11C radiopharmaceutical synthesis system

Abstract

A < 11 > C radiopharmaceutical synthesis system relates to the technical field of radiopharmaceutical synthesis, and adopts the technical scheme that the < 11 > C radiopharmaceutical synthesis system comprises a primary reaction module, a first three-way valve group, an online conversion module, a secondary reaction module, a liquid phase purification module, a solid phase extraction module, a column purification module and a pipetting module. Five < 11 > C-radiopharmaceuticals can be synthesized and comprise sodium acetate, choline, methionine, rachlopride and flumazenil, the sodium acetate, the choline and the methionine are column purification drugs, and the rachlopride and the flumazenil are liquid phase purification drugs; the system also has the functions of pipeline blockage inspection and leakage inspection, and stable operation of the system is guaranteed; except for the injection pump, the capturing column, the infusion pump and the sucking pump, most of pipelines and components are arranged on the upper surface of the mounting panel, and a plurality of three-way valves are integrated into two three-way valve groups, so that the pipelines between two-time synthesis are convenient to replace.

Description

Technical Field

[0001] The present invention relates to the technical field of radioactive drug synthesis, and particularly relates to a 11 11C radioactive drug synthesis system. Background Art

[0002] Using radioactive drugs for the diagnosis and treatment of diseases can comprehensively reflect the lesion genes, molecules, metabolism and functional status, and can more early insight into the molecular information of diseases, so as to achieve early diagnosis and precise treatment. At present, the main imaging diagnosis method used in medical institutions is positron emission tomography (PET) based on fluorodeoxyglucose ( 18 18F-FDG), and the detection accuracy of this method for some tumors is limited. For example, for lung cancer, 18 the lesions that can be detected by 18F-FDG-PET are usually above 10 mm, while 11 the detection accuracy of 11C-Choline-PET can reach 5 mm. In addition, 18 18F-FDG is not effective for the imaging of all malignant tumors. For example, due to the low dependence on glucose and the unobvious abnormal glucose metabolism in some tumor tissues, false negatives in PET / CT imaging can be caused, while 11 11C-PET does not have the above disadvantages. Therefore, 11 11C-PET can be used as 18 an effective supplement to 18F-PET to improve the accuracy and reliability of tomographic imaging.

[0003] In order to reduce the exposure of personnel to radiation, the use of an automatic radioactive drug synthesis module is an inevitable trend. However, at present 11 the types of drugs that can be synthesized by 11C radioactive drug synthesis modules have bottlenecks, and only one or two drugs can be synthesized by the same module. Summary of the Invention

[0004] Aiming at the problem that only one or two 11 11C radioactive drugs can be synthesized by the same synthesis module in the prior art solution, the present invention provides a 11 11C radioactive drug synthesis system.

[0005] The present invention provides the following technical solutions:

[0006] A 11 11C radioactive drug synthesis system, comprising:

[0007] The first - order reaction module includes a carbon dioxide capture device and a first reaction tube. The carbon dioxide capture device includes a cooling container, an annular tube, and a driving device for driving the annular tube in and out of the cooling container. One end of the annular tube is connected to a carbon dioxide input tube, and a stop valve is provided on the carbon dioxide input tube. The first reaction tube is also connected to an injection pump, and a heating device is also provided on the first reaction tube.

[0008] The first three - way valve group includes a first three - way valve, a second three - way valve, a third three - way valve, a fourth three - way valve, a fifth three - way valve, a sixth three - way valve, a seventh three - way valve, and an eighth three - way valve connected in series in sequence. Two interfaces of the first three - way valve are respectively connected to the annular tube and the first reaction tube. The second three - way valve is connected to the first reaction tube. A drying tube is connected between the third three - way valve and the fourth three - way valve. The fifth three - way valve is connected to an exhaust gas pipe.

[0009] The on - line conversion module includes a conversion furnace connected to the eighth three - way valve. The conversion furnace is connected to a ninth three - way valve, and the ninth three - way valve is connected to an exhaust gas pipe.

[0010] The second - order reaction module includes a second reaction tube. The second reaction tube is respectively connected to a thirteenth three - way valve, an eleventh three - way valve, and the ninth three - way valve. Two interfaces of the thirteenth three - way valve are respectively connected to a transfer flask and a first multi - way valve. Multiple reagent bottles are respectively connected to multiple interfaces of the first multi - way valve. The eleventh three - way valve is connected to the sixth three - way valve. A heating device is also provided on the second reaction tube.

[0011] The liquid - phase purification module includes a second multi - way valve connected to the transfer flask. A quantitative loop is connected between two interfaces of the second multi - way valve. Two other interfaces of the second multi - way valve are respectively connected to a chromatographic column and a first waste liquid bottle. The chromatographic column is sequentially connected to an ultraviolet detector and a twelfth three - way valve, and the twelfth three - way valve is connected to the first waste liquid bottle.

[0012] The solid - phase extraction module includes an extraction bottle and a second three - way valve group. The extraction bottle is respectively connected to the eleventh three - way valve and the twelfth three - way valve. An exhaust gas pipe is provided on the extraction bottle, and a heating device is also provided on the extraction bottle. The second three - way valve group includes a plurality of raw material three - way valves and a thirteenth three - way valve connected in sequence. Multiple raw material bottles are connected to multiple raw material three - way valves. The raw material three - way valve at one end of the second three - way valve group is connected to the extraction bottle, and the thirteenth three - way valve at the other end is connected to the eighth three - way valve.

[0013] The column purification module includes a capture column connected to the thirteenth three - way valve. The capture column is connected to a fourteenth three - way valve. Two interfaces of the fourteenth three - way valve are respectively connected to a product bottle and a second waste liquid bottle. An exhaust gas pipe is provided on the second waste liquid bottle.

[0014] The pipetting module includes a nitrogen source, an infusion pump, and a suction pump; the nitrogen source is connected to a seventh three-way valve, and a fifteenth three-way valve is also provided on the carbon dioxide input pipe. The nitrogen source is connected to the fifteenth three-way valve. The nitrogen source is connected to the first reaction tube and is provided with a stop valve. The nitrogen source is also connected to a third multi-way valve, and multiple interfaces of the third multi-way valve are respectively connected to multiple reagent bottles and a transfer bottle; the infusion pump is connected to the second multi-way valve; the suction pump is connected to a fourth multi-way valve, and multiple interfaces of the fourth multi-way valve are respectively connected to the extraction bottle, the product bottle, and the second waste liquid bottle. The cooling container is a liquid nitrogen container with an open top, and the driving device is a lift connected to the annular tube.

[0015] Preferably, the heating devices are all provided with ventilation openings, and the ventilation openings are all connected to an air source and are provided with stop valves. The air source provides an air flow to generate convection near the heating device and the reaction tube or the extraction bottle to accelerate cooling.

[0016] Preferably, an eddy current refrigeration tube is further provided on the pipeline connecting the ventilation openings of the heating devices of the first reaction tube and the second reaction tube to the air source.

[0017] Preferably, the capture column includes a C18 column and a CM column connected in sequence.

[0018] Preferably, the exhaust pipes are all provided with one-way valves or stop valves to prevent gas from entering.

[0019] Preferably, the nitrogen source is sequentially connected with a stop valve, a flow meter, a pressure gauge, and a sixteenth three-way valve. One port of the sixteenth three-way valve is connected to the seventh three-way valve, and the pipeline connected to the other port of the sixteenth three-way valve is respectively connected to the fifteenth three-way valve, the first reaction tube, and the third multi-way valve through multiple three-way pipes.

[0020] Preferably, it further includes an installation panel. Except for the injection pump, the capture column, the infusion pump, and the suction pump, the primary reaction module, the first three-way valve group, the on-line conversion module, the secondary reaction module, the liquid phase purification module, and the solid phase extraction module are all arranged on the upper surface of the installation panel.

[0021] The beneficial effects of the present invention are as follows: A radioactive drug synthesis system is provided, which can synthesize five 11 11C-radioactive drugs, including sodium acetate, choline, methionine, raclopride, and flumazenil. Among them, sodium acetate, choline, and methionine are column purification drugs, and raclopride and flumazenil are liquid phase purification drugs; the present invention also has the functions of pipeline blockage inspection and leakage inspection to ensure the stable operation of the system; except for the injection pump, the capture column, the infusion pump, and the suction pump, most pipelines and components are arranged on the upper surface of the installation panel, and multiple three-way valves are integrated into two three-way valve groups, which is convenient for replacing the pipelines between two syntheses. Brief Description of the Drawings

[0022] Figure 1 It is a schematic diagram of an embodiment of the synthesis system.

[0023] Reference Numerals: 11 - Cooling Container, 12 - Annular Tube, 21 - Drying Tube, 31 - Transfer Bottle, 41 - Quantitative Loop, 42 - Chromatographic Column, 43 - First Waste Liquid Bottle, 51 - Capture Column, 52 - Product Bottle, 53 - Second Waste Liquid Bottle, 61 - Nitrogen Source, 71 - Air Source, 72 - Vortex Refrigeration Tube, 81 - Upper Surface, A1 - Raw Material Bottle, A2 - Raw Material Bottle, A3 - Raw Material Bottle, B1 - Reagent Bottle, B2 - Reagent Bottle, B3 - Reagent Bottle, C1 - First Reaction Tube, C2 - Second Reaction Tube, C3 - Extraction Bottle, L1 - Syringe Pump, M1 - Lift, M2 - Conversion Furnace, M3 - Infusion Pump, M4 - Air Extraction Pump, M5 - UV Detection Device, V1 - Stop Valve, V2 - Sixteenth Three - way Valve, V3 - Fifteenth Three - way Valve, V4 - Stop Valve, V5 - First Three - way Valve, V6 - Second Three - way Valve, V7 - Third Three - way Valve, V8 - Fourth Three - way Valve, V9 - Fifth Three - way Valve, V10 - Sixth Three - way Valve, V11 - Seventh Three - way Valve, V12 - Eighth Three - way Valve, V13 - Ninth Three - way Valve, V14 - Thirteenth Valve, V15 - Eleventh Three - way Valve, V16 - Third Multiport Valve, V17 - First Multiport Valve, V18 - Second Multiport Valve, V19 - Twelfth Three - way Valve, V20 - Raw Material Three - way Valve, V21 - Raw Material Three - way Valve, V22 - Raw Material Three - way Valve, V23 - Thirteenth Three - way Valve, V24 - Fourteenth Three - way Valve, V25 - Stop Valve, V27 - Stop Valve, V28 - Fourth Multiport Valve, V31 - Stop Valve, V32 - Stop Valve. Detailed Embodiments

[0024] The following further elaborates on the embodiments of the present invention in conjunction with the drawings and reference numerals, enabling those skilled in the art to implement it after studying this specification. It should be understood that the specific embodiments described herein are only for explaining the present invention and not for limiting the present invention.

[0025] Embodiment 1

[0026] The present invention provides a Figure 1 shown 11 C radioactive drug synthesis system, including a primary reaction module, a first three - way valve group, an online conversion module, a secondary reaction module, a liquid - phase purification module, a solid - phase extraction module, a column purification module, and a pipetting module. The above - mentioned modules are all detachably connected to the mounting panel.

[0027] The first - order reaction module includes a carbon dioxide capture device and a first reaction tube C1. The carbon dioxide capture device includes a cooling container 11, an annular tube 12, and a driving device for driving the annular tube 12 in and out of the cooling container 11. One end of the annular tube 12 is connected to a carbon dioxide input tube, and a cut - off valve V31 is provided on the carbon dioxide input tube. Usually, the cooling container 11 is a liquid nitrogen container with an open top, and the driving device is a lift M1 connected to the annular tube 12. The first reaction tube C1 is connected to an injection pump L1. The first reaction tube C1 is also provided with a heating device, and the heating device is also provided with a ventilation opening, and its ventilation opening is connected to an air source 71 and is provided with a cut - off valve V25 and an eddy current refrigeration tube 72.

[0028] The first three - way valve group includes a first three - way valve V5, a second three - way valve V6, a third three - way valve V7, a fourth three - way valve V8, a fifth three - way valve V9, a sixth three - way valve V10, a seventh three - way valve V11, and an eighth three - way valve V12 connected in series in sequence. Two interfaces of the first three - way valve V5 are respectively connected to the annular tube 12 and the first reaction tube C1. The second three - way valve V6 is connected to the first reaction tube C1 and the pipeline extends to the bottom of the first reaction tube C1. A drying tube 21 is connected between the third three - way valve V7 and the fourth three - way valve V8. The fifth three - way valve V9 is connected to an exhaust pipe, and the exhaust pipe is provided with a one - way valve that only allows exhaust.

[0029] The on - line conversion module includes a conversion furnace M2 connected to the eighth three - way valve V12. The conversion furnace M2 is connected to a ninth three - way valve V13. The ninth three - way valve V13 is connected to an exhaust pipe, and the exhaust pipe is provided with a one - way valve that only allows exhaust.

[0030] The second - order reaction module includes a second reaction tube C2. The second reaction tube C2 is respectively connected to a thirteenth three - way valve V14, an eleventh three - way valve V15, and the ninth three - way valve V13. One interface of the thirteenth three - way valve V14 is connected to the second reaction tube C2 and the pipeline extends to the bottom of the second reaction tube C2. The other two interfaces are respectively connected to a transfer bottle 31 and a first multi - way valve V17. Multiple interfaces of the first multi - way valve V17 are respectively connected to a reagent bottle B1, a reagent bottle B2, and a reagent bottle B3, and the pipeline extends to the bottom of the reagent bottle. The eleventh three - way valve V15 is connected to the sixth three - way valve V10. The second reaction tube C2 is also provided with a heating device, and the heating device is also provided with a ventilation opening, and its ventilation opening is connected to an air source 71 and a cut - off valve V26 and an eddy current refrigeration tube 72 are provided on the pipeline.

[0031] The liquid-phase purification module includes a second multi-way valve V18 connected to the transfer bottle 31. A quantitative loop 41 is connected between two interfaces of the second multi-way valve V18. The other two interfaces of the second multi-way valve V18 are respectively connected to a chromatographic column 42 and a first waste liquid bottle 43. The chromatographic column 42 is sequentially connected to an ultraviolet detection device M5 and a twelfth three-way valve V19, and the twelfth three-way valve V19 is connected to the first waste liquid bottle 43.

[0032] The solid-phase extraction module includes an extraction bottle C3 and a second three-way valve group. The extraction bottle C3 is respectively connected to the eleventh three-way valve V15 and the twelfth three-way valve V19. The extraction bottle C3 is provided with an exhaust pipe, and the exhaust pipe is provided with a cut-off valve V32. The extraction bottle C3 is further provided with a heating device, and the heating device is further provided with a ventilation port, and its ventilation port is connected to an air source 71 and is provided with a cut-off valve V27. The second three-way valve group includes a raw material three-way valve V20, a raw material three-way valve V21, a raw material three-way valve V22 and a thirteenth three-way valve V23 connected in sequence. The raw material three-way valve V20 is connected to a raw material bottle A1, the raw material three-way valve V21 is connected to a raw material bottle A2, the raw material three-way valve V22 is connected to a raw material bottle A3. One end of the raw material three-way valve V20 is connected to the extraction bottle C3 and the pipeline extends to the bottom of the extraction bottle C3. Two interfaces of the thirteenth three-way valve V23 are respectively connected to the eighth three-way valve V12 and the capture column 51.

[0033] The column purification module includes the capture column 51. The capture column 51 is connected to a fourteenth three-way valve V24. Two interfaces of the fourteenth three-way valve V24 are respectively connected to a product bottle 52 and a second waste liquid bottle 53. The second waste liquid bottle 53 is provided with an exhaust pipe, and the exhaust pipe is provided with a one-way valve that only allows air to escape. The capture column 51 is a composite column, including a C18 column and a CM column connected in sequence.

[0034] The pipetting module includes a nitrogen source 61, an infusion pump M3 and a vacuum pump M4. The nitrogen source 61 is sequentially connected to a cut-off valve V1, a flow meter 62, a pressure gauge 63 and a sixteenth three-way valve V2. One port of the sixteenth three-way valve V2 is connected to the seventh three-way valve V11. The pipeline connected to the other port of the sixteenth three-way valve V2 is respectively connected to the fifteenth three-way valve V3, the cut-off valve V4, and the third multi-way valve V16 through a plurality of three-way pipes. The fifteenth three-way valve V3 is connected to a carbon dioxide input pipe. The cut-off valve V4 is connected to the first reaction tube C1. Multiple interfaces of the third multi-way valve V16 are respectively connected to a reagent bottle B1, a reagent bottle B2, a reagent bottle B3, and the transfer bottle 31. The infusion pump M3 can adopt a peristaltic pump and is connected to the second multi-way valve V18. The vacuum pump M4 is connected to a fourth multi-way valve V28. Multiple interfaces of the fourth multi-way valve V28 are respectively connected to the extraction bottle C3, the product bottle 52 and the second waste liquid bottle 53.

[0035] Except for the injection pump L2, the capture column 51, the infusion pump M3, and the air extraction pump M4, the primary reaction module, the first three-way valve group, the on-line conversion module, the secondary reaction module, the liquid-phase purification module, and the solid-phase extraction module are all arranged on the upper surface 81 of the mounting panel. Figure 1 The mounting panel is represented by thick lines, and the three thick-line frames respectively represent its upper surface 81 and both side surfaces.

[0036] Example 2

[0037] Using the synthesis system provided in Example 1, complete 11 the synthesis of C-remoxipride.

[0038] Before synthesis, the first reaction tube C1 is filled with lithium aluminum hydride in tetrahydrofuran (THF) solution; desmethyl remoxipride is dissolved in acetone, and then sodium hydroxide solution is added and added to the second reaction tube C2 as a precursor; the injection pump L2 is filled with hydroiodic acid; the extraction bottle C3 is filled with sterile water; the raw material bottle A1 is filled with sterile water; the raw material bottle A2 is filled with ethanol; the raw material bottle A3 is filled with physiological saline; the conversion furnace M2 is filled with a mixture of silver trifluoromethanesulfonate and graphite powder; the mobile phase, an acetonitrile-ammonium formate solution, is added to the reagent bottle B1.

[0039] The synthesis process includes the following steps.

[0040] S1, Nitrogen enters through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the eighth three-way valve V12, and the thirteenth three-way valve V23, and then is respectively filled into the raw material bottles A1, A2, and A3 through multiple raw material three-way valves to increase the pressure in the raw material bottles.

[0041] S2, Use a cyclotron to generate 14 N(p,α) 11 C reaction to produce 11 CO2, which enters the carbon dioxide input pipe through the stop valve V31; nitrogen enters the carbon dioxide input pipe through the stop valve V1, the sixteenth three-way valve V2, and the fifteenth three-way valve V3 to mix with carbon dioxide. Under the carrier of nitrogen, carbon dioxide enters the annular tube 12 and sublimes into dry ice under the action of liquid nitrogen in the cooling container 11 to complete the capture, and the excess gas is discharged through the first reaction tube C1, the second to fifth three-way valves, and the exhaust pipe. After the capture is completed, the driving device moves the annular tube 12 out of the liquid nitrogen, and the carbon dioxide generated after the sublimation of dry ice enters the first reaction tube C1 through the first three-way valve V5. The sublimation process of dry ice can be accelerated by heating devices such as a hot air gun.

[0042] S3, 11After the CO2 is completely absorbed by the solution in the first reaction tube C1, nitrogen is introduced into the first reaction tube C1 through the stop valve V1, the sixteenth three-way valve V2, the fifteenth three-way valve V3, and the first three-way valve V5, and the first reaction tube C1 is heated to remove tetrahydrofuran. The waste gas is discharged through the second three-way valve V6, the third three-way valve V7, the fourth three-way valve V8, the fifth three-way valve V9, and the waste gas pipe.

[0043] S4, the syringe pump L1 adds hydroiodic acid to the first reaction tube C1 for iodination reaction.

[0044] S5, the first reaction tube C1 is heated, and nitrogen is introduced into the first reaction tube C1 through the stop valve V1, the sixteenth three-way valve V2, and the stop valve V4. A positive pressure is generated to press the liquid in the first reaction tube C1 into the conversion furnace M2 through the first to eighth multi-way valves for conversion. The product after conversion enters the second reaction tube C2 through the ninth multi-way valve V13 and undergoes a secondary reaction with the precursor.

[0045] S6, nitrogen is filled into the reagent bottle B1 through the stop valve V1, the sixteenth three-way valve V2, and the third multi-way valve V16, and the mobile phase inside it is added to the second reaction tube C2 through the first multi-way valve V17 and the thirteenth valve V14 to quench the secondary reaction.

[0046] S7, nitrogen enters the second reaction tube C2 through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the sixth three-way valve V10, and the eleventh three-way valve V15, and the secondary reaction product is pressed into the transfer bottle 31 through the thirteenth valve V14.

[0047] S8, nitrogen enters the transfer bottle 31 through the stop valve V1, the sixteenth three-way valve V2, and the third multi-way valve V16, and the product is transferred to the sampling loop 41 through the second multi-way valve V18.

[0048] S9, the liquid delivery pump M3 inputs an acetonitrile-ammonium formate solution to the second multi-way valve V18 to transfer the product from the sampling loop to the chromatographic column 42 for purification. The total purification time is 10 minutes. The solution separated at 7 - 9 minutes enters the extraction bottle C3 through the twelfth three-way valve V19 to be mixed with the diluent, and the solution at other times enters the first waste liquid bottle 43 through the twelfth three-way valve V19.

[0049] S10, nitrogen enters the extraction bottle C3 through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the sixth three-way valve V10, and the eleventh three-way valve V15. At the same time, the air pump M4 sucks the gas in the second waste liquid bottle 53 through the fourth multi-way valve V28 to generate a negative pressure, and the liquid in the extraction bottle C3 is transferred to the capture column 51 through multiple raw material three-way valves and the thirteenth three-way valve V23. The product is captured by the C18 column, and the waste liquid enters the second waste liquid bottle 53 through the fourteenth three-way valve V24.

[0050] S11. The air pump M4 sucks the gas in the second waste liquid bottle 53 to generate negative pressure, sucks the sterile water in the raw material bottle A1 to the C18 column for cleaning, and the waste liquid enters the second waste liquid bottle 53 through the fourteenth three-way valve V24.

[0051] S12. The air pump M4 sucks the gas in the product bottle 52 to generate negative pressure, transfers the ethanol in the raw material bottle A2 to the C18 column, and elutes the product to the product bottle 52.

[0052] Example 3

[0053] Using the synthesis system provided in Example 1, complete 11 the synthesis of C-flumazenil.

[0054] Before synthesis, the syringe pump L1 is filled with hydroiodic acid solution; the first reaction tube C1 is pre-filled with lithium aluminum hydride in tetrahydrofuran solution; the second reaction tube C2 is filled with demethylated FMZ precursor and DMF solution containing sodium hydride; the extraction bottle C3 is pre-filled with sterile water; the raw material bottle A1 is filled with sterile water; the raw material bottle A2 is filled with ethanol; the raw material bottle A3 is filled with water for injection. The reagent bottle B1 is filled with the mobile phase, which is an acetonitrile - acetic acid - aqueous solution. The synthesis process includes the following steps.

[0055] S1. Nitrogen enters through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the eighth three-way valve V12, and the thirteenth three-way valve V23, and then is respectively filled into the raw material bottle A1, the raw material bottle A2, and the raw material bottle A3 through multiple raw material three-way valves.

[0056] S2. Using a cyclotron through 14 N(p,α) 11 C reaction to generate 11 CO2, which enters the carbon dioxide input pipe through the stop valve V31; nitrogen enters the carbon dioxide input pipe through the stop valve V1, the sixteenth three-way valve V2, and the fifteenth three-way valve V3 to be mixed with carbon dioxide. Under the carrier of nitrogen, carbon dioxide enters the annular tube 12, sublimes into dry ice under the action of liquid nitrogen in the cooling container 11 to complete capture, and the excess gas is discharged through the waste gas pipe. After the capture is completed, the driving device moves the annular tube 12 out of the liquid nitrogen, and the carbon dioxide generated after the sublimation of dry ice enters the first reaction tube C1 through the first three-way valve V5. The sublimation process of dry ice can be accelerated by heating devices such as a hot air gun.

[0057] S3. 11 After CO2 is completely absorbed by the solution in the first reaction tube C1, nitrogen is introduced into the first reaction tube C1 through the stop valve V1, the sixteenth three-way valve V2, the fifteenth three-way valve V3, and the first three-way valve V5, and the first reaction tube C1 is heated to remove tetrahydrofuran, and the waste gas is discharged through the second three-way valve V6, the third three-way valve V7, the fourth three-way valve V8, the fifth three-way valve V9, and the waste gas pipe.

[0058] S4. Cool the first reaction tube C1 to below 80°C, and the syringe pump L1 adds hydroiodic acid to the first reaction tube C1 to carry out the iodination reaction.

[0059] S5. Heat the first reaction tube C1 to 180°C, and pass nitrogen gas into the first reaction tube C1. The evaporated CH3I gas enters the second reaction tube C2 through the second three-way valve V6, the third three-way valve V7, the drying tube 21, the fourth to sixth three-way valves, and the eleventh three-way valve V15 to carry out the labeling reaction. Then heat the second reaction tube C2 to 55°C and keep it at a constant temperature for 2 minutes.

[0060] S6. Nitrogen gas enters the reagent bottle B1 through the stop valve V1, the sixteenth three-way valve V2, and the third multi-way valve V16, transfers the mobile phase to the second reaction tube C2 to dilute the reactants, and releases pressure through the ninth three-way valve V13 and the waste gas pipe.

[0061] S7. Nitrogen gas enters through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the sixth three-way valve V10, and the eleventh three-way valve V15 to transfer the liquid in the second reaction tube C2 to the transfer bottle 31.

[0062] S8. Nitrogen gas enters through the stop valve V1, the sixteenth three-way valve V2, and the third multi-way valve V16, and transfers the liquid in the transfer bottle 31 to the quantitative loop 41 through the second multi-way valve V18.

[0063] S9. The infusion pump M3 inputs acetonitrile - acetic acid - aqueous solution to the second multi-way valve V18, transfers the liquid from the quantitative loop to the chromatographic column 42 for purification. The total purification time is 10 minutes. The solution separated at 7 - 9 minutes enters the extraction bottle C3 through the twelfth three-way valve V19 to be mixed with the diluent, and the solution at other times enters the first waste liquid bottle 43 through the twelfth three-way valve V19.

[0064] S10. Nitrogen gas enters the extraction bottle C3 through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the sixth three-way valve V10, and the eleventh three-way valve V15. At the same time, the air pump M4 sucks the gas in the second waste liquid bottle 53 to generate negative pressure, and transfers the liquid in the extraction bottle C3 to the capture column 51 through multiple raw material three-way valves and the thirteenth three-way valve V23. The product is captured by the C18 column, and the waste liquid enters the second waste liquid bottle 53 through the fourteenth three-way valve V24.

[0065] S11. The air pump M4 sucks the gas in the second waste liquid bottle 53 to generate negative pressure, sucks the sterile water in the raw material bottle A1 to the C18 column for cleaning, and the waste liquid enters the second waste liquid bottle 53 through the fourteenth three-way valve V24.

[0066] S12. The air pump M4 sucks the gas in the product bottle 52 to generate negative pressure. First, transfer the ethanol in the raw material bottle A2 to the C18 column, elute the product into the product bottle 52, and then transfer the sterile water in the raw material bottle A1 to the C18 column for washing, and the liquid enters the product bottle 52.

[0067] Example 4

[0068] Using the synthesis system provided in Example 1, complete 11 The synthesis of C-sodium acetate.

[0069] Before synthesis, the syringe pump L1 is filled with hydrochloric acid; the first reaction tube C1 is filled with CH3MgBr THF solution; the raw material bottle A1 is filled with NaHCO3 solution; the raw material bottle A2 is filled with normal saline. The synthesis process includes the following steps.

[0070] S1. Nitrogen enters through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the eighth three-way valve V12, and the thirteenth three-way valve V23, and then enters the raw material bottle A1 through multiple raw material three-way valves.

[0071] S2. Use a cyclotron to generate 14 N(p,α) 11 C reaction to produce 11 CO2, which enters the carbon dioxide input pipe through the stop valve V31; nitrogen enters the carbon dioxide input pipe through the stop valve V1, the sixteenth three-way valve V2, and the fifteenth three-way valve V3 to be mixed with carbon dioxide. Under the carrier of nitrogen, carbon dioxide enters the annular tube 12, sublimes into dry ice under the action of liquid nitrogen in the cooling container 11, and the capture is completed. The excess gas is discharged through the waste gas pipe. After the capture is completed, the driving device moves the annular tube 12 out of the liquid nitrogen, and the carbon dioxide generated after the sublimation of dry ice enters the first reaction tube C1 through the first three-way valve V5. The sublimation process of dry ice can be accelerated by heating devices such as a hot air gun.

[0072] S3. 11 After CO2 is completely absorbed, the syringe pump L1 adds hydrochloric acid to the first reaction tube C1 for hydrolysis reaction.

[0073] S4. Nitrogen enters the first reaction tube C1 through the stop valve V1, the sixteenth three-way valve V2, and the stop valve V4, and transfers the liquid to the extraction bottle C3 through the first to eighth three-way valves, the thirteenth three-way valve V23, and multiple raw material three-way valves.

[0074] S5. The air pump M4 sucks the gas in the extraction bottle C3 to generate negative pressure, and transfers the NaHCO3 solution in the raw material bottle A1 into the extraction bottle C3 for secondary hydrolysis.

[0075] S6. The air pump M4 sucks the gas in the extraction bottle C3 to vacuum and heats the extraction bottle C3 to 100 °C.

[0076] In S7, the air pump M4 sucks the gas in the extraction bottle C3 to generate negative pressure, and transfers the normal saline in the raw material bottle A2 to the extraction bottle C3 for dilution.

[0077] In S8, nitrogen enters the extraction bottle C3 through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the sixth three-way valve V10, and the eleventh three-way valve V15. At the same time, the air pump M4 sucks the gas in the product bottle 52 to generate negative pressure, and transfers the product from the extraction bottle C3 to the product bottle 52.

[0078] Example 5

[0079] Using the synthesis system provided in Example 1, complete 11 the synthesis of C-choline.

[0080] Before synthesis, the HI solution is loaded into the syringe pump L1; the raw material bottle A1 is loaded with absolute ethanol; the raw material bottle A2 is loaded with injection water, and the raw material bottle A3 is loaded with normal saline. The synthesis process includes the following steps.

[0081] In S1, nitrogen enters through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the eighth three-way valve V12, and the thirteenth three-way valve V23, and then is respectively filled into the raw material bottle A1, the raw material bottle A2, and the raw material bottle A3 through multiple raw material three-way valves.

[0082] In S2, using a cyclotron through 14 N(p,α) 11 C reaction to produce 11 CO2, which enters the carbon dioxide input pipe through the stop valve V31; nitrogen enters the carbon dioxide input pipe through the stop valve V1, the sixteenth three-way valve V2, and the fifteenth three-way valve V3 to be mixed with carbon dioxide. Under the carrier of nitrogen, carbon dioxide enters the annular tube 12 and sublimes into dry ice under the action of liquid nitrogen in the cooling container 11 to complete the capture, and the excess gas is discharged through the waste gas pipe. After the capture is completed, the driving device moves the annular tube 12 out of the liquid nitrogen, and the carbon dioxide generated after the sublimation of dry ice enters the first reaction tube C1 through the first three-way valve V5. The sublimation process of dry ice can be accelerated by heating devices such as a hot air gun.

[0083] In S3, 11 After CO2 is completely absorbed, nitrogen is introduced into the first reaction tube C1 through the stop valve V1, the sixteenth three-way valve V2, the fifteenth three-way valve V3, and the first three-way valve V5, and the first reaction tube C1 is heated to remove tetrahydrofuran, and the waste gas is discharged through the second three-way valve V6, the third three-way valve V7, the fourth three-way valve V8, the fifth three-way valve V9, and the waste gas pipe.

[0084] In S4, the reaction tube is cooled to below 50 °C, and the syringe pump L1 adds hydroiodic acid to the first reaction tube C1 for iodination reaction.

[0085] S5. Heat the first reaction tube C1 to 180 °C. The air pump M4 aspirates the gas in the second waste liquid bottle 53 to create a negative pressure. The CH3I gas enters the capture column 51 through the second three-way valve V6, the third three-way valve V7, the drying tube 21, the fourth to eighth three-way valves, and the thirteenth three-way valve V23, and a labeling reaction is carried out on the C18 column.

[0086] S6. The air pump M4 aspirates the gas in the second waste liquid bottle 53 to create a negative pressure, sucks the ethanol in the raw material bottle A1 into the capture column 51 for cleaning. The product adheres to the CM column, and the waste liquid enters the second waste liquid bottle 53.

[0087] S7. The air pump M4 aspirates the gas in the second waste liquid bottle 53 to create a negative pressure, sucks the injection water in the raw material bottle A2 into the capture column 51 for cleaning. The product adheres to the CM column, and the waste liquid enters the second waste liquid bottle 53.

[0088] S8. The air pump M4 aspirates the gas in the product bottle 52 to create a negative pressure, sucks the normal saline in the raw material bottle A3 into the capture column 51, and elutes the product on the CM column into the product bottle 52.

[0089] Example 6

[0090] Using the synthesis system provided in Example 1, complete 11 the synthesis of C-methionine.

[0091] Before synthesis, the injection pump L1 is filled with hydrogen iodide solution; the raw material bottle A1 is filled with normal saline; the first reaction tube C1 is pre-filled with lithium aluminum hydride tetrahydrofuran solution; the second reaction tube C2 is pre-filled with a solution prepared from water, acetone and the precursor; the extraction bottle C3 is pre-filled with hydrochloric acid; the reagent bottle B1 is pre-filled with sodium hydroxide solution. The pipe connecting the eleventh three-way valve V15 to the second reaction tube C2 is inserted into the bottom of the second reaction tube C2. The synthesis process includes the following steps.

[0092] S1. Nitrogen enters through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the eighth three-way valve V12, and the thirteenth three-way valve V23, and then enters the raw material bottle A1 through multiple raw material three-way valves.

[0093] S2. Use the cyclotron to generate 14 N(p,α) 11 C reaction to produce 11CO2 enters the carbon dioxide input pipe through the stop valve V31; nitrogen enters the carbon dioxide input pipe through the stop valve V1, the sixteenth three-way valve V2, and the fifteenth three-way valve V3 and mixes with carbon dioxide. Under the entrainment of nitrogen, carbon dioxide enters the annular pipe 12, sublimes into dry ice under the action of liquid nitrogen in the cooling container 11, and the capture is completed. The excess gas is discharged from the waste gas pipe. After the capture is completed, the driving device moves the annular pipe 12 out of the liquid nitrogen, and the carbon dioxide generated after the sublimation of dry ice enters the first reaction tube C1 through the first three-way valve V5. The sublimation process of dry ice can be accelerated by heating devices such as hot air guns.

[0094] S3, 11 After CO2 is completely absorbed, nitrogen is introduced into the first reaction tube C1 through the stop valve V1, the sixteenth three-way valve V2, the fifteenth three-way valve V3, and the first three-way valve V5, and the first reaction tube C1 is heated to remove tetrahydrofuran. The waste gas is discharged through the second three-way valve V6, the third three-way valve V7, the fourth three-way valve V8, the fifth three-way valve V9, and the waste gas pipe.

[0095] S4, Cool the reaction tube to below 50 °C. The syringe pump L1 adds hydroiodic acid to the first reaction tube C1 for iodination reaction.

[0096] S5, Heat the first reaction tube C1 to 180 °C, and the air pump M4 sucks the gas in the second waste liquid bottle 53 to generate negative pressure, and the CH3I gas enters the capture column 51 through the second three-way valve V6, the third three-way valve V7, the drying tube 21, the fourth to eighth three-way valves, and the thirteenth three-way valve V23 for labeling reaction on the C18 column.

[0097] S6, Nitrogen enters the reagent bottle B1 through the stop valve V1, the sixteenth three-way valve V2, and the third multi-way valve V16, and transfers the NaOH solution to the second reaction tube C2 for hydrolysis ring-opening reaction.

[0098] S7, Nitrogen enters the second reaction tube C2 through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the eighth three-way valve V12, and the ninth three-way valve V13, transfers the internal liquid to the extraction bottle C3 through the eleventh three-way valve V15, and opens the stop valve V32 to relieve pressure.

[0099] S8, Heat the extraction bottle C3 to evaporate the liquid. After drying, the air pump M4 sucks the gas in the extraction bottle C3 to generate negative pressure, and transfers the normal saline in the raw material bottle A1 to the extraction bottle to obtain the product.

[0100] S9, Nitrogen enters the extraction bottle C3 through the stop valve V1, the sixteenth three-way valve V2, the seventh three-way valve V11, the sixth three-way valve V10, and the eleventh three-way valve V15. The air pump M4 then sucks the gas in the product bottle 52, and transfers the product from the extraction bottle C3 to the product bottle 52.

[0101] Example 7

[0102] Using the synthesis system provided in Embodiment 1, check whether there are blockages and leaks in the pipelines related to the first and second reaction tubes. The specific steps are as follows:

[0103] S1, Pipeline blockage inspection; Nitrogen enters the first reaction tube C1 through the stop valve V1, the sixteenth three-way valve V2, the fifteenth three-way valve V3, and the first three-way valve V5, and then enters the second reaction tube C2 through the second three-way valve V6, the third three-way valve V7, the drying tube 21, the fourth three-way valve V8, the fifth three-way valve V9, the sixth three-way valve V10, and the eleventh three-way valve V15, and finally exits through the ninth three-way valve V13 and the exhaust pipe. If the pressure gauge reading does not change, it indicates that there is no blockage in the pipeline.

[0104] S2, Pipeline leak inspection; Nitrogen enters the first reaction tube C1 through the stop valve V1, the sixteenth three-way valve V2, the fifteenth three-way valve V3, and the first three-way valve V5, and then enters the second reaction tube C2 through the second three-way valve V6, the third three-way valve V7, the drying tube 21, the fourth three-way valve V8, the fifth three-way valve V9, the sixth three-way valve V10, and the eleventh three-way valve V15, and the ninth three-way valve V13 is closed. After increasing the pressure in the pipeline to 0.2 MPa, close the stop valve V1. If the pressure gauge reading does not drop by more than 0.01 MPa within 10 minutes, it is considered that there is no leak in the pipeline.

[0105] In the above embodiments, when transferring liquid or gas once, only the corresponding pipelines are opened and other pipelines are closed.

[0106] The above are one or more implementation manners of the present invention, and the description is relatively specific and detailed, but it should not be understood as a limitation to the scope of the present invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several deformations and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent should be subject to the appended claims.

Claims

1. A 11 C radiopharmaceutical synthesis system, characterized in that, include: The primary reaction module comprises a carbon dioxide capture device and a first reaction tube, wherein the carbon dioxide capture device comprises a cooling container, an annular tube and a driving device for driving the annular tube to enter and exit the cooling container, one end of the annular tube is connected to a carbon dioxide input pipe, and the carbon dioxide input pipe is provided with a stop valve; the first reaction tube is also connected to an injection pump, and the first reaction tube is also provided with a heating device; A first three-way valve group includes a first three-way valve, a second three-way valve, a third three-way valve, a fourth three-way valve, a fifth three-way valve, a sixth three-way valve, a seventh three-way valve, and an eighth three-way valve connected in series in sequence, wherein two interfaces of the first three-way valve are respectively connected to the annular tube and the first reaction tube, the second three-way valve is connected to the first reaction tube, a drying tube is connected between the third three-way valve and the fourth three-way valve, and the fifth three-way valve is connected to an exhaust pipe; An online conversion module, comprising a conversion furnace connected to the eighth three-way valve, the conversion furnace is connected to a ninth three-way valve, and the ninth three-way valve is connected to an exhaust pipe; A secondary reaction module, comprising a second reaction tube, wherein the second reaction tube is respectively connected to a thirteenth-way valve, an eleventh three-way valve and the ninth three-way valve; two interfaces of the thirteenth-way valve are respectively connected to a transfer bottle and a first multi-way valve, and multiple interfaces of the first multi-way valve are respectively connected to multiple reagent bottles; the eleventh three-way valve is connected to the sixth three-way valve; and the second reaction tube is also provided with a heating device; A liquid phase purification module, comprising a second multi-way valve connected to the transfer bottle, a quantitative loop being connected between two interfaces of the second multi-way valve, and the other two interfaces of the second multi-way valve being respectively connected to a chromatographic column and a first waste liquid bottle, the chromatographic column being sequentially connected to an ultraviolet detection device and a twelfth three-way valve, and the twelfth three-way valve being connected to the first waste liquid bottle; A solid phase extraction module, comprising an extraction bottle and a second three-way valve group; the extraction bottle is respectively connected to the eleventh three-way valve and the twelfth three-way valve, the extraction bottle is provided with an exhaust pipe, and the extraction bottle is also provided with a heating device; the second three-way valve group comprises a plurality of raw material three-way valves and a thirteenth three-way valve connected in sequence, and the plurality of raw material three-way valves are all connected to a raw material bottle, the raw material three-way valve at one end of the second three-way valve group is connected to the extraction bottle, and the thirteenth three-way valve at the other end is connected to the eighth three-way valve; A column purification module, comprising a capture column connected to the thirteenth three-way valve, the capture column being connected to a fourteenth three-way valve, two interfaces of the fourteenth three-way valve being respectively connected to a product bottle and a second waste liquid bottle, the second waste liquid bottle being provided with a waste gas pipe; A pipetting module comprises a nitrogen source, an infusion pump and an exhaust pump; the nitrogen source is connected to the seventh three-way valve, the carbon dioxide input pipe is also provided with a fifteenth three-way valve, the nitrogen source is connected to the fifteenth three-way valve, the nitrogen source is connected to the first reaction tube and is provided with a stop valve, the nitrogen source is also connected to a third multi-way valve, and multiple interfaces of the third multi-way valve are respectively connected to multiple reagent bottles and transfer bottles; the infusion pump is connected to the second multi-way valve; the exhaust pump is connected to a fourth multi-way valve, and multiple interfaces of the fourth multi-way valve are respectively connected to the extraction bottle, the product bottle and the second waste liquid bottle.

2. A method according to claim 1 11 C radiopharmaceutical synthesis system, characterized in that, The cooling container is a liquid nitrogen container with an opening at the top, and the driving device is a lift connected to the annular tube.

3. A method according to claim 1 11 C radiopharmaceutical synthesis system, characterized in that, The heating devices are all provided with ventilation openings, which are connected to an air source and are provided with a stop valve.

4. A method according to claim 3 11 C radiopharmaceutical synthesis system, characterized in that, The pipes connecting the ventilation ports of the first reaction tube and the second reaction tube heating devices to the air source are also provided with vortex cooling pipes.

5. A method according to claim 1 11 C radiopharmaceutical synthesis system, characterized in that, The capture column includes a C18 column and a CM column connected in sequence.

6. A method according to claim 1 11 C radiopharmaceutical synthesis system, characterized in that, The exhaust pipes are all provided with a one-way valve or a stop valve to prevent gas from entering.

7. A method according to claim 1 11 C radiopharmaceutical synthesis system, characterized in that, The nitrogen source is connected to a stop valve, a flow meter, a pressure gauge and a sixteenth three-way valve in sequence, one port of the sixteenth three-way valve is connected to the seventh three-way valve, and a pipeline connected to another port of the sixteenth three-way valve is respectively connected to the fifteenth three-way valve, the first reaction tube and the third multi-way valve through multiple three-way pipes.

8. A method according to claim 1 11 C radiopharmaceutical synthesis system, characterized in that, It also includes an installation panel. In addition to the injection pump, capture column, infusion pump, and vacuum pump, the primary reaction module, the first three-way valve group, the online conversion module, the secondary reaction module, the liquid phase purification module, and the solid phase extraction module are all arranged on the upper surface of the installation panel.

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