JP2000086632A - Production of mdl 100,907 labeled with c-11 - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing C-11 labeled MDL 100, 907 having a high specific radioactivity and suitable for PET measurement. SOLUTION: This method for producing MDL 100,907 labeled with C-11 comprises (1) synthesizing 11C-labeled carbon dioxide ([11C]CO2) by 14N(p,α)11C reaction, (2) treating the carbon dioxide with LiAlH4 to produce Li(11CH3O)4Al, (3) reacting the obtained Li(11CH3O)4Al with hydrogen iodide to synthesize 11C-labeled methyl iodide, and subsequently (4) reacting the labeled methyl iodide with MDL 105,725 as the precursor of MDL 100,907 to methylate the phenolic OH group into a methoxy group. Therein, dimethyl sulfoxide(DSMO) is used as a reaction solvent under a heating condition, and the introduction rate of the methyl iodide is optimized.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a C-11 labeled MD.
The present invention relates to a production method for synthesizing L100907.

[0002]

2. Description of the Related Art In order to measure the 5-HT _2A neuroreceptor of serotonin, which is one of neurotransmitters, imaging and quantification by positron emission tomography (PET) is widely performed. For this purpose,
C-11-labeled MDL100907 in which the methyl group of the phenolic O methoxy group of MDL100907 is labeled with carbon-11 as a positron-labeling element has been produced and used (Life Science, vol. 58, No. 10, pp. 187-). 192,1996).

In the present specification, (R)-(+)-4- (1-
Hydroxy-1- (2,3-dimethoxyphenyl) methyl) -N-2- (4-fluorophenylethyl) piperidine is abbreviated as MDL100907 and is represented by (R)-(+)-4
-(1-Hydroxy-1- (2-methoxyphenyl) methyl) -N-2- (4-fluorophenylethyl) piperidine is abbreviated as MDL105725.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a high specific activity C-11 labeled MDL100907 suitable for PET measurement.
It is an object of the present invention to provide a method for producing the same.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems of the prior art, and (1) ¹⁴ N (p,
The alpha) ¹¹ C reaction, ¹¹ C-labeled carbon dioxide ^([11 C] CO
₂ ) to synthesize (2) the carbon dioxide with LiAlH ₄ to Li ( ¹¹ C
H ₃ O) ₄ Al, (3) the Li ( ¹¹ CH ₃ O) ₄ Al was hydrogen iodide to synthesize ¹¹ C-labeled methyl iodide, and (4) a precursor of the methyl iodide and MDL100907. MDL10
When methylating a phenolic OH group into a methoxy group by reaction with 5725, dimethyl sulfoxide (DMSO) is used as a reaction solvent under heating conditions, and the introduction rate of the methyl iodide is optimized. By doing so, a method for producing C-11 labeled MDL100907 was found, and the present invention was completed.

That is, the present invention provides a C-11-labeled MDL.
In the production method for synthesizing 100907, (1) ¹⁴ N (p,
The alpha) ¹¹ C reaction, ¹¹ C-labeled carbon dioxide ^([11 C] CO
₂ ) to synthesize (2) the carbon dioxide with LiAlH ₄ to Li ( ¹¹ C
And H ₃ O) ₄ Al, (3) by the _{^{Li (11 CH 3 O) 4}} Al hydroiodic, to synthesize ¹¹ C-labeled methyl iodide, (4) the methyl iodide of the low flow rate not MDL1057 by active gas
25 is introduced into dissolved dimethyl sulfoxide in which H.25 is dissolved for O-methylation.

Hereinafter, the present invention will be described according to embodiments.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION
An object of the present invention is to provide a C11-labeled MDL100907 having a sufficient production amount (represented by GBq) usable under an object of T measurement and under measurement conditions.

Specifically, in a single synthesis operation, a C11-labeled MDL100907 having substantially 100% purity and a production amount of at least 0.3 GBq or 10 mCi or more,
Production volume is at least 1.5GBq or 40mCi if needed
The above can be provided.

(Production conditions) C11-labeled MD according to the present invention
As shown in FIGS. 1 and 2, the production method of L100907 is obtained by first synthesizing ¹¹ C-labeled carbon dioxide ([ ¹¹ C] CO ₂ ) by ¹⁴ N (p, α) ¹¹ C reaction. Carbon dioxide
LiAlH ₄ to Li ( ¹¹ CH ₃ O) ₄ Al, then Li ( ¹¹ CH ₃ O) ₄ A
l with hydrogen iodide, ¹¹ C-labeled methyl iodide ([ ¹¹
C] CH ₃ I) was synthesized and its methyl iodide and MDL100
In each step of the reaction with MDL105725, which is the precursor of 907, methylation of the phenolic OH group is performed to obtain C11-labeled MDL100907, and the obtained crude product is isolated and purified.

According to such a manufacturing method, the object of the present invention, C
In order to obtain 11-labeled MDL100907, each reaction needs to be highly selective and high yield. further,
In order to obtain C11-labeled MDL100907 as a final purified product, not only must each reaction be highly selective and in high yield, but also the time required from synthesis (or preparation) to isolation and purification should be as short as possible. It needs to be short.

Accordingly, the present invention provides a C11-labeled MDL10
In order to obtain 0907, the reaction in each step is not only highly selective and high yield, but also optimizes the time required for the final isolation and purification. In addition, for such optimization, in the present invention, it is usually necessary to remotely control all the steps. Therefore, it is preferable to carry the intermediates and the like obtained in the above steps to the next step by an inert gas flow. In this case, it is important to control the flow rate of the inert gas.

That is, the present invention is characterized in that dimethyl sulfoxide (DMSO) is used as an O-methylation reaction solvent, and the reaction uses DMSO under heating conditions for an appropriate reaction time. The heating conditions for such DMSO are preferably 150 ° C. or higher, more preferably 180 ° C. or higher. Since it is known that the boiling point of DMSO under one atmosphere is 186 ° C., the above temperature includes the boiling point of DMSO as its upper limit. At such a temperature, the concentration of ¹¹ C-labeled methyl iodide introduced in DMSO (which can be determined by the maximum value of the radioactivity) becomes smaller as compared with DMSO at lower temperatures, but the Is present at a sufficient concentration.

Further, the manufacturing method according to the present invention is characterized in that
(4) The method according to (4), wherein the rate of introduction of ¹¹ C-labeled methyl iodide into DMSO is optimized. That is, ¹¹ C-labeled methyl iodide is as described in the above (1)-
According to (3), it is introduced into DMSO by an inert gas, and it is necessary to optimize the flow rate of such introduction. There is no particular limitation on such an optimization method. Type of inert gas (eg, nitrogen gas) (eg, nitrogen gas), ¹¹
Depending on the concentration of C-labeled methyl iodide, the shape of the reaction apparatus, and the like, the flow rate at which the concentration in DMSO becomes maximum (which can be determined by the maximum value of radioactivity) can be set. If the flow rate is too high, a sufficient amount of ¹¹ C-labeled methyl iodide will not accumulate, resulting in low yields of C1
One labeled MDL 100907 will be obtained.

(Manufacturing Apparatus) FIG. 3 shows one preferred embodiment of an apparatus using the method according to the present invention. Hereinafter, each device will be described.

(A) [ ¹¹ C] CO ₂ generator system In the apparatus 1 for generating ¹¹ C-labeled carbon dioxide ([ ¹¹ C] CO ₂ ), generated [ ¹¹ C] CO ₂ is converted by an inert gas. There is an inert gas flow system moving to the first reaction vessel. Such an inert gas flow system flows from the gas supply source 2 through the valve 3 into the generator. This gas pressure is monitored by a pressure gauge 4. [ ¹¹ C] CO ₂ generated by the inflowing gas flows into the flow control device 8 through the valves 5 and 6. The pressure of the gas system whose flow rate is controlled is monitored by manometers 7 and 9. The gas containing [ ¹¹ C] CO ₂ flowing out of the flow control device 8 is introduced into the exhaust system through the three-way valve 10 or into the first reaction vessel 12 through the valve 11. [ ¹¹
C] The CO ₂ generator 1 is not particularly limited, and a generally known device or a commercially available device can be preferably used. The generation capacity is preferably about 5 GBq.

Further, there is no particular limitation on the inert gas flow system for moving the generated [ ¹¹ C] CO ₂ , but at least the flow control device 8 (specifically, 585 from Brooks)
0i). Further, it is preferable that the flow path is as short as possible.

(B) Hydrogen iodide water supply system Hydrogen iodide water container 14 for supplying hydrogen iodide water to first reaction vessel 12 through valve 13, and hydrogen iodide water 1
An inert gas system (consisting of an inert gas source 17, a pressure gauge 16, and a three-way valve 13) for moving the sample 8 to the first reaction vessel is provided. It is preferable that the hydrogen iodide water 18 be put in the hydrogen iodide water container 14 in advance, and the capacity thereof is not particularly limited, but is preferably about 0.5 ml. The concentration of the hydrogen iodide water is usually about 55%. In addition, hydrogen iodide water
The inert gas system for moving to the reaction vessel is not particularly limited, but it is easy to optimize the pressure for quickly moving to the first reaction vessel with an inert gas such as nitrogen.

(C) The first reaction vessel 12 is made of Li ( ¹¹ CH ₃ O) ₄ A using ¹¹ C-labeled carbon dioxide ([ ¹¹ C] CO ₂ ) and LiAlH _4.
was prepared l as an intermediate, it is further reactor for synthesizing ^{1 1} C-labeled methyl iodide by the hydrogen iodide.
Therefore, a predetermined amount of LiAl
H ₄ is dissolved or suspended in an appropriate solvent, and the above [ ¹¹ C] CO ₂ is introduced into the solvent at a predetermined temperature using an inert gas stream. Here, the solvent is not particularly limited.
Any anhydrous polar solvent that does not react with LiAlH ₄ can be preferably used. Specific examples include anhydrous tetrahydrofuran (THF).

In order to heat the solvent, the first reaction vessel 12 has a temperature control device 1 whose outer periphery is temperature-controlled.
9 are provided. The cooling and heating temperature of the solvent is usually -1.
The temperature is from around 0 ° C. to around the boiling point of the solvent (for example, about 80 ° C. in THF). The temperature is monitored by a thermometer 20. Examples of the temperature control device 19 include a device using temperature-controlled air and a device using a temperature-controlled liquid medium. Further, a cooling pipe 21 (and a cooling water valve 59) is provided in the first reaction vessel in order to complete the reaction by heating the solvent to near the boiling point to accelerate the reaction. FIG. 3 shows the case of air whose temperature has been adjusted by the air heating device 22 and the cooling device 23. Such air for temperature control is supplied from an air source 24 through a valve 25 and a speed controller 26, and the pressure is measured by a pressure gauge 27,
Maintained and monitored at 28.

Next, the above intermediate is prepared in the first reaction vessel.
After preparing Li ( ¹¹ CH ₃ O) ₄ Al, THF as a solvent is heated and evaporated in an inert gas stream and removed to the exhaust system 31 through valves 29 and 30. The resulting intermediate Li ( ¹¹ C
An HI solution is further added to H ₃ O) ₄ Al to prepare ¹¹ C-labeled methyl iodide ([ ¹¹ C] CH ₃ I). At this time, the reaction is heated to about 70 ° C. to accelerate the reaction. Further, the radioactivity in the first reaction vessel is monitored by the radiation meter 32.

(D) The second reaction vessel 33 further contains ¹¹ C-labeled methyl iodide ([ ¹¹ C] CH ₃ I) and MDL1057.
This is a device for synthesizing C11-labeled MDL100907 by reacting with M25.

In the reaction vessel 33, a predetermined amount of MDL105725 is dissolved or suspended in a suitable solvent in advance, and the above-mentioned [ ¹¹ C] CH ₃ I is added at a predetermined temperature using an inert gas flow. It is introduced into the solvent. Here, DMSO is preferred as the solvent.

In order to heat the solvent, the second reaction vessel 33 is controlled by a temperature control device 3 so that the outer periphery thereof is controlled in temperature.
4 are provided. The cooling and heating temperature of the solvent is usually -1.
From around 5 ° C. to around the boiling point of the solvent (for example, in DMSO,
About 186 ° C). Such temperature control devices include those using temperature-controlled air and those using a temperature-controlled liquid medium. The temperature is monitored by a thermometer 37. Further, the solvent is heated until it is near the boiling point to accelerate the reaction. FIG. 3 shows the case of the air whose temperature is adjusted by the air heating device 35 and the cooling device 36. The air for temperature control is supplied from an air source 24 through a valve 25 and a speed controller 26, and the pressure is maintained and monitored by pressure gauges 27 and 28. Further, the radioactivity in the second reaction vessel is monitored by the radiation meter 32.

Specifically, a predetermined value (for example, 0.5 mg) of MDL105725 is added to DMSO (for example, DMSO 1 m
l and NaOH (5N, 10 [mu] l) were dissolved in a mixed solution) in while heating the temperature to a predetermined temperature (e.g. 180 ° C.), ^[11
C] CH ₃ I is introduced into the solvent using a stream of inert gas.
[ ¹¹ C] CH ₃ I is moved by an inert gas flow from the aqueous solution in the first reaction vessel 12 and contains a large amount of water.
It is preferable to dry using, for example, Ascalite / P ₂ O ₅ . Since the introduction of the dried [ ¹¹ C] CH ₃ I is performed through the three-way valve 42 together with the inert gas, the flow rate of the [ ¹¹ C] CH ₃ I in the reaction solvent of the second reaction vessel 33 depends on the flow rate.
The saturation concentration reached by I changes. Therefore, if the flow rate is too large, a sufficient saturation concentration will not be reached. Preferably, it is about 50 ml / min. Further, the reaction temperature is preferably about 180 ° C. in order to complete the reaction quickly. The O-methylation reaction in the second reaction vessel progresses very rapidly under such high temperature conditions as compared to room temperature. Specifically, it is completed in about 5 minutes, so that it is possible to proceed to the purification step while keeping the radioactivity which usually attenuates largely in this step high. Further, the second reaction vessel 33 is provided with a syringe-type device 44 and a syringe driving valve 60 to which another solvent 43 can be added through the valve 41. This syringe is supplied from an air source 24. The pressure in the second reaction vessel 33 is adjusted by the valves 45 and 30.

(E) The column chromatograph is operated by the second
C11 from the crude product synthesized in the reaction vessel 33
It is used to isolate and purify labeled MDL100907. Such a purification column chromatograph needs to be rapid and have a purity of substantially 100%. Various column chromatography devices can be used to achieve such an object. FIG. 3 specifically shows column 4
6. A developing solvent 47, a detector 48, and a developing solvent valve 4 for supplying a solvent required for the chromatographic apparatus.
9, 50 are shown. Further, a pressure vessel 51 for pressure adjustment, a valve 52 for pressure adjustment, and a bubbler 56 are provided together with a valve 57. Further, a valve 53 and a container 54 for storing a fraction to be isolated, and a container 5 for collecting unnecessary fractions
5 are provided. The radioactivity is monitored by radioactivity meter 56.

(F) The obtained final product, C11-labeled MDL100907, is filled in a container 54,
Provided for measurement.

[0028]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist.

Synthesis and purification of C11 labeled MDL100907
In manufacturing Example ^{1-14 (1) [11 C]} CO 2 generator system ^{in, 14 N (p, α)} 11 by C-reactive, was synthesized ^[11 C] CO ₂ 5GBq.

(2) The obtained [ ¹¹ C] CO ₂ was converted into a N ₂ gas flow (1 atm, 400 ml / min) introduced from a gas supply source.
And introduced into the first reaction vessel. At this time, LiAlH ₄ was previously dissolved in THF as a solvent in the first reaction vessel. [ ¹¹ C] C with the first reaction vessel at -15 ° C
O ₂ was introduced to synthesize Li ( ¹¹ CH ₃ O) ₄ Al.

(3) THF was heated and evaporated at 80 ° C. in the first reaction vessel, and was removed through a valve. After cooling to room temperature, Li ( ¹¹ CH ₃ O) ₄ Al was passed through a N ₂ gas stream ( 0.5at
m), add 0.5 ml of a 55% strength HI solution,
The mixture was heated at 70 ° C. to synthesize [ ¹¹ C] CH ₃ I. (4) generating a gaseous state the _{^{[11 C] CH 3 I,}} N 2 gas stream (1 atm) as a carrier, through the drying device low flow rates (approximately 50ml /
Min) into the second reaction vessel. At this time, MDL105725 (0.5 mg) was previously placed in the second reaction vessel.
It had been dissolved in a mixed solution of DMSO (0.5 ml) and NaOH (5 N, 10 μl). Then, [ ¹¹ C] CH ₃ I was supplied while heating the second reaction vessel. When the radioactivity reached a maximum, the supply of [ ¹¹ C] CH ₃ I was stopped and another 18
The reaction was carried out at 0 ° C. for 5 minutes, and C11-labeled MDL100907
Was synthesized.

(5) The generated C11-labeled MDL1009
The 07 crude product was transferred to a column chromatograph using an N ₂ gas stream (1 atm) and isolated and purified.

Table 1 shows the obtained results (production amount).

[0034]

[Table 1]

Comparative Example 1-5 The amount of the raw material (MDL105725) was 0.5 mg, acetone (0.5 ml) was used as a solvent, the flow rate of methyl iodide was 200 ml / min, and the methyl iodide trap condition was about -15 ° C. C11-labeled MDL100907 was obtained in the same manner as in the above example except that the duration was 1.5 minutes.

Table 2 shows the obtained results (production amount).

[0037]

[Table 2]

[0038]

According to the present invention, dimethyl sulfoxide (DMSO) is used as an O-methylation reaction solvent, and DMS is used.
O is used under heating conditions (150 ° C. or higher, preferably 180 ° C. or higher) for an appropriate reaction time. Solvent DM
At such a high temperature of SO, the reaction between ¹¹ C-labeled methyl iodide and MDL 105725 proceeds very quickly, so that the time required for the reaction is shortened, and thus the production of C11-labeled MDL 100907 obtained as a final product is reduced. The amount (yield) increases.

[Brief description of the drawings]

FIG. 1 shows an MD that can be used in the method according to the invention.
It is a figure which shows the synthesis route of L100907.

FIG. 2 shows C11-labeled MDL10 by the method according to the invention.
It is a figure which shows the manufacturing method of 0907.

FIG. 3 shows C11 that can use the method according to the present invention.
It is a figure showing an example of a manufacturing device of sign MDL100907.

[Explanation of symbols]

1 ... ^[11 C] CO ₂ generator, 2 ... a gas supply source, 3 ... valve, 4 ... pressure gauge, 5 ... valve, 6 ... valve, 7 ... pressure gauge, 8
... Flow control device, 9 ... Pressure gauge, 10 ... Three-way valve, 11
... Valve, 12 ... First reaction vessel, 13 ... Three-way valve, 1
4: Hydrogen iodide water container, 15: Three-way valve, 16: Pressure gauge, 17: Inert gas source, 18: Hydrogen iodide, 19 ...
Temperature control device, 20 thermometer, 21 cooling pipe, 22 air heating device, 23 air cooling device, 24 air source, 25
... Valve, 26 ... Speed controller, 27 ... Pressure gauge, 28 ... Pressure gauge, 29 ... Valve, 30 ... Valve, 31
... exhaust system, 32 ... radiation measuring instrument, 33 ... second reaction vessel,
34 temperature control device, 35 air heating device, 36 air cooling device, 37 thermometer, 38 drying device, 39 valve, 40 valve, 41 three-way valve, 42 three-way valve, 43 solvent 44: syringe type device, 45: valve, 46: column, 47: developing solvent, 48: detector,
49 ... three-way valve for developing solvent, 50 ... valve for developing solvent, 51 ... pressure vessel, 52 ... valve for pressure adjustment, 53 ...
Three-way valve, 54 ... container, 55 ... container, 56 ... radioactivity measuring instrument, 57 ... three-way valve, 58 ... bubbler.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hideo Tsukada 1126 Nomachi, Hamamatsu City, Shizuoka Prefecture 1 Hamamatsu Photonics Co., Ltd. F term (reference) 4C054 AA02 CC03 DD01 EE01 FF05 FF12

Claims (2)

[Claims] 1. A method for synthesizing C-11 labeled MDL100970, comprising: (1) a ¹⁴ N (p, α) ¹¹ C reaction
¹¹ C-labeled carbon dioxide ([ ¹¹ C] CO ₂ ) is synthesized, (2) the carbon dioxide is converted to Li ( ¹¹ CH ₃ O) ₄ Al by LiAlH ₄ , and (3) the Li ( ¹¹ CH ₃ O) ₄ Al is synthesized with hydrogen iodide to synthesize ¹¹ C-labeled methyl iodide, and (4) the methyl iodide is introduced into a heated dimethyl sulfoxide in which MDL105725 is dissolved by a low flow rate inert gas to O-methylate. A method comprising: 2. The method according to claim 1, wherein the dimethyl sulfoxide is heated to at least 180 ° C. in the step (4).