5, followed by deprotection by hydrogenation of the benzyloxycarbonyl group, and fractionated purification by HPLC to obtain (S) -α-methyl-4-fluoromethoxy. Phenylalanine (8.5 mg) was obtained.

The NMR spectrum of the obtained compound was as follows.

Reference Example 7: Synthesis of (S) -N-tert-butoxycarbonyl-α-methyl- {2,5-dibromo-4- (2-hydroxyethyl)} phenylalanine tert-butyl ester

According to Reference Example 4, methyl 4- (2-hydroxyethyl) benzoate is allowed to react with 1,3-dibromo-1,3,5-triazine-2,4,6-trione in a 70% aqueous sulfuric acid solution. To give methyl 2,5-dibromo-4- (2-hydroxyethyl) benzoate. This was protected with a methoxymethyl group by reaction with chloromethyl methyl ether in the presence of diisopropylethylamine in a toluene solvent.

This is then reduced with diisobutylaluminum hydride in tetrahydrofuran solvent to give 2,5-dibromo-4- (2-methoxymethoxyethyl) benzyl alcohol in the presence of triethylamine in dichloromethane solvent. The mesylation is carried out by reacting with methanesulfonic acid chloride, 2,5-dibromo-4- (2-methoxymethoxyethyl) benzyl bromide is obtained by replacing the solvent with tetrahydrofuran and reacting with lithium bromide. It was.

This 2,5-dibromo-4- (2-methoxymethoxyethyl) benzyl bromide was prepared using N of (R) -Marukaka catalyst (registered trademark; manufactured by Nagase Sangyo Co., Ltd .; (CAS: 887938-70-7)). -Asymmetric alkylation reaction of benzylidenealanine tert-butyl ester under phase transfer catalytic conditions is carried out. After completion of the reaction, the solvent is replaced with methanol, and concentrated hydrochloric acid is added to remove the benzylidene moiety and methoxymethyl group. Deprotection gave (S) -α-methyl- {2,5-dibromo-4- (2-hydroxyethyl)} phenylalanine tert-butyl ester.

This is reacted with ditert-butyl dicarbonate in tetrahydrofuran solvent to give (S) -N-tert-butoxycarbonyl-α-methyl- {2,5-dibromo-4- (2-hydroxyethyl)} Phenylalanine tert-butyl ester was obtained.

Example 17: Synthesis of (S) -α-methyl- {2,5-dibromo-4- (2-fluoroethyl)} phenylalanine

(S) -N-tert-butoxycarbonyl-α-methyl- {2,5-dibromo-4- (2-hydroxyethyl)} phenylalanine tert-butyl ester (0.53 g, 1. 0 mmol) was added with 5 mL of pyridine and paratoluenesulfonic acid chloride (2.11 g, 1.1 mmol), and the mixture was stirred at 0 ° C. for 12 hours. Water (20 mL) and ethyl acetate (20 mL) were added for liquid separation, the organic layer was concentrated, and the concentrated residue was purified by silica gel column chromatography to obtain (S) -N-tert-butoxycarbonyl-α-methyl- { 2,5-Dibromo-4- (2-tosyloxyethyl)} phenylalanine tert-butyl ester (0.30 g, 0.43 mmol) was obtained in 43% yield.

This (S) -N-tert-butoxycarbonyl-α-methyl- {2,5-dibromo-4- (2-tosyloxyethyl)} phenylalanine tert-butyl ester (50 mg, 67 μmol) was dissolved in t-butanol solvent. , 18-crown-6-ether as a phase transfer catalyst and reacted with potassium fluoride to give (S) -N-tert-butoxycarbonyl-α-methyl- {2,5-dibromo-4- (2 -Fluoroethyl)} phenylalanine tert-butyl ester, then deprotected by stirring with 95% aqueous trifluoroacetic acid at room temperature for 2 hours, concentrated under reduced pressure, and 7 mL of water and 3 mL of acetonitrile were added to the concentrated residue. And diluted with HPLC, and subjected to preparative purification by HPLC to obtain the desired (S) -α-methyl- {2,5- Mo-4- (2-fluoroethyl)} phenylalanine (2.3 mg, 16% yield).

The NMR spectrum of the obtained compound was as follows.

(Example 18)
Compounds 1 to 21 shown below were synthesized according to Reference Examples 1 to 7 and Examples 1 to 17, respectively. The obtained compound and NMR spectrum are shown below.

(Example 19: Synthesis of radioactive compound (1))

The following synthesis was performed through an automatic synthesizer.

Cyclotron; at (CYPRIS HW-12S manufactured by Sumitomo Heavy Industries, Industrial ^Co.), [18 O] from _{^{H 2 O, [18 F]}} F - was synthesized, anion exchange resin (SepPak Light Accell plus QMA anion exchange cartridge ; manufactured by Waters Co.) ^was used to remove the [18 O] _{H 2} O.

A solution containing [ ¹⁸ F] F ⁻ eluted from the cartridge is received in a reaction vessel, and a mixture of acetonitrile (700 μL) and 0.21 M potassium carbonate aqueous solution (200 μL) is mixed with Cryptofix 2.2.2 (Merck a solution of Millipore Japan Co.) (22 mg), in the same manner as described above was added to the reaction vessel through the cartridge, ^[18 F] of about 9.0GBq F ^- solution was prepared. The obtained solution was concentrated under reduced pressure at 100 ° C. for 5 minutes, then acetonitrile (1000 μL) was added, and azeotropic dehydration was performed at 100 ° C. for 6 minutes.

Thereafter, (S) -N-tert-butoxycarbonyl-α-methyl- {3- (2-tosyloxyethoxy)-obtained in Example 1 was dissolved in acetonitrile (500 μL) in a cooled reaction vessel. 4-Iodo} phenylalanine tert-butyl ester (A) (12 mg) was added and heated at 110 ° C. for 10 minutes. Then, 2N hydrochloric acid aqueous solution (500 μL) was added and heated at 120 ° C. for 10 minutes. Then, 2N aqueous sodium hydroxide solution (1000 μL) was added and left at room temperature for 1 minute. The obtained contents were injected into a semi-preparative column (Cosmosil 5C18-AR-II, 20 mm id × 250 mm, detector: UV, γ-ray) and eluted under isocratic conditions. The organic solvent was concentrated under reduced pressure at 150 ° C. from the fraction containing the target product, and (S) -3- [ ¹⁸ F] fluoroethoxy-4-iodophenylalanine (0.013 mg) (hereinafter referred to as “[ ¹⁸ F] Compound 7”). I got).

The obtained [ ¹⁸ F] compound 7 was confirmed to have a radiochemical purity and a chemical purity by HPLC of 99.0% or more, respectively. This [ ¹⁸ F] compound 7 (0.013 mg) was dissolved in 2 mL of brine and subjected to the following PET experiment.

(Example 20: Synthesis of radioactive compound (2))
Example instead of (S) -N-tert-butoxycarbonyl-α-methyl- {3- (2-tosyloxyethoxy) -4-iodo} phenylalanine tert-butyl ester (A) obtained in Example 1 (S) -N-tert-butoxycarbonyl-α-methyl- {4- (2-tosyloxyethoxy) -3-iodo} phenylalanine tert-butyl ester (A) (12 mg) obtained in 18 was used. Except for the above, (S) -4- [ ¹⁸ F] fluoroethoxy-3-iodophenylalanine (0.016 mg) (hereinafter referred to as “[ ¹⁸ F] Compound 3”) was obtained in the same manner as Example 19.

The obtained [ ¹⁸ F] compound 3 was confirmed to have a radiochemical purity and a chemical purity by HPLC of 99.0% or more, respectively. This [ ¹⁸ F] compound 3 (0.016 mg) was dissolved in 2 mL of saline and subjected to the following PET experiment.

(Example 21: Synthesis of radioactive compound (3))
Example instead of (S) -N-tert-butoxycarbonyl-α-methyl- {3- (2-tosyloxyethoxy) -4-iodo} phenylalanine tert-butyl ester (A) obtained in Example 1 (S) -N-tert-butoxycarbonyl-α-methyl- {4- (2-tosyloxyethyl) -3-iodo} phenylalanine tert-butyl ester (A) (12 mg) obtained in 18 was used. Except for the above, (S) -4- [ ¹⁸ F] fluoroethyl-3-iodophenylalanine (0.011 mg) (hereinafter referred to as “[ ¹⁸ F] Compound 1”) was obtained in the same manner as Example 19.

The obtained [ ¹⁸ F] compound 1 was confirmed to have radiochemical purity and chemical purity by HPLC, which were 99.9% and 76.2%. This [ ¹⁸ F] Compound 1 (0.011 mg) was dissolved in 2 mL of saline and subjected to the following PET experiment.

(Comparative Example 1: Synthesis of radioactive compound (4))
[ ¹¹ C] methyl iodide was prepared according to known methods (J. Nucl. Med., 1987, 28, 1037).

N-benzylidene (4-methoxymethoxy) phenylalanine tert-butyl ester (10.43 mg, 76% toluene solution) and (S) -Maruoka catalyst (8.1 mg, manufactured by Nagase Sangyo Co., Ltd.) as raw materials were added to anhydrous toluene. Then, 80% cesium hydroxide (1.6 g) was added dropwise under ice cooling. After stirring for 1 hour, [ ¹¹ C] methyl iodide prepared at the time of use was bubbled into the reaction solution. After stirring at 0 ° C. for 10 minutes, it was quenched with water (1.0 mL). After separating the lower layer, a 5N aqueous hydrochloric acid solution (0.5 mL) was added to the upper layer, and the mixture was heated at 100 ° C. for 5 minutes while bubbling nitrogen. After cooling the reaction solution, the aqueous layer was separated, water (0.4 mL) was added and re-extraction was performed. The resulting solution was fractionated by semi-preparative HPLC (Cosmosil HILIC (manufactured by Nacalai Tesque), 20 mm id x 250 mm) (sorting conditions: acetonitrile: 100 mM ammonium acetate (85:15 (volume ratio)). ), UV detector (230 nm), RI detector (γ-ray)). The obtained fraction was concentrated at 150 to 200 ° C. under reduced pressure to obtain (S) -α- [ ¹¹ C] methyltyrosine (0.010 mg) (hereinafter referred to as “[ ¹¹ C] α-Me-Tyr”). It was.

The obtained [ ¹¹ C] α-Me-Tyr was confirmed to have radiochemical purity and chemical purity by HPLC, which were 99.9% and 81.3%. This [ ¹¹ C] α-Me-Tyr (0.010 mg) was dissolved in 2 mL of saline and subjected to the following PET experiment.

(Comparative Example 2: Synthesis of radioactive compound (5))
In place of (S) -N-tert-butoxycarbonyl-α-methyl- {3- (2-tosyloxyethoxy) -4-iodo} phenylalanine tert-butyl ester (A) obtained in Example 1 In the same manner as in Example 19 except that (S) -N-triphenylmethyl-4- (2-tosyloxyethoxy) phenylalanine tert-butyl ester (A) (12 mg) synthesized by the method was used, ¹⁸ F] -fluoroethoxyphenylalanine (0.005 mg) (hereinafter referred to as “[ ¹⁸ F] FET”) was obtained.

The obtained [ ¹⁸ F] FET was confirmed to have radiochemical purity and chemical purity by HPLC, which were 99.3% and 99.0% or higher. This [ ¹⁸ F] FET (0.005 mg) was dissolved in 2 mL of saline and subjected to the following PET experiment.

(Comparative Example 3: Synthesis of radioactive compound (6))
In the same manner as in Comparative Example 1, except that N-benzylidenephenylalanine tert-butyl ester (10 mg) was used instead of N-benzylidene (4-methoxymethoxy) phenylalanine tert-butyl ester used in Comparative Example 1, (S) -α- [ ¹¹ C] phenylalanine (0.031 mg) (hereinafter referred to as “[ ¹¹ C] α-Me-Phe”) was obtained.

The obtained [ ¹¹ C] α-Me-Phe was confirmed to have a radiochemical purity and a chemical purity by HPLC of 99.9%, respectively. This [ ¹⁸ F] FET (0.031 mg) was dissolved in 2 mL of brine and subjected to the following PET experiment.

(Comparative Example 4: Synthesis of radioactive compound (7))
L-homocysteine thiolactone hydrochloride (15 mg) was mixed with 1 mL of a (1: 1) solution of sodium hydroxide and ethanol at room temperature. 0.4 mL of this mixture was injected into a Sep-Pack Plus C18 cartridge (Waters). [ ¹¹ C] methyl iodide prepared at the time of use in a C18 cartridge was collected at 200 mL / min for 4 minutes. Immediately after collection, the reaction product was washed from the C18 cartridge with 3 mL of 0.5% acetic acid solution for neutralization, collected in a rotary evaporator flask, and excess acetic acid was concentrated under reduced pressure at 150 ° C. together with the solvent. - methyl - ^[11 C] - methionine (hereinafter, "that ^[11 C] MET") was obtained.

The obtained [ ¹¹ C] MET was confirmed to have a radiochemical purity by HPLC of 99.5% or more. This [ ¹¹ C] MET was dissolved in 6 mL of saline and subjected to the following PET experiment.

(Example 22: PET experiment using radioactive compound)
LNZ308 (human glioblastoma cell line (provided by Kyorin University)) was transplanted to the right forelimb root of an 8-week-old female mouse (BALB / c nu / nu; Claire Japan) (5 × 10 ⁶ / 100 μL (sc)), and after 16 weeks of age, the left forelimb root was treated with terpentine oil (50 μL (im)) 72 hours before the experiment.

For the mouse, the compound obtained in Example 19 ([ ¹⁸ F] Compound 7), the compound obtained in Example 20 ([ ¹⁸ F] Compound 3), the compound obtained in Example 21 ([ ¹⁸ F] Compound 1), the compound obtained in Comparative Example 1 ([ ¹¹ C] α-Me-Tyr), the compound obtained in Comparative Example 2 ([ ¹⁸ F] FET), the compound obtained in Comparative Example 3 ( Each of [ ¹¹ C] α-Me-Phe) and the compound obtained in Comparative Example 4 ([ ¹¹ C] MET) was needles placed in the tail vein based on a dose of 7.4 MBq / 100 μL. By administration. Next, 1.5% isoflurane anesthesia was performed using an animal anesthesia machine NS-5000A (manufactured by Acoma Medical Industry Co., Ltd.), and 37.5 using a body temperature maintaining apparatus for small animals (manufactured by Bioresearch Center Co., Ltd.). The body temperature was maintained at 0 ° C., and PET diagnosis was performed using a PET device for small animals, microPET Focus220 (manufactured by Siemens). The scan time was 90 minutes.

The results obtained are shown in FIG. 1 for tumor tracer comparison and in FIG. 2 for bladder tracer comparison. 1 and 2, the vertical axis (SUV mean) of each graph indicates the degree of PET tracer accumulation in each organ, and the higher the value, the greater the degree of accumulation in the organ.

As shown in FIG. 1 and FIG. 2, in particular, the compound obtained in Example 19 ([ ¹⁸ F] Compound 7) is administered to the bladder over time because a part thereof is excreted into the bladder after administration. The value of SUVmean increased (Fig. 2), and the tumor reached a plateau from about 3000 seconds after increasing gradually after administration. This indicates that the compound obtained in Example 19 ([ ¹⁸ F] Compound 7) accumulates in the tumor as a good PET tracer and stays without being excreted. In addition, although the compound obtained in Example 20 ([ ¹⁸ F] Compound 3) shows an increase after administration to the tumor (FIG. 1), a gradual decrease tendency is observed, so the value of the SUV mean of the tumor is low. It was. On the other hand, a difference is observed in comparison with the bladder (FIG. 2), and it can be seen that it can be used as a PET tracer for tumor diagnosis.

Using the above diagnosis results, the ratio of the SUV value of the tumor part to the SUV value of normal tissues (muscles) of the same individual using each of the compounds of Examples 19 to 21 and Comparative Examples 1 to 4, The “tumor / muscle” value was calculated by quantifying the maximum uptake value (SUVmax) in the tumor and normal muscle from an image created by adding data from 5 minutes to 90 minutes after administration. The obtained results are shown in Table 22.

As shown in Table 22, the compounds obtained in the examples of the present invention were compared with the normal [ ¹⁸ F] FET of Comparative Example 2, which is also known as a tracer compound. It was also found that the ability to accumulate in the tumor was excellent. Furthermore, [ ¹⁸ F] compound 7 obtained in Example 19 is particularly excellent in the ability to accumulate in tumors, and is found to be particularly useful as a PET diagnostic tracer.

According to the present invention, it is possible to provide an amino acid and a precursor thereof, and a method for producing them, in which uptake into normal cells is suppressed and can be selectively taken up into tumor cells. Since the compound of the present invention can incorporate any radioactive isotope into its structure, it can provide a compound having a relatively long physicochemical half-life. Thereby, it is useful as, for example, a PET diagnostic tracer or a building block of a pharmaceutical intermediate.

Claims

The compound represented by the following formula (I):

here,
R 1 is
C 1 -C 5 alkyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C 2 -C 5 alkenyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C 2 -C 5 alkynyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability Group;
C 1 -C 5 alkyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An oxy group;
C 2 -C 8 alkoxy optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An alkyloxy group;
C 2 -C 5 alkenyl optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability An oxy group; or C 3 optionally having a branch or ring substituted with at least one group selected from the group consisting of a halogen atom which may be a radioisotope and a functional group having a leaving ability ~ C 5 alkynyloxy group;
And
R 2 and R 3 are each independently
Hydrogen atom;
A C 1 -C 8 alkyl group which may form a branch or a ring and may be substituted with a halogen atom;
A C 1 -C 5 alkyl group, a C 2 -C 5 alkenyl group, a C 2 -C 5 alkynyl group, a C 1 -C 5 alkyloxy group, or a benzyl group optionally substituted with a halogen atom; or a protecting group;
And
X 1 and X 2 are each independently a group selected from the group consisting of a hydrogen atom and a halogen atom, and Y may contain a radioisotope and may form a branch or a ring A good C 1 -C 3 alkyl group.
The compound represented by the formula (I) is represented by the following formula (I ′):

The compound of Claim 1 represented by these.
R 1 is
A C 1 -C 5 alkyl group optionally substituted with a radioisotope 18 F, optionally having a branch or ring;
A C 2 -C 5 alkenyl group optionally substituted by a radioisotope 18 F, optionally having a branch or ring;
A C 2 -C 5 alkynyl group optionally substituted with a radioisotope 18 F, optionally having a branch or ring;
A C 1 -C 5 alkyloxy group optionally substituted with a radioisotope 18 F and optionally having a branch or ring;
A C 2 -C 8 alkoxyalkyloxy group optionally substituted by a radioisotope 18 F, optionally having a branch or ring;
Substituted with a radioactive isotope 18 F, which may have a branched or cyclic C 2 ~ C 5 alkenyloxy group; or substituted with a radioactive isotope 18 F, may be branched or cyclic A C 3 -C 5 alkynyloxy group;
The compound according to claim 1 or 2, wherein
R 1 is
A C 1 -C 5 alkyl group which may be branched or ring-substituted with a functional group capable of leaving;
Replaced with a functional group having a leaving Hanareno, which may have a branched or cyclic C 2 ~ C 5 alkenyl group;
A C 2 -C 5 alkynyl group optionally substituted with a functional group having a leaving ability, which may be branched or ringed;
A C 1 -C 5 alkyloxy group optionally having a branch or ring, substituted with a functional group having a leaving ability;
A C 2 -C 8 alkoxyalkyloxy group which may be branched or ring-substituted with a functional group capable of leaving;
A C 2 -C 5 alkenyloxy group optionally substituted with a functional group having a leaving ability, or a branched or ring substituted with a functional group having a leaving ability; An optionally substituted C 3 -C 5 alkynyloxy group;
The compound according to claim 1 or 2, wherein
A compound represented by the following formula (II):

here,
R 1 is
A C 1 -C 5 alkyl group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C 2 -C 5 alkenyl group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C 2 -C 5 alkynyl group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C 1 -C 5 alkyloxy group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C 2 -C 8 alkoxyalkyloxy group optionally substituted with a halogen atom, which may be a radioisotope, and optionally having a branch or ring;
A C 2 -C 5 alkenyloxy group optionally substituted with a halogen atom which may be a radioisotope; or a halogen atom which may be a radioisotope; A C 3 -C 5 alkynyloxy group which may have a branch or a ring;
And
X 1 and X 2 are each independently a group selected from the group consisting of a hydrogen atom and a halogen atom, and Y may contain a radioisotope and may form a branch or a ring A good C 1 -C 3 alkyl group.
The compound represented by the formula (II) is represented by the following formula (II ′):

The compound of Claim 5 represented by these.
R 1 is
A C 1 -C 5 alkyl group optionally substituted with a radioisotope 18 F, optionally having a branch or ring;
A C 2 -C 5 alkenyl group optionally substituted by a radioisotope 18 F, optionally having a branch or ring;
A C 2 -C 5 alkynyl group optionally substituted with a radioisotope 18 F, optionally having a branch or ring;
A C 1 -C 5 alkyloxy group optionally substituted with a radioisotope 18 F and optionally having a branch or ring;
A C 2 -C 8 alkoxyalkyloxy group optionally substituted by a radioisotope 18 F, optionally having a branch or ring;
Substituted with a radioactive isotope 18 F, which may have a branched or cyclic C 2 ~ C 5 alkenyloxy group; or substituted with a radioactive isotope 18 F, may be branched or cyclic A C 3 -C 5 alkynyloxy group;
The compound according to claim 5 or 6, wherein
The compound according to claim 5 or 6, wherein Y is a C 1 -C 3 alkyl group containing the radioisotope 11 C and optionally forming a branch or ring.
A method for producing a compound represented by formula (II) according to claim 5,
A method comprising hydrolyzing a compound represented by formula (I) according to claim 1.
The method according to claim 9, wherein the hydrolysis step is performed under acidic conditions.
A PET diagnostic tracer comprising the compound according to claim 7.