KR20150072030A - Method for preparing [18F]Fluoro-L-Dopa with high radiochemical and enantiomeric purity - Google Patents

Abstract

The present invention relates to a manufacturing method and a purifying method of [^18f] fluoro-L-dopa with high purity and high specific radioactivity, which is automatically manufactured wherein the [^18f] fluoro-L-dopa requires at least one solution process in each manufacturing step and accordingly has good reproducibility and stable yield, thereby being used in an auto-manufacturing apparatus, and is purified by using a high performance liquid chromatography which uses a solid phase extraction method and chiral column, thereby having good high purity and high specific radioactivity.

Description

(18F) Fluoro-L-Dopa with high purity and high radioactivity [18F] fluoro-L-

The present invention relates to a method for preparing and purifying [ ¹⁸ F] fluoro-L-dopa, which is a radiopharmaceutical capable of automated synthesis.

While the quality of life improves with the development of modern civilization and the life span of human beings increases with the development of medicine, brain diseases such as Parkinson's disease, depression, schizophrenia, and Alzheimer's disease; Heart disease due to stress and dietary changes; And the incidence of various cancers due to human exposure to various harmful substances has been increasing. Therefore, it is required to develop an imaging method that can diagnose these diseases early. Currently, a variety of imaging modalities are commercially available, but positron emission tomography (PET) is a method that is readily applicable to clinical practice. The positron emission tomography (PET) It is a method to visualize the distribution and biochemical change process of the radiopharmaceuticals in vivo by intravenous injection in vivo. Therefore, it is possible to quantitatively measure the biochemical changes of a living body in a lesion site through positron emission tomography (CT), so that the degree of development of the disease can be measured and the degree of treatment can be predicted.

With a radioactive isotope that is used for positron emission tomography include fluorine ^([18 F] F), Carbon ^([15 C] C), nitrogen ^([13 N] N), oxygen ^([15 O] O) and gallium ( [ ⁶⁸ Ga] Ga), among which [ ¹⁸ F] fluoride has a size similar to that of hydrogen, forms a stable bond with the carbon of an organic compound, is easy to produce, has a suitable half- Has been known to be very suitable for performing positron emission tomography. [ ¹⁸ F] fluoride can be prepared by irradiating a proton to [ ¹⁸ O] H ₂ O using a cyclotron, which is generally a circular accelerator.

PET or PET / CT imaging using [ ¹⁸ F] fluorodopa, a radiopharmaceutical for positron emission tomography (PET), is used to measure the disappearance of the dopamine nerve endings in the brain striatum, And can be used to differentiate between essentiality and Parkinsonism. In addition, it can measure the pathophysiological functions of tissues or organs with increased intracellular transport and decarboxylation of dihydroxyphenylalanine, which is an amino acid, and is used for the diagnosis and localization of insulin species with and without insulinosis in infants and children do. In general, [ ¹⁸ F] fluorodophores used in Europe use [ ¹⁸ F] F ₂ gas using an electrophilic substitution reaction, in which not only [ ¹⁸ F] but also [ ¹⁹ F] There is a drawback that a low [ ¹⁸ F] fluorodopa is produced. Thus, instead of an electrophilic substitution reaction ^[18 F] are made of a fluoride of a nucleophilic substitution reaction the specific activity is high ^[18 F] fluoro also actively studied for synthesis of the wave through using, this time using method, which a multi-step synthesis ^[18 F] fluoride via reaction, reduction reaction, the iodination reaction, the alkylation reaction and the hydrolysis reaction ^[18 F] fluoro also be synthesized wave.

In the synthesis of [ ¹⁸ F] fluorodophores reported so far, the reduction reaction is mainly carried out by dissolving sodium borohydride (NaBH ₄ ) in water and performing a reduction reaction in a column state using an excess amount of sodium borohydride do. Next, the iodination reaction was carried out using diiodosilane (DIS) or hydrogen halide (HX) gas, and recently, it has been reported that HI (57%) solution was used. In addition, in the alkylation reaction, which determines the hand symmetry of [ ¹⁸ F] fluorodophores, it is necessary to use 95% or more of L-form using a hand symmetric catalyst for clinical use.

As described above, the method using DIS in the iodination reaction is disadvantageous in that the reaction efficiency is inferior because the stability of DIS is low. When HX gas is used, it is not easy to apply it to mass production using an automated synthesizer, It is difficult to expect. Also, in order to make 95% or more of L-form [ ¹⁸ F] fluorodophores using a hand symmetric catalyst in the alkylation reaction, it is generally necessary to use a low temperature or to exert an excellent catalytic effect. If any of the above conditions are not met and the purity is less than 95%, it can not be used in patients. For easy clinical application, the production yield and purity of [ ¹⁸ F] fluorodopa should be high.

Therefore, the old ^[18 F] fluoro also by solving the problems of the manufacturing method of the wave, and the purification of the impurities produced in the manufacturing process to as ^[18 F] fluoro having a high purity and high boiling radioactivity need for research on the file, such as the Is desperately required.

The present inventors have searched for a method for producing and purifying L-form [ ¹⁸ F] fluorodophores having high purity and high radioactivity. When all the steps of the preparation are carried out in a solution state, they exhibit high reproducibility and stable yield, It is confirmed that L-type [ ¹⁸ F] fluorodopara of high purity and high radioactivity can be obtained by purification by using solid-phase extraction method and high-performance liquid chromatography using chiral column, Thereby completing the invention.

Accordingly, the present invention seeks to provide a process for the preparation and purification of [ ¹⁸ F] fluoro-L-dopa of high purity and high radioactivity capable of automated production.

The present invention also provides high purity and high radioactivity [ ¹⁸ F] fluoro-L-dopa using the above preparation and purification methods.

The present invention provides a method for preparing and purifying [ ¹⁸ F] fluoro-L-dopa of high purity and high radioactivity capable of automated production.

The present invention also provides high purity and high radioactivity [ ¹⁸ F] fluoro-L-dopa using the above-described preparation and purification methods.

The L-form [ ¹⁸ F] fluorodorane according to the present invention exhibits high reproducibility and stable yield by performing all the preparation steps in a solution state, and is suitable for application to an automated manufacturing apparatus. Further, the L- Purification using liquid chromatography has an effect of exhibiting high purity and high radioactivity.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram showing the chromatogram of a radiation-thin layer chromatography (radio-TLC) of the product according to the preparation steps of the present invention.
FIG. 2 is a diagram showing a chromatogram of [ ¹⁸ F] fluoro-L-dopa purified using a chiral column of [ ¹⁸ F] fluorodophores according to the production method of the present invention.
3 is a chart showing the chromatogram of the radiochemical and optical purity of [ ¹⁸ F] fluoro-L-dopa according to the production method of the present invention.

The present invention

(1) reacting 4,5-dimethoxy-2-nitrobenzaldehyde (compound 1) with [ ¹⁸ F] fluoride to prepare compound 2;

(2) reacting the compound 2 with a reducing agent to prepare a compound 3;

(3) reacting the compound 3 with an iodine flame to prepare a compound 4;

(4) reacting the compound 4 with an ester compound to prepare a compound 5; And

(5) hydrolyzing the compound 5 to prepare a compound 6, wherein the step of (1) to (5) above is carried out in a solution state, and [ ¹⁸ F] fluorodopa Of the present invention.

[Reaction Scheme 1]

The present invention also provides L-form [ ¹⁸ F] fluorodophores having a non-radioactivity of 2 to 3 x 10 ⁷ mCi / mmol and a purity of 95 to 100% prepared by the above method.

Hereinafter, the present invention will be described in detail.

The process for preparing [ ¹⁸ F] fluorodophores according to the present invention is suitable for application to automated production equipment by carrying out all the preparation steps in a solution state, and furthermore, by using solid-phase extraction and high performance liquid chromatography using a chiral column, % Or more of high purity L-form [ ¹⁸ F] fluoro wave.

The step (1) is a [ ¹⁸ F] fluorination reaction step in which Compound 2 is prepared using Compound 1 as a precursor,

X in the compound 1 is a nitro group or a tertiary ammonium group. More specifically, the alkyl group of the tertiary ammonium is a primary or secondary alkyl group of C ₁ to C ₅ , and the tertiary ammonium conjugate is a methanesulfonyl group, A trifluoromethanesulfonyl group, a p-nitrobenzenesulfonyl group, or a 4-toluenesulfonyl group, but is not limited thereto.

The ^[18 F] fluoride is not that it is preferable thereto only mate with a lithium, sodium, potassium, cesium, rubidium, or a quaternary ammonium cation, an alkyl group of the quaternary ammonium is a C ₁ ~ C _{10 1} difference Or a secondary alkyl group, but is not limited thereto.

The step (2) is a reduction reaction step in which Compound 2 is reduced to produce Compound 3,

The reducing agent can be used without limitation as long as it can reduce the aldehyde of Compound 2 to produce an alcohol. According to one embodiment of the present invention, 5 to 40 equivalents of sodium borohydride (NaBH ₄ ) relative to compound 1 is used in the same solvent as the reaction solvent of step (1). If NaBH ₄ is used in an amount of less than 5 equivalents, the reduction reaction may not occur completely, and when it is used in an amount of more than 40 equivalents, there is a problem that high pressure is applied in the purification process using solid phase extraction.

The reaction of steps (1) and (2) is preferably performed in the same reaction solvent, but is not limited thereto.

The aprotic solvent may include, but is not limited to, acetonitrile, dimethylformamide, and dimethylsulfoxide. Examples of the aprotic solvent include methanol, Primary alcohols containing ethanol, n - propanol, n - butanol, n - amyl alcohol, n - hexyl alcohol, n - heptanol or n - octanol; Secondary alcohols including isopropanol, isobutanol, isoamyl alcohol, or 3-pentanol; Propanol, t -butanol, t -amyl alcohol, 2,3-dimethyl-2-butanol, 2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-methyl- Cyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol, 1-methylcyclohexanol, 1-methylcyclohexanol, 1-methylcyclopentanol, -Ethylcyclohexanol, or tertiary alcohols comprising 1-methylcycloheptanol, but are not limited thereto.

The step (3) is an iodination reaction step in which compound 3 is iodinated to produce compound 4, which is preferably carried out in a solution state using an inorganic compound (MX ₄ ).

M in the MX ₄ may be titanium, zirconium, hafnium or ruthenium metal as a metal, but it is preferably zirconium in the present invention, and X may be fluoride, chloride, bromide or iodide, Chloride.

According to one embodiment of the present invention, 1 to 5 equivalents of zirconium chloride (ZrCl ₄ ) relative to Compound 1 is mixed with sodium iodide (NaI) to perform iodination reaction in a solution state. If ZrCl ₄ is used in an amount of less than 1 equivalent, the iodination reaction may not occur, and if it is used in an amount of more than 5 equivalents, excess precipitate may occur.

The step (4) is an alkylation reaction step in which compound 4 is alkylated to produce compound 5, which is preferably carried out using a base and a chiral phase transfer catalyst (PTC). The chiral phase transfer catalyst and the reaction temperature The ratio of L-form and D-form [ ¹⁸ F] fluorodophores is determined.

The base may be sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide or tetrabutylammonium hydroxide, but potassium hydroxide or cesium sulphate is preferred in the present invention.

The step (5) is preferably a hydrolysis step of hydrolyzing the compound 5 to prepare the compound 6, and hydrolyzing the compound 6 using 40 to 50% of hydrogen bromide (HBr) and potassium iodide (KI).

The method for producing [ ¹⁸ F] fluorodopara of the present invention is characterized in that after the step (5)

(6) purifying the compound 6 by a solid phase extraction method; And

(7) separating the purified Compound 6 by Liquid chromatography using L-form [ ¹⁸ F] fluorodophores.

In the step (6), the reaction solution containing the compound 6 prepared in the step (5) is purified by solid phase extraction to remove impurities except for [ ¹⁸ F] fluorodophores.

The cartridge used in the solid phase extraction method may be a reversed phase, an ion exchange, or a mixed cartridge, but is not limited thereto. In the present invention, it is preferable that the cartridge is a cation exchange cartridge.

The (7) comprises: (6) the type and L- ^[18 F] of the D- type purification step to remove the par-fluoro also by high performance liquid chromatography (HPLC) using a chiral column of the highly purified type L- ^[18 F] fluorodophores.

The L-type [ ¹⁸ F] fluorodora according to the present invention exhibits a remarkably low production failure rate due to the progress of all the reactions in the solution state, and exhibits a non-radioactivity of 2 to 3 x 10 ⁷ mCi / mmol and a purity of 95 to 100% .

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

Example 1. [ ¹⁸ ≪ RTI ID = 0.0 > F] < / RTI &

1-1. 2-[ ¹⁸ F] fluoro-4,5-dimethoxybenzaldehyde ([ ¹⁸ F] fluorination reaction)

The process for the preparation of 2- [ ¹⁸ F] fluoro-4,5-dimethoxybenzaldehyde (Compound 2) is shown in step (1) of Scheme 1 above. Specifically, quaternary ammonium salts support (Chromafix or QMA) in the ^[18 F] was passed through a fluoride to adsorb the ^[18 F] fluoride in an anion exchange system to a quaternary ammonium salt support, it is adsorbed by the quaternary ammonium salts support [ ¹⁸ F] fluoride was eluted into the reaction vessel using an eluent containing potassium carbonate and cryptopix (K222). After the elution, the eluent was completely removed by azeotropic mixed distillation while injecting nitrogen gas at 100 ° C. 0.5 mL of dimethylformamide in which 5-10 mg of 4,5-dimethoxy-2-nitrobenzaldehyde (Compound 1) was dissolved was placed in the reaction vessel, and the mixture was reacted at 140 ° C for 10 minutes to prepare Compound 2.

The labeling efficiency of the compound 2 prepared above was confirmed by radiation-thin layer chromatography (radio-TLC).

division K222 (mg) K ₂ CO ₃ (mg) Compound 1 (mg) Label Efficiency (%) 5 minutes 10 minutes One 15 3.5 5 61.48 83.68 2 15 3.5 10 64.34 82.41

As shown in Table 1, it can be confirmed that there is no change in labeling efficiency depending on the amount of Compound 1. Therefore, since the amount of all the reagents is set to an equivalent amount to Compound 1, a small amount of 5 mg is more suitable.

1-2. (2-[ ¹⁸ F] fluoro-4,5-dimethoxyphenyl) methanol (reduction reaction)

(2 - [ ¹⁸ F] fluoro-4,5-dimethoxyphenyl) methanol (Compound 3) is shown in step (2) of Scheme 1. Specifically, 5-100 equivalents of sodium borohydride (NaBH ₄ ) was added with 0.5 mL of dimethylformamide to a reaction vessel containing Compound 2 in which the above Reaction Scheme 1 had been completed, and then the mixture was stirred at room temperature or 100 ° C. for 20 minutes To give Compound 3.

The reduction efficiency of the compound 3 prepared above was confirmed by radiation-thin layer chromatography (radio-TLC).

division NaBH ₄ (equivalent) Temperature (℃) Reduction efficiency (%) 5 minutes 10 minutes 15 minutes 20 minutes One 5 Room temperature 18.54 11.84 16.97 19.24 2 20 Room temperature 21.29 26.05 28.37 35.52 3 50 Room temperature 22.12 19.67 21.59 23.50 4 100 Room temperature 24.78 24.27 32.03 32.57 5 20 100 67.95 67.71 69.11 73.16

As shown in Table 2, when 20 equivalents of NaBH ₄ at 100 ° C was used (Category 5), the reduction efficiency was 70% or more.

1-3. One-[ ¹⁸ F] fluoro-2- (Iodomethyl) -4,5-dimethoxybenzene (iodination reaction)

The process for the preparation of 1- [ ¹⁸ F] fluoro-2- (iodomethyl) -4,5-dimethoxybenzene (compound 4) is shown in step (3) of Scheme 1 above. Specifically, 1 mL of acetonitrile containing 0.5-10 equivalents of zirconium chloride (ZrCl ₄ ) and sodium iodide (NaI) was added to Compound 3, and the reaction was conducted at 100 ° C for 5 minutes to prepare Compound 4.

The iodination reaction efficiency of the compound 4 prepared above was confirmed by radiation-thin layer chromatography (radio-TLC).

division ZrCl ₄ (eq) NaI (equivalent) Iodination Reaction Efficiency (%) One 0.5 1.0 43.5 ± 1.5 2 1.0 2.25 46.6 ± 5.9 3 2.0 2.25 92.1 ± 1.6 4 5.0 2.25 91.7 ± 2.4 5 10 4.5 48.06

As shown in Table 3, when the amount of ZrCl ₄ is less than 1 equivalent, the iodination reaction is not stably performed, but when the amount of ZrCl ₄ is equal to or greater than 2 equivalents, the yield is more than 90%. In addition, it was confirmed that the use of excess ZrCl ₄ reduced the reaction efficiency (Category 5). When ZrCl ₄ of 5 equivalents or more was used, many precipitates were formed, which made it difficult to use an automated synthesizer.

1-4. Methyl 2- (diphenylmethyleneamino) -3- (2- [ ¹⁸ F] fluoro-4,5-dimethoxyphenyl) propenoate (alkylation reaction)

Preparation of methyl 2- (diphenylmethyleneamino) -3- (2- [ ¹⁸ F] fluoro-4,5-dimethoxyphenyl) propenoate (Compound 5) Respectively. Specifically, a base, a chiral phase transfer catalyst (PTC), and an ester compound were added to Compound 4, and then reacted at room temperature for 10 minutes to prepare Compound 5.

The alkylation reaction efficiency of the compound 5 prepared above was confirmed by radiation-thin layer chromatography (radio-TLC).

division Base (equivalent) Ester compound
(equivalent weight) Alkylation reaction efficiency (%) One CsOH (70) 6.4 78.9 ± 12 2 TBAOH (24) 6.4 75.67 3 TBAOH (6) 1.5 43.11 4 KOH / K222 (6.4) 6.4 17.21

A chromatogram of the product according to the steps 1-1 to 1-4 above is shown in FIG. 1 by radiation-thin layer chromatography (radio-TLC).

1-5. [ ¹⁸ F] fluorodophores (hydrolysis and solid phase extraction)

The process for preparing [ ¹⁸ F] fluorodopa (compound 6) is shown in step (5) of Scheme 1 above. Specifically, 48% hydrogen bromide (HBr) and potassium iodide (KI) were added to Compound 5, and the mixture was hydrolyzed at 150 ° C for 10 minutes and neutralized with 6 N sodium hydroxide solution to prepare Compound 6.

Example 2. Solid phase extraction purification

Compound 6 prepared according to Example 1 was passed through a cation exchange cartridge to allow the [ ¹⁸ F] fluorodophores to stay in the cartridge, and then the cartridge was rinsed with water to remove residual impurities. Using a phosphate buffer solution, The eluted [ ¹⁸ F] fluorodophores were eluted to obtain purified [ ¹⁸ F] fluorodophores.

Example 3. High Performance Liquid Chromatography Tablets and Preparations Using Chiral Columns

Since the [ ¹⁸ F] fluorodopa purified in Example 2 above is a mixture of L-form and D-form, a pure L-form [ ¹⁸ F] fluorodopar was separated using a chiral column. For the stability of [ ¹⁸ F] fluorodophores prepared, they were formulated under conditions of maintaining ascorbic acid and low pH.

The chromatogram of the separated L-form [ ¹⁸ F] Flu + Orodpheres is shown in FIG.

Experimental Example 1. [ ¹⁸ F] Fluorophore Preparation and Quality Control

The purity and non-radioactivity values for the L-form [ ¹⁸ F] fluorodophores prepared and purified according to Examples 1 to 3 are shown in Table 5, and the chromatograms for the radiochemical and optical purity are shown in FIG. 3 .

Test Items Reference value Result value water Radiochemical purity:> 90% 100% Individual radiochemical impurities: <2% 0 % L-form [ ¹⁸ F] fluorodopa: > 95% 100% Non-radioactive > 100 mCi / mmol Lowest 2.3 x 10 ⁷ mCi / mmol

As shown in Table 5 and FIG. 3, the [ ¹⁸ F] fluorodophores according to the present invention have remarkably low production failure rates due to the progress of all reactions in a solution state, A high purity [ ¹⁸ F] fluoro wave having no radioactivity can be stably produced.

Comparative Example 1. High performance liquid chromatography purification

Compound 6 prepared according to Example 1 was purified by high performance liquid chromatography to obtain [ ¹⁸ F] fluorodopara.

Compound 6 prepared according to Example 1 was purified by solid phase extraction and high performance liquid chromatography, respectively, and the results are shown in Table 6.

division Refining method Refining time Recovery rate (%) Example 2 Solid phase extraction 3 minutes 76.62 Comparative Example 1 High Performance Liquid Chromatography 15 minutes 65.8 ± 8.7

As shown in Table 6, when purified by the solid phase extraction method according to the present invention, the recovery rate and the short purification time were higher than those of the conventional purification method using high performance liquid chromatography.

Claims (14)

(1) reacting 4,5-dimethoxy-2-nitrobenzaldehyde (compound 1) with [ ¹⁸ F] fluoride to prepare compound 2;
(2) reacting the compound 2 with a reducing agent to prepare a compound 3;
(3) reacting the compound 3 with an iodine flame to prepare a compound 4;
(4) reacting the compound 4 with an ester compound to prepare a compound 5; And
(5) hydrolyzing the compound 5 to prepare a compound 6, wherein the step of (1) to (5) above is carried out in a solution state, and [ ¹⁸ F] fluorodopa &Lt; / RTI &gt;
[Reaction Scheme 1]

The method according to claim 1, wherein in step (1), X of the compound 1 is a nitro group or a tertiary ammonium, the alkyl group of the tertiary ammonium is a primary or secondary alkyl group of C ₁ to C ₅ , sulfonyl group, methane sulfonyl trifluoromethyl, p- nitro benzene sulfonyl group, or 4-toluenesulfonyloxy group that method also characterized, ^[18 F] fluoro-wave production. The method of claim 1, wherein in step (1), [ ¹⁸ F] fluoride has lithium, sodium, potassium, cesium, rubidium or quaternary ammonium as a counter cation and the alkyl group of the quaternary ammonium is C ₁ -C ₁₀ Lt; RTI ID = 0.0 &gt; [ ¹⁸ F] &lt; / RTI &gt; fluorodopa. 2. The method of claim 1, wherein (2) the reducing agent in step is the manufacture of NaBH also, ^[18 F] _fluoro-4, characterized in that the wave. The method of claim 1, wherein the step (1) and (2) the reaction of step is carried out under the same reaction solvent, the reaction solvent is an aprotic solvent or a positive even by, ^[18 F] fluoro, characterized in that the magnetic solvents Method of manufacturing wave. The method of claim 5, wherein the aprotic solvent is prepared in acetonitrile, dimethyl formamide, dimethyl and also characterized in that any one of selected from the group consisting of sulfoxide, ^[18 F] fluoro-wave. The method of claim 5, wherein the protonic solvent is selected from the group consisting of methanol, ethanol, n -propanol, n -butanol, n -amyl alcohol, n -hexyl alcohol, n -heptanol or n -octanol; Secondary alcohols including isopropanol, isobutanol, isoamyl alcohol, or 3-pentanol; Propanol, t -butanol, t -amyl alcohol, 2,3-dimethyl-2-butanol, 2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-methyl- Cyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol, 1-methylcyclohexanol, 1-methylcyclohexanol, 1-methylcyclopentanol, -ethyl cyclohexanol, or l-methyl-cyclopropyl-heptanol also, ^[18 F] fluoro, characterized in that any one of selected from the group consisting of tertiary alcohols method of producing a file containing. The method according to claim 1, wherein the reaction of step (3) is carried out using an inorganic compound (MX ₄ ), M of the MX ₄ is titanium, zirconium, hafnium, or ruthenium, X is fluoride, Bromide, or iodide. &Lt; RTI ID = 0.0 &gt; ^{18. &lt}; / RTI &gt; The process according to claim 1, wherein the reaction of step (4) is carried out using a base and a chiral phase transfer catalyst (PTC), and the base is sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, or tetrabutylammonium hydroxide &Lt; RTI ID = 0.0 &gt; [ ¹⁸ F] &lt; / RTI &gt; The process for producing [ ¹⁸ F] fluorodophores according to claim 1, wherein the reaction of step (5) is carried out using 40 to 50% of hydrogen bromide (HBr) and potassium iodide (KI) . The method according to claim 1, wherein, after the step (5)
(6) purifying the compound 6 by a solid phase extraction method; And
(7) A process for producing [ ¹⁸ F] fluorodophores, which further comprises separating L-form [ ¹⁸ F] fluorodophores of purified compound 6 using liquid chromatography. The method of claim 11 wherein the 6 cartridges used in solid phase extraction in step is prepared in the reversed phase, ion exchange, and also, ^[18 F] fluoro, characterized in that any one of selected from the group consisting of mixing cartridge wave Way. In the above (7) in step-performance liquid chromatography is high performance liquid chromatography method for producing a (HPLC) is also characterized in that, ^[18 F] fluoro-wave that using a chiral column according to claim 11. 14. L-form [ ¹⁸ F] fluorodophores having a non-radioactivity of 2 to 3 x 10 ⁷ mCi / mmol and a purity of 95 to 100%, prepared by the method of any one of claims 1 to 13.

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