JPS6345647B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to an apparatus for automatically synthesizing ^11C to methyl iodide for medical diagnosis using radioisotope (RI), that is, radioactive carbon isotope ^11C , synthesized using a small cyclotron, for example. It is used for new diagnoses such as quantitative and dynamic diagnosis of various organs including the brain, early detection of stroke, myocardial infarction, and malignant tumors, and investigation of the causes of mental illness. [Prior Art] The recent development of ultra-small cyclotrons and the appearance of positron tomography devices have played a major role in the development of nuclear medicine. Especially β ⁺
It is a released nuclide. By using nuclides that can label biological substances such as ¹¹ C, ¹³ N, ¹⁵ O, and ¹⁸ F, it is possible to obtain not only 3-dimensional static images but also 4-dimensional diagnostic information through dynamic analysis. This is expected to contribute to more accurate diagnosis. Short-lived radionuclides ( ^11C , ^13N , ^15O , ^18F ) produced by microcyclotrons are currently available in simple inorganic chemical forms (e.g. ^11CO2 _,
¹¹ CO, ¹⁸ F ₂ , ¹³ NOx, etc.), but it is essential to convert these nuclides into labeled organic compounds equivalent to biological substances. However, this chemical treatment requires a special micro-synthesis technique because it handles a trace amount of radioactive isotope that is almost carrier-free, and because it is a short-lived nuclide with a half-life of about 20 minutes, rapid processing is required. . Furthermore, in order to synthesize these short-lived RI standard compounds, since the starting stage involves handling amounts of radioactivity ranging from several hundred to several thousand mCi, only experts who are familiar with synthesis reactions can carry out the synthesis operations, and routine diagnosis is difficult. It was impossible for general hospitals to use it, and it was possible only in very limited research facilities. [Object of the present invention] ^11C -Methyl iodide is an intermediate raw material in the synthesis of caffein, ephedrin, methionine, morphine, etc., which interacts with brain centers.
The commercialization of ^{the 11} C-methyl iodide automatic synthesis device paved the way for clinical application in brain diagnosis, promoted the spread of cyclotron nuclear medicine diagnostic systems that utilize short-lived radionuclides, and enabled quantitative and dynamic diagnosis. It can contribute to the establishment of new diagnostic fields such as the early detection of stroke, myocardial infarction, and cancer, which are the three major causes of death, and the investigation of the causes of mental illness. The present invention provides such an automatic ¹¹ C-methyl iodide synthesis apparatus, which differs from conventional laboratory-based systems in that it includes a series of operations from the start of synthesis to the end of synthesis, temperature control of various reaction vessels, and All settings such as the gas flow rate of the system are automatically controlled by a computer-based sequence controller.
This system enables even those who are inexperienced in chemical synthesis operations to efficiently and safely produce ¹¹ C-methyl iodide. [Configuration of Embodiment] An embodiment of the present invention will be described in detail below with reference to the drawings. As shown in the first diagram, a cylinder 1 filled with _N2 gas, which is a raw material for methyl iodide containing a carbon isotope ¹¹ C, is connected to a target box 3 of a small cyclotron 2, and the target box 3 is connected to a solenoid valve.
It communicates with the reduction tank 4 via V ₂ and TV ₁ . The upper part of this reduction tank 4 is equipped with a solenoid valve TV ₂ and a check valve CV _2.
It communicates with the discharge port 5 via. Further, this reduction tank 4 is connected to a THF (tetrahydrofuran) tank 6 in which LiAlH ₄ (lithium aluminum hydride) is dissolved through a solenoid valve V ₀ . Above solenoid valve
Between V ₂ and solenoid valve TV ₁ is a solenoid valve V ₁ and a flow meter FM.
and communicates with a pressurizing nitrogen gas cylinder 7 via a needle valve NV ₂ . A heater 8 is provided below the reduction tank 4, and a cooling pipe 9 outside the heater 8 communicates with liquid carbon dioxide via a high-pressure solenoid valve _V3 . An automatic water injection device 10 is connected to the reduction tank 4 through a check valve _CV1 . This automatic water filling device 10 has a water storage tank 11 and a glass meter 12, and the upper part of the water storage tank 11 communicates with the cylinder 7 via a solenoid valve V ₆ and a needle valve NV ₁ .
The lower part of this water storage tank 11 communicates with the lower part of a glass quantitative meter 12 for quantifying H ₂ O used in the reduction reaction through a solenoid valve TV _{7 .} It communicates with the check valve CV ₁ through. The upper part of this glass quantitative meter 12 is connected to the needle valve via a solenoid valve _V4 .
It communicates with NV ₁ and also with the outside world via solenoid valve V ₅ . This glass quantitative meter 12 is provided with a liquid level sensor 13 for detecting the level of water therein. The upper part of this reduction tank 4 is connected to HI via solenoid valve TV ₃ .
It communicates with tank 14. A heater 15 for heating the HI tank 14 is provided at the bottom of the HI tank 14. This HI tank 14
Soda lime 17, phosphorus pentoxide 18, and a solenoid valve are connected to the slanted upper part of the unit through a cooling pipe 16 cooled with cooling water.
It communicates via TV ₄ with the lower part of a trap vial 21 surrounded by dry ice 20 in the dewar bottle 19, and the upper part of this trap vial 21 communicates with the check valve CV ₂ via a solenoid valve TV ₅ . Note that the reduction tank 4 and HI tank 14 are made of transparent glassware to enable visual observation of the reaction inside. In addition, the connection parts of the main bodies of the quantitative meter 12, reduction tank 4, HI tank 14, and trap vial 21 are
A joint on the ring holder is used to make it easier to attach and detach these glassware and to prevent leakage of radioactive gas. In addition, in particular, the parts inside the apparatus where radioactive gas may leak are sealed, and soda lime 17 is provided in the part connected to the outside air to completely prevent radioactive gas from leaking to the outside. Furthermore, the casing of this device has a sealed structure to further completely prevent leakage of radioactive gas. Furthermore, reduction tank 4, HI
The tank 14 is equipped with an automatic temperature control mechanism that measures the temperature with a thermocouple (not shown) during heating and cooling, and controls the temperature by feeding back the signal to a temperature control device to ensure the safety of the reaction. The above solenoid valves V ₁ , V ₂ ..., solenoid valves TV ₁ , TV ₂ ...,
The operations of the heaters 8 and 15 are shown in the table below.

[Operation of the present invention]

Next, the operation of the apparatus will be explained with respect to the flow shown in the third figure. At step P ₁ , needle valve NV ₁ , solenoid valve V ₆ ,
The TV ₇ is opened, and the water in the water storage tank 11 is quantitatively supplied into the glass meter 12 by the pressure of the nitrogen gas in the cylinder 7 to the level detected by the liquid level sensor 13 thereof. The adoption of this automatic water injection device simplifies the water injection operation and enables precise control of the amount of water injection. At step _P2 , the solenoid valve _TV2 opens and the heater 8 is energized. As a result, the inside of the reduction tank 4 is heated, and the moisture therein evaporates and is discharged to the outlet 5 via the solenoid valve TV ₂ and the check valve CV ₂ , and the inside of the reduction tank 4 is dried. Next, in step _P3 , the solenoid valve _V3 is opened, and liquid carbon dioxide flows into the cooling pipe 9 outside the reduction tank 4, cooling the reduction tank 4 to about -20°C. Next, in step P ₄ , the solenoid valve V ₀ is opened, whereby THF in which LiAlH ₄ has been dissolved flows into the reduction tank 4 . Thus, in step _P5 , the small cyclotron 2 is started, and in step _P6 , the solenoid valves _V2 and _TV1 are opened. As a result, the _N2 gas, which is the raw material for methyl iodide containing ¹¹ C isotopic carbon atoms, filled in the cylinder 1 is sent to the target box 3 of the small cyclotron 2, where part of it becomes ¹¹ C isotopic carbon atoms. Combines with oxygen. The ¹¹ CO ₂ gas thus produced by the small cyclotron 2 is sent in the form of bubbles to the THF in the reduction tank 4 through the solenoid valves V ₂ and TV ₁ , and undergoes the following reaction with LiAlH ₄ in the THF. and 4 ¹¹ CO ₂ +3LiAlH ₄ →AlLi(O ¹¹ CH ₃ ) ₄
+ _2AlLiO2 . Next, in step _P7 , current is applied to the heater 8, and the solenoid valve TV ₂ is opened, and the reduction tank 4 is heated to a temperature of 120°C to 130°C.
Heat to ℃. As a result, THF in the reduction tank 4
is evaporated and discharged to the outlet 5 via the solenoid valve TV ₂ and check valve CV ₂ . Next, in step _P8 , the heater 8 is turned off, the heater 15 is turned on, and the solenoid valve _V3 is opened to cool the reduction tank 4. Next, in step _P9 , the needle valve _NV1 , solenoid valve _V4 , and _TV6 are opened. Also, in step _P10 , the solenoid valve
Open TV ₃ and turn on heaters 8 and 15 in step _P11 .
A current is passed through. As a result, a certain amount of water in the glass quantitative meter 12 flows into the reduction tank 4 due to the pressure of the nitrogen gas in the cylinder 7, and is heated and the LiAl
The following reaction occurs with (O ¹¹ CH ₃ ) ₄ , LiAl(O ¹¹ CH ₃ ) ₄ +4H ₂ O→4 ¹¹ CH ₃ OH+
LiOH + Al(OH) ₃ produces methanol. This methanol evaporates and then flows into the HI solution in the HI tank 14 as bubbles, where it is heated by the heater 15 and undergoes the following reaction: ¹¹ CH ₃ OH + HI→ ¹¹ CH ₃ I + H ₂ O, iodination. Produces methyl. Next, in step _P12 , open solenoid valves TV ₄ and TV ₅ ,
This methyl iodide is cooled by cooling water through a cooling pipe 16, and unreacted with soda lime 17.
¹¹ CH ₃ OH, ¹¹ CO ₂ , and HI are removed, and water is further removed with phosphorus pentoxide 18, and it accumulates as ¹¹ CH ₃ I 22 in a trap vial 21 that is cooled with dry ice 20 in a dewar bottle 19. . [Effects] As described above, according to the present invention, ¹¹ C methyl iodide can be automatically synthesized, so that workers can perform the work safely without risk of exposure. Therefore, the automatic ^11C -methyl iodide synthesizer according to the present invention can be used for routine diagnosis in general hospitals, neurology departments, etc. of university hospitals, where there are no experts who are familiar with synthesis operations, and it can be used for routine diagnosis using short-lived positron-emitting nuclides. This will promote diagnosis and contribute to the development of nuclear medicine.

[Brief explanation of the drawing]

FIG. 1 is an explanatory diagram showing an outline of an embodiment of the present invention, FIG. 2 is a block diagram of its control device, and FIG. 3 is its flow diagram. 1...Cylinder, 2...Small cyclotron, 3
...Target boxes, V ₀ ~ V ₆ , TV ₁ ~ _{TV 7}
... Solenoid valve, 4 ... Reduction tank, CV ₁ , CV ₂ ... Check valve, 10 ... Automatic water injection device, 14 ...
HI tank, 21...Trap vial, P ₁ ~ _{P 11} ...
Step.

Claims (1)

[Claims] 1 A cylinder filled with N ₂ gas, which is the raw material for methyl iodide containing the carbon isotope ¹¹ C, is connected to a target box of a small cyclotron, and the target box is connected to a reduction tank via solenoid valves V ₂ and TV ₁ . However, check valve CV ₁ is installed in the above reduction tank.
The upper part of this reduction tank is connected to the HI tank through solenoid valve TV ₃ , and this
The HI tank is connected to a low-temperature trap vial via a purification device, and the ¹¹ CO ₂ gas produced in the cyclotron is transferred to a reduction tank containing THF (tetrahydrofuran) in which LiAlH ₄ (lithium aluminum hydride) is dissolved. means to send the ¹¹ C methanol produced here as bubbles into the HI of the HI tank, and
An automatic methyl iodide synthesis device comprising means for storing ¹¹ C methyl iodide in a purified trap vial at a low temperature.