JP2003026659A - Muscarinic acetylcholine neural system-labeling compound and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a muscarinic acetylcholine neural system-labeling compound in good efficiency, capable of securing a sufficient stability from the synthesis to a PET measurement, and also performing the PET measurement with a high accuracy, and a method for producing the same. SOLUTION: This muscarinic acetylcholine neural system-labeling compound is expressed with formula (1) [wherein, W is a group expressed by the following general formula (2) or (3) (wherein, R is a<18> F-labeled fluoromethyl group,<18> F- labeled fluoroethyl group or<18> F labeled fluoropropyl group), and the compound expressed by the formula (1) is a (+) - form, when the W is expressed by the formula (2)].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a muscarinic acetylcholine nervous system labeling compound, more specifically, positron emission tomography (PE).
T) A muscarinic acetylcholine nervous system labeling compound useful in measurement.

[0002]

2. Description of the Related Art With the aging of society, an increase in the number of patients with dementia and an increase in economic burden has become a social problem. It is necessary to elucidate the pathology of such dementia and to develop an effective anti-dementia drug. Has been done.

Although the pathology of dementia has not been elucidated yet, conventional studies have suggested that one of the causes thereof is a decrease in the function of the acetylcholine nervous system. Therefore, in elucidating the pathology of dementia and developing anti-dementia drugs, evaluating the function of the acetylcholine nervous system plays a very important role, and a non-invasive method for performing the evaluation,
And the development of labeled compounds suitable for use in the method is highly desired.

As a non-invasive method for evaluating the function of the acetylcholine nervous system, a method of performing positron emission tomography (hereinafter referred to as PET) measurement using a labeled compound having a positron (positron) emitting nuclide is known. . In this method, a acetylcholine nervous system receptor is labeled with a labeling compound, and the γ-rays emitted upon binding and annihilation of positrons emitted from the emitting nuclide and the constituent electrons are measured, It measures the distribution of the body.

As a muscarinic acetylcholine nervous system labeling compound used for PET measurement, [ ¹¹ C] N-methyl-4-piperidyl benzyl ester (hereinafter referred to as
[ ¹¹ C] 4-NMPB) has been proposed. However, in the PET measurement using [ ¹¹ C] 4-NMPB, (i) because of its low ionicity in blood, it has high lipophilicity and good transferability to tissues, but muscarinic acetylcholine nerves in tissues are high. Since the amount of [ ¹¹ C] 4-NMPB that binds non-specifically to the receptor of the system is large, an error may occur when measuring the amount of [ ¹¹ C] 4-NMPB that specifically binds to the receptor. (Ii) It has a structure in which optical isomers do not exist. Therefore, there is an error in measuring the amount of [ ¹¹ C] 4-NMPB that specifically binds to the receptor of the muscarinic acetylcholine nervous system. (Iii) Since the affinity for the receptor is high and the dissociation constant (k ₄ ) is very small, its kinetics in the brain is easily affected by the local change in blood flow, With a decrease in circulation In a disease state or disease model, it is possible to discriminate whether the measured result is due to a change in the activity of a true muscarinic acetylcholine nervous system receptor or simply due to a change in a local blood flow in the brain. Difficult; (iv) Muscarinic acetylcholine The preganglionic nerve evoked by neurotransmission because its affinity for receptors in the nervous system is much higher than that of the endogenous neurotransmitter acetylcholine. However, there is a problem that it is difficult to measure the competition between the acetylcholine released from the and the labeled compound on the receptor.

Therefore, in order to perform PET measurement with high accuracy, use of various labeling compounds has been proposed.
For example, Japanese Patent Application Laid-Open No. 11-152270 discloses a muscarinic acetylcholine nervous system labeling compound [ ¹¹ C].
By using (±) N-methyl-3-piperidyl benzyl ester (hereinafter, referred to as [ ¹¹ C] (±) 3-NMPB), the accuracy is higher than that when [ ¹¹ C] 4-NMPB is used. It is described that the PET measurement of is possible.

[0007]

However, the above-mentioned conventional labeled compounds are labeled with ¹¹ C, which has a relatively short half-life of 20 minutes, and therefore, when performing PET measurement using these labeled compounds. After synthesizing the labeled compound,
The process up to the ET measurement had to be performed in a short time, and it was necessary to attach a cyclotron, an automatic synthesizer and the like to a medical facility to synthesize the labeled compound for each PET measurement.

Further, even with the above conventional labeled compound,
In order to obtain sufficient accuracy in PET measurement, it took a relatively long time from the administration of the labeled compound to the PET measurement, or it was necessary to administer a relatively large amount of the labeled compound.

The present invention has been made in view of the above problems of the prior art, has a sufficiently long half-life, and has a sufficiently high specific binding ability to receptors of the muscarinic acetylcholine nervous system. , Synthesis of labeled compounds from PET
An object of the present invention is to provide a muscarinic acetylcholine nervous system labeling compound and a method for producing the same, which can ensure a sufficient time until the measurement and can perform PET measurement efficiently with sufficiently high accuracy.

[0010]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the inventors of the present invention have identified a specific benzylic acid fluorinated alkylbiperidyl ester labeled with ¹⁸ F as a muscarinic acetylcholine. The inventors have found that the above problems can be solved by using the compound as a nervous system labeling compound, and have completed the present invention.

That is, the muscarinic acetylcholine nervous system labeling compound of the present invention has the following general formula (1):

[Chemical 11] [Wherein W is the following general formulas (2) and (3):

[Chemical 12]

[Chemical 13] (Wherein, R ¹⁸ F-labeled methyl fluoride group, ¹⁸ denotes F-labeled fluorinated ethyl and ¹⁸ F-labeled one selected from the group consisting of fluoride propyl) consisting of groups represented by Represents one kind selected from the group, and when W is a group represented by the general formula (2), the compound represented by the general formula (1) is a (+)-form.] A muscarinic acetylcholine nervous system labeling compound characterized.

Further, the method for producing the muscarinic acetylcholine nervous system labeling compound of the present invention comprises a ¹⁸ F-labeled fluorinated alkylsulfonic acid ester or halide represented by the following general formula (4): RX (4). And the following general formula (5):

[Chemical 14] By the reaction with benzylic acid piperidyl ester represented by the following general formula (1):

[Chemical 15] And a step of obtaining a compound represented by: [Wherein, R represents one selected from the group consisting of ¹⁸ F-labeled methyl fluoride group, ¹⁸ F-labeled fluorinated ethyl and ¹⁸ F-labeled fluorinated propyl group, X is the following formula (6) ~
(15):

[Chemical 16]

[Chemical 17]

[Chemical 18] -Cl (9) -Br (10) -I (11) -O-SO 2 -CH 3 (12) -O-SO 2 -CF 3 (13) -O-SO 2 -CF 2 H (14) - O—SO ₂ —CFH ₂ (15) represents a group represented by any one of the formulas, and W ′ represents (+)-
Represents one selected from the group consisting of a 3-piperidyl group and a 4-piperidyl group, and W represents the following general formulas (2) and (3):

[Chemical 19]

[Chemical 20] (Wherein, R ¹⁸ F-labeled methyl fluoride group, ¹⁸ denotes F-labeled fluorinated ethyl and ¹⁸ F-labeled one selected from the group consisting of fluoride propyl) consisting of groups represented by Represents one selected from the group. ]

The muscarinic acetylcholine nervous system labeling compound of the present invention has a sufficiently long half-life of 110 minutes.
^Since it is labeled with ¹⁸ F, compared with the conventional labeled compound labeled with ¹¹ C, PE from the synthesis of the labeled compound
It is possible to secure a sufficient time until T measurement. Therefore, it is not necessary to install a cyclotron or a synthesizing device in a medical facility, and the labeled compound of the present invention synthesized in a predetermined facility can be transported to another facility for PET measurement. Further, when performing PET measurement using the muscarinic acetylcholine nervous system labeling compound of the present invention, it is possible to efficiently perform PET measurement with sufficiently high accuracy even with a small dose as compared with conventional labeling compounds. It will be possible. The muscarinic acetylcholine nervous system labeling compound of the present invention having such excellent properties can be efficiently and reliably obtained by the production method of the present invention.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION Preferred embodiments of the present invention will be described in detail below. The muscarinic acetylcholine nervous system labeling compound of the present invention (hereinafter sometimes referred to as “the labeling compound of the present invention”) has the following general formula (1):

[Chemical 21] [Wherein W is the following general formulas (2) and (3):

[Chemical formula 22]

[Chemical formula 23] (Wherein, R ¹⁸ F-labeled methyl fluoride group, ¹⁸ denotes F-labeled fluorinated ethyl and ¹⁸ F-labeled one selected from the group consisting of fluoride propyl) consisting of groups represented by Represents one kind selected from the group, and when W is a group represented by the general formula (2), the compound represented by the general formula (1) is a (+)-form.] It is a feature, and more specifically, the following formula (1-a):

[Chemical formula 24] [ ¹⁸ F] (+)-N-fluoromethyl-3-
Piperidyl benzylate ([ ¹⁸ F] (+)-N-fluoromethyl-3-
piperydyl benzilate, hereafter [ ¹⁸ F] (+) 3-NF
MPB); the following formula (1-b):

[Chemical 25] [ ¹⁸ F] (+)-N-fluoroethyl-3-
Piperidyl benzylate ([ ¹⁸ F] (+)-N-fluoroethyl-3-p
iperydyl benzilate, hereafter [ ¹⁸ F] (+) 3-NFE
PB); the following formula (1-c):

[Chemical formula 26] [ ¹⁸ F] (+)-N-fluoropropyl-3 represented by
− Piperidyl benzylate ([ ¹⁸ F] (+)-N-fluoropropyl-
3-piperydyl benzilate, hereafter [ ¹⁸ F] (+) 3-N
FPPB); the following formula (1-d):

[Chemical 27] [ ¹⁸ F] N-fluoromethyl-4-piperidyl benzylate ([ ¹⁸ F] N-fluoromethyl-4-piperydyl be
nzilate, hereinafter referred to as [ ¹⁸ F] 4-NFMPB); the following formula (1-e):

[Chemical 28] In represented by ^[18 F] N-fluoroethyl-4-piperidyl benzilate ^{([18 F] N-fluoroethyl} -4-piperydyl ben
zilate, hereinafter referred to as [ ¹⁸ F] 4-NFEPB); and the following formula (1-f):

[Chemical 29] In represented by ^[18 F] N-fluoropropyl-4-piperidyl benzilate ^{([18 F] N-fluoropropyl} -4-piperydyl
benzilate, hereinafter referred to as [ ¹⁸ F] 4-NFPPB). If the carbon number of the fluoroalkyl group bonded to the nitrogen atom of the piperidyl group is 4 or more, the affinity for the muscarinic acetylcholine nervous system receptor is markedly reduced, and sufficient accuracy is obtained during PET measurement. Can't get

[0015] The above formula (1-c), ¹⁸ F-labeled propyl group in (1-f) is ¹⁸ F-labeled n- propyl group, ¹⁸
Although it may be any of F-labeled iso-propyl group, ¹⁸ F-labeled n-propyl group is preferable from the viewpoint of easy production.

Further, the above formulas (1-a) to (1-c) are used.
Each of the labeled compounds is an optical isomer ([[¹⁸F]
(−) 3-NFMPB, [¹⁸F] (-) 3-NFEP
B, [ ¹⁸F] (−) 3-NFPPB) exists, but this
In the invention, a mixture of (+)-form and (-)-form
(Ie [¹⁸F] (±) 3-NFMPB, [¹⁸F]
(±) 3-NFEPB, [¹⁸F] (±) 3-NFPP
B), isolated from the mixture (+)
-The body may be used alone. In addition, these optical isomers
The method for isolating the (+)-form from the mixture of
Optical analysis using a column in which a polysaccharide derivative is supported on kagel
Split column chromatograph and the like can be mentioned.

In addition, [¹⁸F] (−) 3-NFMPB, [
¹⁸F] (−) 3-NFEPB and [ ¹⁸F] (-) 3-N
FPPB is a muscarinic acetylcholine nervous system receptor
Since it has no specific binding ability to the body, for example (+)-
PET measurement is performed using the body alone and the corresponding (-)-
By comparing with the measurement results when the body was used alone
The amount of labeled compound that specifically binds to the receptor
Can be obtained with higher accuracy.

Next, the method for producing the labeled compound of the present invention will be described. The labeled compound (1) of the present invention has the following reaction formula (A):

[Chemical 30] (In the formula, R and W represent the same definition contents as R and W in the general formula (1), and X represents the following formulas (6) to (15):

[Chemical 31]

[Chemical 32]

[Chemical 33] -Cl (9) -Br (10) -I (11) -O-SO 2 -CH 3 (12) -O-SO 2 -CF 3 (13) -O-SO 2 -CF 2 H (14) - O—SO ₂ —CFH ₂ (15) represents a group represented by any one of the formulas, and W ′ represents (+)-
(Representing one selected from the group consisting of 3-piperidyl group and 4-piperidyl group), that is, ¹⁸ F-labeled fluorinated alkyl ester or halide (4)
It can be obtained by the reaction of benzylic acid piperidyl ester (5).

The reaction represented by the above reaction formula (A) can be carried out in a predetermined solvent. Examples of such a solvent include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, malforane, tetrahydrofuran, N-methylpiperidone, acetonitrile and the like.

The reaction temperature for carrying out the reaction represented by the above reaction formula (A) is not particularly limited, but is preferably 50 to 1
It is 50 ° C. The reaction time varies depending on the reaction temperature and other conditions, but is preferably 5 to 30 minutes.

In the above reaction formula (A), the starting compound [
¹⁸ F] The method for synthesizing the labeled fluorinated alkyl sulfonic acid ester or alkyl halide is not particularly limited. For example, the following reaction formula (B):

[Chemical 34] (In the formula, R ′ represents one selected from the group consisting of a methylene group, an ethylene group and a propylene group, X and X ′ each represent the same definition as X in the general formula (4), and R
Represents the same definition as R in formula (1), that is, the reaction of K ¹⁸ F with alkylene glycol di-sulfonate or alkylene glycol dihalide (6) in acetonitrile. Can be obtained by K ¹⁸ F is obtained by irradiating [ ¹⁸ O] H ₂ O with an H ⁺ beam and recovering it at a He pressure to obtain an [ ¹⁸ F] aqueous solution.
8 etc.) to collect [ ¹⁸ F] F ⁻ ions and treat the ion exchange resin with an aqueous K ₂ CO ₃ solution. The K ¹⁸ F thus obtained, after sufficiently removing water by azeotropic dehydration with acetonitrile or the like,
It is preferable to use the reaction represented by the above reaction formula (A). Further, as the alkylene glycol di-sulfonic acid ester or the alkylene glycol dihalide (6), a commercially available product may be used, or one obtained by a conventionally known synthesis method may be used.

The reaction temperature of the reaction represented by the above reaction formula (B) is not particularly limited, but is preferably 60 to 130 ° C. The reaction time varies depending on the reaction temperature and other conditions, but is preferably 5 to 20 minutes.

In the above reaction formula (A), the method for synthesizing the starting compound benzylic acid piperidyl ester (5) is not particularly limited. For example, the following reaction formula (C):

[Chemical 35] (Wherein R ″ represents an alkyl group and W ′ represents one selected from the group consisting of a 3-piperidyl group and a 4-piperidyl group), that is, a benzyl ester (7) It can be obtained by reaction with piperidinol (8).

The benzyl ester and piperidinol (8), which are the starting compounds in the above reaction formula (C), may be commercially available products, or those obtained by a conventionally known synthetic method may be used. Good.

The reaction temperature of the reaction represented by the above reaction formula (C) is not particularly limited, but is preferably -10 to 120 ° C.
Is. The reaction time varies depending on the reaction temperature and other conditions, but it is preferably 20 to 120 minutes.

Since the labeled compound of the present invention thus obtained has a sufficiently long half-life, it is used for the steps from the synthesis of the labeled compound to the PET measurement, or the step of quantitative analysis of metabolites in arterial blood. It is possible to secure sufficient time. Therefore, stable PET measurement can be performed,
The labeled compound of the present invention is very useful in that the labeled compound synthesized in the synthesis facility can be transported to a medical facility or the like, and the labeled compound required for multiple PET measurements can be obtained in one synthesis step. Is.

Further, the labeled compound of the present invention has a sufficiently high affinity for a receptor of muscarinic acetylcholine nervous system and has a dissociation constant (k ₄ ) from the receptor.
Indicates a relatively large value. For this reason, the binding to the receptor and the dissociation from the receptor easily occur in a relatively short time, and the PET measurement can be efficiently performed in a short time. Furthermore, in the case of the labeled compound of the present invention, sufficiently high accuracy is achieved even if the dose to the subject is relatively small, so that the exposure dose of the subject is reduced and the quantitative analysis of metabolites in arterial blood is performed. It is possible to realize the reduction of the radioactive dose required for

The labeled compound of the present invention was used for PET.
When carrying out the measurement, the measuring method is not particularly limited and can be carried out according to a conventionally known method (H. O.
noe, O. Inoue, K. Suzuki, H. Tsukada, T. Itoh, N. M
ataga, Y. Watanabe, BrainResearch 663 , 191-198 (199
Four)). Specifically, a tomographic image of the brain of a subject such as an unanesthetized rhesus monkey is obtained using a nuclear magnetic resonance tomographic imaging apparatus (MRI), and a region of interest (ROI) is determined based on this tomographic image. Next, the labeled compound of the present invention is administered through the vein of the subject, and PET measurement is performed for each region of interest using the PET system. In the PET system, annihilation photons, that is, γ-rays, which are emitted by the combination of the positrons emitted from the emission nuclide of the labeled compound and the surrounding constituent electrons, are measured. In addition, if necessary,
The obtained measurement data can be processed by image reconstruction software to obtain an image image of the region of interest.
Here, using a PET system having excellent spatial resolution (for example, SHR-7700 manufactured by Hamamatsu Photonics Co., Ltd.) and image reconstruction software (for example, SHR Controll II manufactured by Hamamatsu Photonics Co., Ltd.) Even if the brain is small, it is preferable in that it can discriminate the details of the brain.

[0029]

EXAMPLES The present invention will be described in more detail based on the following examples and comparative examples, but the present invention is not limited to the following examples.

Example 1 (Synthesis of Labeling Compound) [ ¹⁸ O] as Liquid Target
₂ ml of H ⁺ beam (20 μA, 18 MeV) is applied to ₂ ml of H ₂ O.
Irradiation was carried out for 0 minutes, and the mixture was recovered by He pressure to obtain a [ ¹⁸ F] aqueous solution. From the obtained [ ¹⁸ F] aqueous solution, ion exchange resin AG1-X8 (OH ⁻ type, 100 to 200 mesh, B
[ ¹⁸ F] F ⁻ ions are collected by using io rad), and the ion exchange resin is treated with 0.5 ml of a K ₂ CO ₃ aqueous solution to obtain a K ¹⁸ F aqueous solution, and further Kriptofix.
2,2,2 (2,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8,8,8] hexacosane, Aldrich) 2 mg (5.4 μm)
2 ml of acetonitrile containing ol) was added to carry out azeotropic dehydration to completely remove water.

Next, ethylene glycol was added to the residue after dehydration.
Containing 2 mg (5.4 μmol) of lugi-p-tosylate
Add 1 ml of acetonitrile and at 100 ℃ for 10 minutes
Fluorinated. Add the reaction mixture to Sep Pak Pl
us Silica cartridge (manufactured by Waters)
And extract it by loading into 1.5 m of dichloromethane.
It was washed twice with 1. Mix the extraction liquid and the washing liquid and
The solvent was distilled off at 100 ° C. under the flow,¹⁸F] 2-fluoro
Obtained ethyl tosylate. Before and after solvent evaporation [ ¹⁸F] 2
HPL obtained for fluoroethyl tosylate
C charts are shown in FIGS. 1 and 2, respectively. In addition, this
HPLC (column: Inertsil ODS) for analysis
-3, 5μ, 4.6mm x 150mm, GL Science
Mobile phase: acetonitrile / 30 mM ammonium acetate
Um / acetic acid = 350/650/2, flow rate: 2 ml / mi
n) was used.

0.5 ml of dimethylsulfoxide containing 3.4 mg (10.9 μmol) of (+)-3-piperidyl benzoate was added to the obtained [ ¹⁸ F] 2-fluoroethyl tosylate, and fluoroethyl was added at 140 ° C. for 10 minutes. The chemical reaction was carried out. The reaction mixture was subjected to high performance liquid chromatography (HPLC) mobile phase (acetonitrile / 3).
0 mM ammonium acetate / acetic acid = 400/600/2)
Dilute with 1 ml and HPLC (column: Inertsil
ODS-3, 10μ, 7.6mm x 250mm, GL
Purified by Science, flow rate: 6 ml / min). The collected fractions were concentrated under reduced pressure, and 3m of physiological saline was added to the residue.
l was added to give a solution again, and the solution was filtered through a 0.22 μm membrane filter to give the desired labeled compound ([18
F] (+)-3-N- (2-fluoroethyl) -piperidyl benzylate) was obtained.

An HPLC chart of the obtained labeled compound when measured in RI mode is shown in FIG. 3, and an HPLC chart when measured in UV mode is shown in FIG. 4 (detection wavelength: 235 nm). The specific activity of the obtained labeled compound was 2 GBq / μmol or more, and the radiochemical purity was 99% or more.

(PET measurement) Using the labeled compound thus obtained, the following references: H. Onoe, O. Inoue, K. Suzuki, H. Tsukada, T. Itoh,
N. Mataga, Y. Watanabe, Brain Research 663 , 191-1
PET measurement was performed according to the method described in 98 (1994).

First, an unanesthetized rhesus macaque of about 5 kg in weight, which is a subject, is placed in a PET device (SH manufactured by Hamamatsu Photonics KK).
R-7700), and the transmission was measured for absorption correction of PET measurement. Then, about 100 MBq / kg body weight of the labeled compound was administered from the vein of each subject, and dynamic measurement was performed for 60 minutes. In addition,
In each measurement, the same subject is measured in advance using a nuclear magnetic resonance tomography apparatus (MRI) to obtain a tomographic image (FIG. 5A), and based on the tomographic image, the cerebellum and hippocampus ( hippocampus), occipital lobe (occ c)
tx), basal ganglia (Striatum), temporal lobe (temp ctx), frontal lobe (frt ctx), position of cingulate (cingulate),
The time course of radioactivity in each region of interest was measured. FIG. 5B shows a cross-sectional image of the brain after a predetermined time has elapsed, and FIG. 6A shows the correlation between the time and the amount of uptake in each region of interest.

Comparative Example 1 Instead of the [ ¹⁸ F] (+)-3-N- (2-fluoroethyl) -piperidyl benzylate in Example 1,
PET was performed in the same manner as in Example 1 except that [ ¹¹ C] (+)-3-N-methyl-piperidyl benzoate was used.
The measurement was performed. A cross-sectional image of the brain after a predetermined time has passed is shown in FIG.
(C), FIG. 6 (b) shows the correlation between the time and the amount of incorporation in each region of interest.

Comparative Example 2 Instead of [ ¹⁸ F] (+)-3-N- (2-fluoroethyl) -piperidyl benzylate in Example 1,
PET measurement was performed in the same manner as in Example 1 except that [ ¹¹ C] 4-N-methyl-piperidyl benzoate was used. A cross-sectional image of the brain after a predetermined time has passed is shown in FIG.
(D), FIG. 6 (c) shows the correlation between the time and the uptake amount in each region of interest.

As is clear from the results shown in FIGS. 5 and 6, in Example 1, the radioactivity concentration corresponding to the distribution of the labeling compound was high in the basal ganglia and the occipital lobe, and also in the frontal lobe and the temporal lobe. The result was that the radiation concentration was relatively high. These results are in very good agreement with the conventionally known distribution of muscarinic receptors in the acetylcholine nervous system, and it was confirmed that the labeled compound of the present invention has specific binding ability to receptors. .

Further, in the case of Example 1, it was confirmed that the binding of the labeled compound with the receptor and the dissociation of the labeled compound from the receptor occurred in a shorter time than in Comparative Examples 1 and 2. . Further, in Example 1, the amount of the labeled compound taken in was larger than that in Comparative Examples 1 and 2 in any of the regions of interest, and the PET measurement could be performed with sufficiently high accuracy.

[0040]

INDUSTRIAL APPLICABILITY As described above, the muscarinic acetylcholine nervous system labeling compound of the present invention has a sufficiently long half-life and has a sufficiently high specific binding ability to the muscarinic acetylcholine nervous system receptor. Therefore, it is possible to secure a sufficient time from the synthesis of the labeled compound to the PET measurement, and it is possible to efficiently perform the PET measurement with sufficiently high accuracy. In addition, the production method of the present invention makes it possible to efficiently and reliably obtain the muscarinic acetylcholine nervous system labeling compound of the present invention having such excellent properties.

[Brief description of drawings]

FIG. 1 shows the HPL of [ ¹⁸ F] 2-fluoroethyl tosylate before solvent evaporation when measured in UV mode.
It is a graph which shows a C chart.

FIG. 2 shows the HPL of [ ¹⁸ F] 2-fluoroethyl tosylate after solvent evaporation when measured in RI mode.
It is a graph which shows a C chart.

FIG. 3 shows RI of the labeled compound obtained in Example 1.
It is a graph which shows the HPLC chart when it measures in mode.

FIG. 4 shows UV of the labeled compound obtained in Example 1.
It is a graph which shows the HPLC chart when it measures in mode.

5 (a) to (d) are tomographic images showing the state of the brain after a predetermined time has passed, respectively. FIG. 5 (a) is a physiological saline solution.
(B) is a labeled compound of Example 1, (c) is a labeled compound of Comparative Example 1, and (d) is a tomographic image when the labeled compound of Comparative Example 2 is used.

6 (a) to 6 (d) are graphs showing the correlation between the amount of labeled compound incorporated and time, (a) showing the labeled compound of Example 1, and (b) showing the labeled compound of Comparative Example 1. ,
(C) is a graph when the labeled compound of Comparative Example 2 is used.

Claims (2)

[Claims] 1. The following general formula (1): [Wherein W is the following general formula (2) and (3): [Chemical 3] (Wherein, R ¹⁸ F-labeled methyl fluoride group, ¹⁸ denotes F-labeled fluorinated ethyl and ¹⁸ F-labeled one selected from the group consisting of fluoride propyl) consisting of groups represented by Represents one kind selected from the group, and when W is a group represented by the general formula (2), the compound represented by the general formula (1) is a (+)-form.] A muscarinic acetylcholine nervous system labeling compound characterized. 2. An ¹⁸ F-labeled fluorinated alkyl sulfonic acid ester or halide represented by the following general formula (4): R—X (4), and the following general formula (5): By the reaction with benzylic acid piperidyl ester represented by the following general formula (1): A method for producing a muscarinic acetylcholine nervous system-labeled compound, which comprises the step of obtaining the compound represented by: [Wherein, R represents one selected from the group consisting of ¹⁸ F-labeled methyl fluoride group, ¹⁸ F-labeled fluorinated ethyl and ¹⁸ F-labeled fluorinated propyl group, X is the following formula (6) ~
(15): [Chemical 7] [Chemical 8] -Cl (9) -Br (10) -I (11) -O-SO 2 -CH 3 (12) -O-SO 2 -CF 3 (13) -O-SO 2 -CF 2 H (14) - O—SO ₂ —CFH ₂ (15) represents a group represented by any one of the formulas, and W ′ represents (+)-
Represents one selected from the group consisting of a 3-piperidyl group and a 4-piperidyl group, and W is represented by the following general formulas (2) and (3): [Chemical 10] (Wherein, R ¹⁸ F-labeled methyl fluoride group, ¹⁸ denotes F-labeled fluorinated ethyl and ¹⁸ F-labeled one selected from the group consisting of fluoride propyl) consisting of groups represented by Represents one selected from the group. ]