JPS60185730A - Synthesis of radioactive compound using nucleus seed with short life - Google Patents

Abstract

PURPOSE:To obtain advantageously a radioactive compound using a nucleus seed with a short life, by presealing hermetically a given amount of an intermediate for the desired radioactive compound within a reactor, attaching the reactor to a device for synthesizing the radioactive compound in synthesis, carrying out synthetic reaction. CONSTITUTION:In synthesizing a radioactive compound using a nucleus seed with a short life, especially a radioactive drug such as <11>C-N-methylspiperone (dopamine receptor blocking agent) useful for diagnosis, examination, etc. with positron CT100, each of a given amount (necessary amount for one administration) of an intermediate (e.g., alkali salt of spiperone) for the compound together with an inert gas is presealed hermetically within the reactor 70, preserved, the reactor 70 is attached to the device 30 for synthesizing the radioactive compound in case of necessity, and the intermediate is reacted with <11>C-CH3I, etc., so that the desired compound is obtained stably and simply even if a radioactive substance is synthesized by introducing an unstable intermediate or an intermediate of complicated synthesis into a nucleus seed with a short life.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for synthesizing radioactive compounds using short-lived nuclides.
This invention relates to a method for synthesizing radiopharmaceuticals used for diagnosis, testing, etc. using ed tomography.

General K IIQ, IIIN, IIQ, lap Measuring the internal radiation process of various radiation substances in vivo using bio-related substances labeled with short-lived nuclides. 1 Diagnosis, testing, research, etc. Medical. Diagnosis using the I-Citron OT installed in hospitals, which has become widely used in the field, processes the positron-emitting nuclide produced by the cyclotron into an appropriate chemical form and uses it as a radioactive drug, and the accumulation of the drug in the body is investigated. Department? It is detected by Citron OT and reproduced as an image. Short-lived nuclides used for such diagnosis have short half-lives (IIO
(20 minutes), the hospital must be equipped with a short-lived nuclide generator such as a cyclotron and a radiopharmaceutical synthesis unit that introduces the short-lived nuclide and synthesizes the desired labeled compound, so that it can be processed quickly. Additionally, automatic synthesis equipment has been adopted to prevent worker burden and radiation exposure, and has achieved certain results.

However, the synthesis of intermediates for introducing short-lived nuclides is a heavy burden on hospital workers, especially when the intermediates are unstable or cannot come into contact with the outside air. It is a heavy burden because it requires synthesis. In addition, since the quality and yield of the obtained drug changes, strict requirements are placed on the environmental conditions for synthesis and the ability of the workers, which is one of the factors that prevents the widespread use of radiopharmaceuticals in the medical field. It was a book.

The present invention has been made from the above viewpoints, and even when a short-lived nuclide is introduced into an unstable intermediate or a complicated synthetic intermediate to synthesize a radioactive compound, it is possible to synthesize a radioactive compound stably and easily. The purpose of this invention is to provide a synthetic system that can obtain radioactive compounds.

That is, the method for synthesizing a radioactive compound using a short-lived nuclide of the present invention involves preparing an intermediate for the desired radioactive compound in a reaction container sealed in advance, and attaching the reaction container to a radioactive compound synthesis apparatus during synthesis. It is characterized by reaction synthesis.

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings.

FIG. 1 is a flow diagram showing an embodiment of the present invention, in which short-lived nuclides are sent from a short-lived nuclide generator 10 via a line 20 to an automatic radioactive compound synthesis device 30, where they are synthesized in a reaction vessel 70. A radionuclide is introduced into the intermediate through the reaction, and labeled compounds such as 110-N-methylsubiveron IIQ-palmitic acid and 1-"O-2-deoxy-D-glucose are synthesized. The resulting labeled compounds are shown in line 8.
0, injected into the subject 9o, and subjected to positron OT using the positron imaging device 100.

The radioactive compound automatic synthesis apparatus 3o can be detachably attached to a reaction vessel 70, and is equipped with a means for supplying a radionuclide to the reaction vessel 70 and a means for taking out the obtained labeled compound. Figure 2 is a schematic configuration diagram showing the radioactive compound automatic synthesis system W3o with a 7° reaction vessel attached.
The figure is a sectional view showing an example of the configuration of the reaction container 70.

The reaction container 70 has a container body 72 and a sealing lid 76 screwed onto a threaded portion 74 formed in the container body 72, and an intermediate (spiperone alkali salt) is sealed inside the lid 76. Further, a stirrer such as a magnetic stirrer may be stored in the reaction vessel in advance. The reaction vessel 7o was filled with a single gold component intermediate prepared by IIQ in advance, and an inert gas was filled in if necessary. It can be kept stable by storing it in a cool, dark place.

At the time of synthesis, the airtight lid 76 of the reaction container 70 is removed, and as shown in FIG. 2, the reaction container 70 is screwed onto the mounting member 31 of the automatic synthesis apparatus 30 and mounted in an airtight manner.

In the above explanation, the case of mounting by screwing has been explained. A pipe 34 is inserted, and a pipe 36 is inserted from the transfer pipe.
Radioactive nuclides, solvents, inert gases, etc. can be supplied via a, 36 b, and 36 c. Furthermore, a temperature regulator 38 is provided on the outside of the reaction vessel 70 to supply heated air or cooling air in a sealed state, and a stirrer 44 can be rotated by a stirrer 42 .

After the reaction vessel 70 containing the intermediate is installed, an inert gas is introduced from the Dino-9 Luso 36a to create an inert atmosphere, the solvent is introduced from the No-Norzo 36b, and the radionuclide is introduced from the No-Norzo 36c to form the intermediate. A labeled compound with a radionuclide introduced into the molecule is synthesized by reacting with the body. Reference numeral 35 indicates a nozzle for discharging gas and the like.

When the synthesis is completed, 1. An inert gas is introduced from the S-lube 36a, and the reaction product is introduced into the upper part of the purification column 54 from the transfer tube 34 through the nozzle tube 46, filter 48, and nozzle tube 52 by gas pressure.

Next, a solvent (developing solution) is added to the Nolp 58 while suctioning with the Inzo 56, and the target substance (labeled compound) and unnecessary substances are separated in the purification column 54. Purification column 5
The effluent from 4 is detected by an RI detector 62, and the target substance is guided through an S loop 64 to a receiver 66, where the solvent is evaporated by hot air from a heater 68, and the labeled compound obtained can be administered to living organisms. It is formulated for Also, unnecessary items are Nonorupu 63
is discharged from.

FIG. 4 is a cross-sectional view showing another example of the configuration of the reaction vessel 70' used in the present invention, in which a threaded portion 74' that engages with the mounting member 31 is carved in the upper side wall of the vessel body 72'. The upper part is also closed with a sealing plug 78. This reaction vessel 7
0' to the automatic synthesis system N30, first attach the reaction vessel 70' directly or via a jig to the attachment member 3.
1, and then insert a needle-like supply pipe, transfer pipe, etc. through the sealing stopper 78.

In FIG. 4, the case where the container body 72' and the sealing stopper 78 are separate bodies has been described, but it is also possible to integrally mold them from plastic or the like. Further, the reaction vessel Vi is not limited to those shown in FIGS. 3 and 4, but any vessel can be used as long as it can enclose an intermediate and can be attached to a radioactive compound synthesis apparatus during synthesis. Furthermore, the material of the reaction container is generally glass, but is not particularly limited; if it is made of a chemical product such as plastic such as f IJ ethylene, which is easy to mold, it can be obtained at low cost and can be disposable. You can also.

Next, examples of synthesis of typical labeling compounds will be explained in more detail along with a comparison with conventional methods.

11 (Synthesis of 1-N-Methylsubiperone 11Q-N-Methylsubiperone has the following structural formula and is used as a dopamine receptor blocking agent in neuropsychiatry. Methylspiperone can be synthesized using subiveron as a raw material, by reacting the residue with a strong base such as sodium amide or sodium hydride in a solvent to produce an alkali salt of subiverone, and then introducing 110-methyl iodide.

Generally, these reactions are carried out on a micromolar scale, so conventionally, the ratio of subiperone and strong base was not constant during the reaction, and excessive strong base was used to promote the formation of side reactions.
On the other hand, there was a risk that the yield would fluctuate because the amount of dehydrogenating agent was small and the alkali salt of subiperone was often completely formed. In addition, there is a risk that the alkali salt of Subiborone produced in the presence of moisture will return to the original Subiperone, so care must be taken to ensure that the reaction system and reaction vessel are anhydrous.

On the other hand, according to the present invention, it is possible to stably synthesize large amounts of the intermediate subiverone alkali salt under favorable conditions by skilled technicians at appropriate facilities within or outside the hospital. A certain amount (amount required for one administration) is sealed and stored in a reaction container together with an inert gas in advance, and then supplied immediately when needed. Note that spiperone alkaline salt is a powder that can be stored for long periods at room temperature and can be transported over long distances. Therefore, in a hospital, II□ N-methylsubiperone can be easily synthesized by attaching this reaction container to an automatic synthesis device, introducing 110-OH,I, and causing the reaction, which solves the above-mentioned problems. can all be solved.

Figure 5 synthesizes 110-N-methylsubiperone.
1, in which 110 produced by the cyclotron 12 is transformed into the form of IICQ by the CO7 synthesizer 14.

ls O+ Ol-+ ''O01 Next, ■002 is +10-01-1', I guided to an automatic synthesizer, reduced to IICHllOH, and iodinated to synthesize +1O-OH,I.

Rooo, to Shido/:)], II (for, OH"ri"OH
,I This '1O-OH,I is supplied from the line 20 to the radioactive compound automatic synthesis apparatus 30, and in the reaction vessel 70,
It reacts with subiperone alkali salt (Sp-Na), which is an intermediate stored in this container in advance, to form "O-)I jA'
Subipene (Sp"-110H,) is synthesized.

110-OH,l 5pNa Sp-RoOH.

The obtained II□-methylsubiperone H-lys.

The drug is taken out, formulated, and injected into the subject 9o, and diagnosed using a positron OT device.

To explain the process in the automatic synthesis device 30 in more detail with reference to FIG. 2, the reaction container 70 containing 5p-Na and an inert gas is opened and mounted on the mounting member 31,
An inert gas such as N is passed through the nozzle tube 36a to replace the reaction vessel with the inert gas. It was then dissolved in a solvent.”
O-OH,I is introduced from the valve 36c, and the reaction is completed at room temperature or under heating by supplying hot air from the temperature regulator 38, to synthesize Sp-II OH. Also, 11
When 0-OH, I is introduced into the reaction vessel 70 as a gas, it is replaced with an inert gas.

First, a solvent is introduced from the Noronozo 36b, and then I'OH and I gases are introduced from the Nonoruzo 36c to cause bubbling and trapping, thereby terminating the reaction. The obtained reaction product is purified by using a silica gel column as the purification column 54,
J 5p-110H is recovered by a method similar to that described in FIG.

Synthesis of 11C-palmitic acid jlQ-palmitic acid is used for measuring myocardial metabolism, and is synthesized by the following reaction route using the Grignard reaction.

Mg +100゜0BHIl-Br -0,gHllMgBr--→01
1H1,"000Mg'Br Nial intermediate destone Q,,H81MgBr is produced by reacting 1-prompentadecane with magnesium in an anhydrous ether such as diethyl ether or tetrahydrofuran.
Although it is stable in a solvent, it reacts with water to produce pentadecane, and reacts with oxygen to produce pentadecyl alcohol as by-products.Therefore, generally, intermediates are synthesized each time, or The method is to synthesize a large amount, store it in a sealed container at low temperature, and take out the required amount.However, even when stored at low temperature, it deteriorates every time it is opened, and it is necessary to keep it in a completely inert atmosphere. Since it is also difficult, the limit is 1 to 2 weeks.

According to the invention, the intermediate 0111H11Mg B
Since it becomes possible to supply a predetermined amount of r to the reaction vessel, the operator is freed from the above-mentioned complications.7-0 Referring to Figure 2, (EtwH
The reaction vessel 70 containing s+MgBr is attached, and the valve 36c is connected from the supply pipe 32 to 1100. Then, a) Zeta Lude 32b or other S Luzo (not shown) is used to introduce an acid aqueous solution from the supply pipe 32 and hydrolyze it to O, H8, 0OOH. The labeled compound +1(
), yielding q-rumitic acid.

IICDG is used for cancer diagnosis, and is synthesized, for example, by the following process.

ill l)-arabitol↓ (212,3-4,5-di0-inzolobylidene〇-
A2bitol↓ +31 2.3-4.5-di0-inzolobylidene-1
-0-methanesulfonyl~D-75bitol↓ (4) 1-deoxy-2,3-4,5-di0-impropylidene-1-iodo-D-7bitol↓Na ”0N (5) 2- Deoxy-3,4-5,6-di0-isopropylidene-D(1-”O)glucononitrile Since this is the (5) step of introducing the 11C nuclide, (1) to The synthesis of (4) can be carried out in advance in a suitable facility such as outside a hospital, and the iodine compound of (4) can be sealed in chloroform in a reaction vessel and stored in a cool, dark place before being supplied. To synthesize the target product (6), attach the above reaction container to an automatic synthesizer, and
After that, Na'ON is introduced through the supply pipe 32 to carry out the reaction in step (5), and then the palladium black dispersion is introduced through the supply pipe 32 through an appropriate pulp to perform deimpropylidene. As described above, according to the method of the present invention, the iodine compound (4) can be sealed in a reaction container in advance and supplied, eliminating the need for a complicated synthesis process. "OD" that can only be supplied
It becomes possible to supply G-labeled compounds easily.

As is clear from the above description, according to the present invention, intermediates can be synthesized at an appropriate facility such as outside a hospital, and the intermediates can be sealed and stored in reaction containers in required amounts. Therefore, high-quality intermediates can be supplied, and high-quality target products can be obtained.7-o In addition, even unstable intermediates can be stored for a long time and transported over long distances, making it possible to store them at sites of use such as hospitals. The operator can easily obtain the desired product by simply attaching the reaction container to the automatic synthesis equipment, significantly reducing the burden on the operator. Furthermore, the apparatus can be used repeatedly by simply replacing the reaction vessel.

[Brief explanation of drawings]

Figure 1 is a flow diagram showing an example of the present invention, and Figure M5 is a more specific flow diagram for synthesizing II (3,N-methylsubiveron). It is a schematic diagram showing a configuration example of a synthesis apparatus. FIGS. 3 and 4 are sectional views showing a configuration example of a reaction container used in the present invention. 10... Cyclotron 3o... Automatic synthesis device 3
1... Mounting member 32... Supply pipe 34... Transfer pipe 54... Purification column 62... RI detector 66
... Receiver 70.70' ... Reaction container 72.72
'... Container body 76... Airtight lid 78... Airtight stopper 100... Cod? Citron Imaging Vortex “Paper 1 Figure Atsushi 2

Claims (1)

[Claims] 1. In the method of synthesizing a radioactive compound, the intermediate of the desired radioactive compound is prepared in advance in a sealed reaction container at a certain temperature, and during synthesis, the nuclear reaction container is attached to a radioactive compound synthesis apparatus and the reaction is synthesized. A method for synthesizing radioactive compounds using short-lived nuclides.