KR20170076931A

KR20170076931A - A method for preparation of radiopharmaceutical using naphthalene-based organic base as a catalyst

Info

Publication number: KR20170076931A
Application number: KR1020150186604A
Authority: KR
Inventors: 이상윤; 이학정; 정일구; 박재경
Original assignee: (의료)길의료재단; 가천대학교 산학협력단
Priority date: 2015-12-24
Filing date: 2015-12-24
Publication date: 2017-07-05
Also published as: WO2017111220A1; KR101863998B1

Abstract

The present invention relates to a method for producing [ ¹¹ C] radiopharmaceuticals, and specifically discloses a method for producing a radiopharmaceutical comprising the step of performing [ ¹¹ C] methylation of a phenolic precursor in the presence of a naphthalene-based organic base There is.
In the production method of the present invention, in producing a radiopharmaceutical from a phenolic precursor by the [ ¹¹ C] methylation reaction, a proton sponge such as a naphthalene-based organic base is used as a catalyst to promote the methylation reaction of an alcohol, The solubility can be improved, and the radiopharmaceutical can be produced with high yield.

Description

[0001] The present invention relates to a method for preparing a radiopharmaceutical using a naphthalene-based organic base as a catalyst,

The present invention relates to a method for producing [ ¹¹ C] radiopharmaceuticals, and specifically discloses a method for producing a radiopharmaceutical comprising the step of performing [ ¹¹ C] methylation of a phenolic precursor in the presence of a naphthalene-based organic base There is.

Radioactive isotopes are radioactive isotopes that decay into a stable state while emitting radiation. These radioactive isotopes give physical or chemical effects on the material during the transmission of radiation, and other properties such as transmission or scattering depending on the material have different characteristics. Therefore, it is being used in basic research or applied research in various fields such as medicine, agriculture, science, engineering, etc. by utilizing the characteristics of such radioisotope. In addition, radioisotopes can be easily detected even if they are present in very small amounts due to the radiation emitted therefrom, and are particularly used for tracking the movement of substances.

For example, recent positron emission tomography is in the medical field is widely used for diagnostics and basic research in various diseases (PET; Positron Emission Tomography) ^{is, [11 C], [18} F] positron which emits radioactive isotopes such as . For example, a compound which is the same as or similar to a metabolite which is exaggerated when a specific disease occurs can be labeled with any one of the isotopes, or a compound identical or similar to a substance binding to a specific receptor can be labeled with any one of the isotopes, a radiopharmaceutical that serves as a tracer can be produced. After the radiopharmaceuticals thus prepared are administered to the body, the entire body is scanned to detect and interpret the positron distribution, thereby obtaining useful information.

Most of the radioactive drugs labeled with [ ¹¹ C] in the above radiopharmaceuticals are produced by reacting [ ¹¹ C] methane with a desmethyl precursor, that is, a precursor without a methyl group, and the positron emission tomography It has been used for early diagnosis and is now being used for various purposes and applications.

The des-methyl precursor, for example, the phenolic alcohol ^[11 C] methylation ^{([11 C] raclopride, [} 11 C] DTBZ, [11 C] Preparation of fallypride) In general, the strong inorganic base for (NaOH, KOH, NaH Etc.) (Appl. Radiat. Isot., 1997, 48: 763, Appl. Radiat. Isot., 2010, 68: 1079). However, there is a problem in that the yield is not constant and the reproducibility is low even when the synthesis is carried out using the synthetic method using strong inorganic bases in the same manner.

The inventors of the present invention have made extensive efforts to find a catalyst capable of overcoming the disadvantage that the solubility is lowered and the irregular yield is lowered when the inorganic strong base is used in the process for producing radiopharmaceuticals by the [ ¹¹ C] methylation. As a result, The present invention has been accomplished by confirming that the radiopharmaceuticals can be produced in a stable and high yield by absorbing hydrogen ions from phenols and aliphatic alcohols to improve the solubility and promote the methylation reaction of alcohols.

In order to achieve the above object, the present invention provides a method for producing a radioactive pharmaceutical product, which comprises performing [ ¹¹ C] methylation reaction of a phenolic precursor in the presence of a naphthalene-based organic base, wherein the naphthalene- Wherein the pKa value of the conjugated acid is 11.5 to 18 for water, 7 to 17 for dimethylsulfoxide (DMSO), or 8 to 30 for acetonitrile (MeCN).

Hereinafter, the present invention will be described in more detail.

The present invention relates to a process for the preparation of radiopharmaceuticals from phenolic precursors such as (S) -O-desmethyl laclfluoride and 9-O-desmethyl-DTBZ by [ ¹¹ C] methylation reaction catalyzed by inorganic strong bases such as NaOH When the synthesis is carried out in the same manner, it is impossible to provide a uniform yield and the reproducibility of the synthesis is low. The inventors have devised a solution to this problem, Was not completely dissolved in the reaction solution and the homogeneous reaction could not be induced, resulting in an irregular pattern radiochemical yield. Therefore, in order to overcome this disadvantage, when a naphthalene-based organic base having a pKa value is used as a catalyst for the inorganic strong base instead of the inorganic strong base, the solubility is not reduced and the precursor is completely dissolved in the reaction solution, It is a feature of the present invention that it is possible to produce a radiopharmaceutical drug at a constant yield as long as the same conditions are maintained even if the synthesis is reproduced.

For example, the naphthalene-based organic base may be represented by one of the following formulas (1) to (3):

[Chemical Formula 1]

(2)

(3)

In Formula 1,

m and n are the same integer of 0 to 2;

R ¹ and R ³ are each independently C _1-4 alkyl;

R ² and R ⁴ are each independently C _1-4 alkyl or may be connected to each other by C _4-5 alkylene which does not contain or contain an oxygen atom in the middle of the chain;

R ⁵ to R ¹⁰ are each independently C _1-4 alkyl,

In the above Formulas 2 and 3,

R is C _1-4 alkyl.

Compounds having a structure containing a tertiary amine directly or indirectly linked to the naphthalene skeleton as described above can function as a hydrogen acceptor in the [ ¹¹ C] methylation reaction of the tertiary amine, and thus the reactive moiety is sterically limited By using a catalyst, an effect of preventing unnecessary side reactions can also be obtained.

For example, the naphthalene-based organic base may be 1,800 bis (dimethylamino) naphthalene, 1,8-bis (tetramethylguanidino) naphthalene, or 1,8- bis (hexamethyltriaminophosphazenyl) But is not limited thereto.

The phenolic precursor capable of providing [ ¹¹ C] radiopharmaceuticals by the process of the present invention is (S) -3,5-dichloro-N - ((1-ethylpyrrolidin- 2,2-dihydroxybenzamide, (2R, 3R, llbR) - (2-ethylpyrrolidin- (2R, 3R, < RTI ID = 0.0 > 3R) -lH- < / RTI & 11bR) -3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a] isoquinoline-2,9- ((S) -N - (((1-allyl-2-methylpyrrolidin-2-yl) methyl) -5- (3-fluoropropyl) -2- 1-allyl-2-methylpyrrolidin-2-yl) methyl) -5- (3-fluoropropyl) -2-hydroxy-3-methoxybenzamide).

As the reactant for the [ ¹¹ C] methylation reaction, a compound containing a [ ¹¹ C] labeled methyl group may be used. Specifically, the reactant may be, but is not limited to, methyltrifluoromethanesulfonate ([ ¹¹ C] MeOTf) labeled with [ ¹¹ C] in the methyl group.

In addition, the radiopharmaceutical, which may be produced by the production method of the present invention is ^[11 C] la claw Fried ^{([11 C] raclopride),} [11 C] DTBZ or ^[11 C] poly Fried ^([11 C] fallypride ), But is not limited thereto.

The [ ¹¹ C] methylation reaction may be carried out in a solvent of 2-butanone (MEK), but is not limited thereto, and a compound containing a phenolic precursor, a catalyst and a [ ¹¹ C] Any solvent capable of dissolving [ ¹¹ C] methylation can be used without limitation.

For example, the naphthalene-based organic base used in the [ ¹¹ C] methylation reaction may be used in an equivalent ratio of 1: 0.8 to 2.0 to the phenolic precursor used. Or in an equivalent ratio of 1: 1 to 1.5. Preferably 1: 1.1 to 1.3, more preferably 1: 1.2, but is not limited thereto.

For example, the [ ¹¹ C] methylation reaction is carried out by dissolving a phenolic precursor in a solvent together with a naphthalene-based organic base and then adding [ ¹¹ C] labeled methyltrifluoromethane sulfonate ([ ¹¹ C] MeOTf) to the methyl group But it is not limited thereto.

The production method of the present invention promotes the methylation reaction of an alcohol by using a naphthalene-based organic base or a proton sponge as a catalyst in the preparation of a radiopharmaceutical from a phenolic precursor by the [ ¹¹ C] methylation reaction, And thus it is possible to produce a radioactive pharmaceutical product in a stable and high yield.

FIG. 1 shows the reproducibility of the yield in the [ ¹¹ C] methylation reaction using NaOH (Entry 7 to 12 in Table 2) or TMGN (Entry 1 to 6 in Table 1) as catalysts.
Figure 2 shows the prep HPLC profile for [< ¹¹ > C] methylation using NaOH.
Figure 3 shows the prep HPLC profile for [< ¹¹ > C] methylation using TMGN.
Fig. 4 is a diagram showing a visual observation of a solution of a precursor containing no or NaOH or TMGN as a methylation catalyst. Fig.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example One: TMGN Using [ ¹¹ C] Methylation of radioactive drugs ([ ¹¹ C] raclopride

The inventors of the present invention have found that, in the following comparative example, except that TMGN (1,8-bis (tetramethylguinodino) naphthalene, 1.2 equivalents, Sigma Aldrich), which is an organic base, is used instead of NaOH which is an inorganic strong base commonly used as a catalyst [ ¹¹ C] racopride ([ ¹¹ C] raclopride) was prepared in the same manner as in [ ¹ C]. Specifically, the precursor, (S) -O -desmethyllactopride ((S) -O -desmethyllaclopride, 1 mg) was dissolved in 2-butanone (MEK, 300 μl) and TMGN Respectively. A ^[11 C] CO ₂ production in a cyclotron using a synthesizer were ^[11 C] to ^[11 C] MeOTf in the form of gas generated is converted into MeOTf the previously prepared precursor solution at room temperature for about 5 minutes in bubble form injected . The reaction was stopped by adding 1.7 ml (pH ~ 3.7) of 0.1 M ammonium formate buffer to the reaction solution, and the reaction was stopped by separating the solution into a prep-HPLC and eluting with acetonitrile / 0.05 M ammonium formate buffer (35/65) (UV 254 nm, flow rate 3 ml / min, C18 column 250 mm x 9.4 mm, 5 μm pore size). The separated HPLC solution was subjected to solid phase extraction (SPE method, tC ₁₈ ) to remove the organic solvent, and the final compound obtained using ethanol and physiological saline was recovered into a sterilizing vial. The radioactivity of the final product was measured in units of mCi using a gamma ray detector and the specific activity (SA) was determined by HPLC.

The radiochemical yield (EOS) and the radioactivity of [ ¹¹ C] lacclide prepared using TMGN were measured as described above and shown in Table 1 below.

Entry Yield (mCi) S.A. One 178 1.7 2 171 1.3 3 175 1.3 4 176 1.7 5 178 2.2 6 171 2.1

Comparative Example 1: using inorganic strong base [ ¹¹ C] Production of radioactive pharmaceuticals by methylation

Radiation labeling was also performed with methods known in the art (Applied Radiation and Isotopes, 2001, 55: 17-22; and Synthetic Communications, 2004, 34 (10): 1897-1907 et al. [ ¹¹ C] CO ₂ and [ ¹¹ C] MeOTf were prepared under the same conditions (55 μA, 30 min bombardment) for all syntheses. We also prepared [ ¹¹ C] [ ¹¹ C] raclopride by the same synthetic method except for the preparation time of the precursor solution (reacted with NaOH in a vortex mixer for an additional 30 minutes). ^[11 C] prior to ^[11 C] methylation by MeOTf (S) - O - desmethyl la claw Fried - MEK with 0.1M NaOH (3 μl) as the base ((S) O -desmethylraclopride, 1 mg) (2-butanone, 300 [mu] l). The final product was separated by HPLC purification and SPE (tC ₁₈ ), washed with 10% EtOH solution and packed in a sterile vial.

The radiochemical yield (EOS) and specific activities of [ ¹¹ C] laclfrid prepared using 0.1 M NaOH were measured as described above and shown in Table 2 below. As a result of confirming the yield with varying the concentration of NaOH, the highest yield was obtained when the concentration of NaOH was 0.1 M as described above.

Entry Yield (mCi) S.A. One 97 1.1 2 88 1.6 3 110 1.3 4 113 1.6 5 88 1.7 6 48 1.7 7 148 1.6 8 134 2.1 9 111 1.3 10 119 1.6 11 146 1.2 12 126 1.1 13 63 2.1 14 82 1.7 15 116 3.2 16 117 1.6 17 139 1.7 18 137 1.6 19 152 1.8 20 132 1.0

Example 2: TMGN Yield yield

The radioactive drug was prepared by the [ ¹¹ C] methylation reaction using TMGN as a catalyst in the same manner as in Example 2, except that the amount of TMGN was changed (1.0 equivalent, 1.2 equivalent and 1.5 equivalent). The yields and SA values of the radiopharmaceuticals obtained in each case are shown in Table 3 below.

Entry Reaction conditions Yield (mCi) S.A. One TMGN (1.0 eq), MEK 121 0.6 2 TMGN (1.0 eq), MEK 142 1.1 3 TMGN (1.0 eq), MEK 130 0.9 4 TMGN (1.0 eq), MEK 128 0.9 5 TMGN (1.0 eq), MEK 132 1.0 6 TMGN (1.2 eq.), MEK 171 1.3 7 TMGN (1.2 eq.), MEK 178 1.7 8 TMGN (1.2 eq.), MEK 175 1.3 9 TMGN (1.2 eq.), MEK 176 1.7 10 TMGN (1.2 eq.), MEK 178 2.2 11 TMGN (1.2 eq.), MEK 171 2.1 12 TMGN (1.5 eq), MEK 146 1.1 13 TMGN (1.5 eq), MEK 80 0.6 14 TMGN (1.5 eq), MEK 91 0.7 15 TMGN (1.5 eq), MEK 136 0.8 16 TMGN (1.5 eq), MEK 105 0.8

As shown in Tables 1 and 2, it was confirmed that the method using TMGN provided a higher and uniform yield than the method based on NaOH. In the RA profile (Figure 2) from prep HPLC, more byproducts ([< ¹¹ > C] MeOH) were generated by nucleophilic reaction with NaOH. When the precursor solution was prepared, an opaque mixture was formed due to the lowering of solubility when NaOH and precursor were mixed in the solvent MEK (2-butanone), and incomplete dissolution of such reagents caused a low reaction yield 4).

Comparative Example 2: Aliphatic Alcohol Preparation of radiopharmaceuticals using precursors

To the inventors to determine also whether the radiopharmaceutical produced by the ^[11 C] methylation using an organic base in an alcohol other than a phenolic precursor, (S) as a precursor - O - desmethyl la chloride compound of an aliphatic alcohol in place of Fried [ ¹¹ C] methylation experiment was carried out in the same manner as in Example 1 using DWP09031 as a precursor and the yield was measured. However, the measured yield was very low (<10 mCi). On the other hand, the aliphatic alcohols showed higher yields when NaH (pKa ~ 37) was used compared to the case where TMGN was used as a catalyst. This is because alcohols having relatively high acidity (for example, phenolic OH, pKa ~ 10) RTI ID = 0.0 > methylation < / RTI > Other organic bases with high pKa (e. G., HMPN) indicate that they can be good candidates for this purpose.

Claims

[ ^11C ] methylation reaction of a phenolic precursor in the presence of a naphthalene-based organic base,
Wherein the naphthalene organic base has a pKa value of conjugated acid of 11.5 to 18 for water, 7 to 17 for dimethylsulfoxide (DMSO) or 8 to 30 for acetonitrile (MeCN) Way.

The method according to claim 1,
Wherein the naphthalene-based organic base is represented by any one of the following formulas (1) to (3):
[Chemical Formula 1]

(2)

(3)

In Formula 1,
m and n are the same integer of 0 to 2;
R ¹ and R ³ are each independently C _1-4 alkyl;
R ² and R ⁴ are each independently C _1-4 alkyl or may be connected to each other by C _4-5 alkylene which does not contain or contain an oxygen atom in the middle of the chain;
R ⁵ to R ¹⁰ are each independently C _1-4 alkyl,
In the above Formulas 2 and 3,
R is C _1-4 alkyl.

The method according to claim 1,
Wherein the naphthalene-based organic base is DMAN (1,8-bis (dimethylamino) -naphthalene), 1,8-bis (tetramethylguanidino) naphthalene or 1,8-bis (hexamethyltriaminophosphazenyl) Way.

The method according to claim 1,
The phenolic precursor was prepared by reacting (S) -3,5-dichloro-N- ((1-ethylpyrrolidin-2- yl) methyl) -2,6-dihydroxybenzamide ((S) -dichloro-N - ((1-ethylpyrrolidin-2-yl) methyl) -2,6-dihydroxybenzamide), (2R, 3R, llbR) -3-isobutyl-10-methoxy- , 7,11b-hexahydro-1H-pyrido [2,1-a] isoquinoline-2,9-diol ((2R, 3R, llbR) -3-isobutyl- (S) -N- (1-allyl-2-methylpyrrolidin-2-yl) -6,7,11b- hexahydro-lH- pyrido [2,1-a] isoquinoline- Methylpyrrolidin-2-yl) methyl) -5- (3-fluoropropyl) -2-hydroxy-3-methoxybenzamide ((S) -N- (1-allyl- (3-fluoropropyl) -2-hydroxy-3-methoxybenzamide).

The method according to claim 1,
The [ ¹¹ C] methylation reaction is carried out by reacting the methyl group with [ ¹¹ C] labeled methyltrifluoromethanesulfonate ([ ¹¹ C] MeOTf).

The method according to claim 1,
The method of producing the radiopharmaceutical is ^[11 C] la claw Fried ^{([11 C] raclopride),} [11 C] to the DTBZ or ^[11 C] poly Fried ^([11 C] fallypride).

The method according to claim 1,
Wherein the [ ¹¹ C] methylation reaction is carried out in a 2-butanone (MEK) solvent.

8. The method according to any one of claims 1 to 7,
The [ ¹¹ C] methylation reaction is carried out by dissolving a phenolic precursor together with a naphthalene-based organic base in a solvent and then adding [ ¹¹ C] labeled methyltrifluoromethane sulfonate ([ ¹¹ C] MeOTf) to the methyl group &Lt; / RTI >