TWI329021B - - Google Patents

Description

4 1329021 IX. Description of the Invention: [Technical Field] The present invention relates to a method and apparatus for producing a serotonin operator contrast agent, in particular, a serotonin which is 18f positron radioisotope 运转Automatic synthesis of paste making. Manufacturing method 'and its automatic synthesis device. [Prior Art] With the advancement of medicine, the life span of human beings has increased significantly more than before; with it, neurodegenerative diseases, neuropsychiatric dis〇rders, cancer, and Substance abuse has become a major socioeconomic problem in the world. Non-invasive angiography methods, such as positron tomography (PET) and appropriate radioligands (radioHgand_ may provide an objective method for diagnosing and monitoring the therapeutic response of these lesions. The abnormalities of neurotransmitns (in particular, in the dopamine system, have been shown to play an important role in different mental and neurological diseases (1); in other neurotransmitters, serotonin operators (ser〇t〇nintransp〇rters, SERT) is known to be associated with Parkinson's disease, major depression (maj_or depressi〇n), schizophrenia, drug addiction, Anxiety and obsessive compulsive disorders [2'3]' but few in-depth studies may be due to the lack of their specific contrast agents. In the past decade, isotopic carbon _11 calibrated ["q_(+)McN5652 is considered to be the most promising to be a serotonin operator (SERT) positron contrast agent (PETagent); however, the agent has a high Non-specific combination of degrees, and in the study of human positron tomography, only moderate signal contrast; in addition, the pharmacokinetics of ["(:]-(+)]ν^Ν5652 is not ideal, 4 1329021 Because its brain uptake is slow and the half-life of isotope carbon-11 (UC) is short; the compound is labeled with the isotope fluorine-18 (18F) and does not increase its contrast properties [4,5] Recently, a novel class of serotonin reuptake inhibitors known as 7V,7V-dimethyl.-2-(arylthio)benzylamines has been reported to be highly selective and affinitive for serotonin operators (SERT). [6'7], its analogues have also been developed, for example: [123I] IDAM (5-iodo-2-[[2-2-[(dimethylamino)methyl]phenyl]thio) calibrated with isotope iodine-123 ] benzyl alcohol) ' [,23I] ADAM (2-[[2-[[dimethylamino]methyl]phenyl]thio]-5-

Iodophenylamine) and isotope carbon-11 (IDAM, ADAM, MADAM (2-[2-dimethylaminomethyl-phenylsulphanyl]-5-methyl-phenylamine) ' AFM (2-[2-(dimethylaminomethylphenylthio))-5 -fluoromethylphenylamine), AFA (2-[2-[[(dimethylamino)methyl]phenyl]thio]-5-fluorophenylamine), AFE (2-[2-[[(dimethylamino)methyl]phenyl]thio]-5-( 2-fluoroethyl)phenylamine), DAPA (5-bromo-2-[2-(dimethylaminomethylphenylsulfanyl)]phenylamine) and DASB (3-amino-4-[2-(dimethylaminomethylphenylthio)]benzonitrile) as jk-clear activator (SERT) Single-photon emission computed tomography (SPECT) and positron tomography (PET) contrast agents [8-17] 〇 preliminary human studies show that '[123Ι]ADAM has the potential to become The central serotonin system is a radioligand for the study of radioligands in vivo; however, the ligand is still somewhat restricted: (1) 1231-calibrated radioligand needs to possess high-energy particles Unit of high-energy cyclotron Use, this uncertainty will be more or less inconvenient for research progress; (2) Brain ingestion outside the mid-brain (brainuptake) does not show enough contrast signal 'this will cause Semi-quantitative analysis of semi-quantitative computed tomography in areas of prefrontal i〇be, frontal lobe, and temporal lobe

A 6 is difficult, and these areas are very important for assessing neuropsychiatric disorders; (3) it takes a long time (4 hours) for the ligand to reach equilibrium, which may increase the risk of animal testing and long-term occupation. Scan the instrument. Similarly, studies have shown that "C-calibrated ADAM 'MADAM, AFM, AFA, afe, and DASB also have the potential to become radioligands for serotonin in vivo studies, especially radiopharmaceuticals ["C] DASB has been found to be well suited With positron tomography (pET) to detect serotonin reuptake sites and serotonin reuptake inhibitors in the human body ((111(〇(:(叩:31«^)[22- 24]; however, '1呍 丨丨 (^ has many advantages, including: (1) 丨 817 than " C has a lower positron energy (呷: 〇 635MeV, uc : 〇 96MeV), so spatial resolution There are fewer cases of spatial resolution smearing; (2) because the half-life of 丨8F is longer, if necessary, the study of positron tomography can be carried out for 2 more hours, while nc has only a half-life of 20 minutes. The time is extremely short; therefore, using isF can establish a better scanning test procedure; (3) due to the longer half-life of 18F, the use of cesium for radiochemical synthesis (radiosynthesis) is more convenient than using UC; (4) when a positive Tomography inspection site When a particle cyclotron cannot be used to generate a positron contrast agent, it can be supported by other units, and the positron contrast agent of the l8F mark is sent from the outside to the inspection site, so that the positron tomography can be performed as scheduled. The inventor in 2003 A new serotonin radioligand labeled with 181? has been developed, A^V-dimethyl-2-(2-amino-4-丨8F-fluorophenylthio)benzylamine(4-[丨8F]-adam)[25 And the method of synthesizing the ligand by manual operation; as shown in Figure 1, the ligand 4_[18F]-ADAM (5a) is a bromine-precursor with potassium [18F]fluoride / Kryptofix 2.2.2 (2) #,iV-dimethyl-2-(2-nitro-4-bromophenylthio)benzylamine (1 a) or nitric acid _ precursor #, #-dimethyl-2-(2,4-dinitrophenylthio)benzylamine (1 b) for nucleophilic Substitution reaction 1329021

(nucleophilic substitution), formation of A^V-dimethyl-2-(2-nitro-4-18F-fluorophenylthio) benzylamine (3a), followed by reduction with NaBH4/Cu(OAc)2(4), and HPLC Purification of β The synthetic chemical synthesis of 4-[18F]-ADAM was 5-10% (decay corrected), the synthesis time from EOB (End of Bombardment) was 150 minutes, HPLC analysis showed radiochemical purity > 98% The specific activity is 0.6 Ci/μηιοΐ. Preliminary studies in rats showed that 4-[18F]-ADAM has affinity and high specificity for serotonin; and studies with sputum also showed that the intake of 4-[18F]-ADAM in the midbrain was about one after injection. The hour reached its peak and then slowly decreased. At 2 hours and 3 hours after the injection, the proportion of radiation in the midbrain to the cerebellum was 3.2 and 4.2 [26], and it was speculated that 4-[18F]- ADAM is suitable for serotonin in living brains with positron tomography (PET). In addition, 'Huang et al. also published in 2004 the analogue of 4-[18F]-ADAM 4-[18F]-AFM (2-[[2-Amino-4-([18F]fluoromethyl)phenyl]thio]-A ^ iV-dimethylbenzene-methana mine)(5c) ' 4-[18F]-AFE (2-[[2-Amino-4-(2-[18F]fluoroethyl)phenyl]thio]-iV, N-dimethylbenzenemethanamine) 5d) Preparation method of serotonin operator contrast agent such as '4-[18F]-AFP (2-[[2-Amino-4-(3-[18F]fluoro piOpyDphenylJthic^-A^iV-dimethylbenzenemethanamineXSe) [2η, The synthesis procedure is the same as that of 4-[18F]-ADAM(5a), which is carried out by: (1) separation of [18F] ions; (2) nucleophilic substitution reaction of related precursors with K[18F]/K2.2.2 (3) Prepare with NaBH4/Cu(OAc)2; (4)^HPLC; (5) 酉己方4匕 (Formulation) 〇Please refer to Figure 1 '4-[18F]-AFM (5c), The preparation steps of 4-[18F]-AFE (5d), 4-[18F]-AFP (5e) and other serotonin contrast agents are shown in Figure 1. First, the respective precursors are 2-[(^ -(chloiOmethyl^-nitrophenylJthi.]-·^ iV'-dimethylbenzenemethanamine 8 1329021 (1 c)' 4-[[2-(dimethylamino)methyl]phenyl]thio]-3-nitrobenzeneethanol 4-methyl benezenesulfon Eate (Id), 4-[[2-(dimethylamino)methyl]phenyl]thio]-3-nitrobenzenepropanol 4-methylbenezenesulfonate (le) nucleophilic substitution reaction with potassium [18F]fluoride / Kryptofix2.2.2 (2), The intermediate product 2-[[2-nitro-4-([18F]fluoromethyl)phenyl]thio]-iV, iV-dimethylbenzene-methanami .ne (3c) ' 2-[[2-nitro-4-(2) -[18F]fluoroethyl)phenyl]thio]-7/,7\^-dimethyl benzene v methanamine (3d) ' 2-[[2-nitro-4-(3-[18F]fluoropropyl) phenyl]thio]-A ^, after iV- dimethylbenzenemethanamine (3e), and then with NaBH4/Cu(OAc)2 (4) • 'Reaction' gives 4_[丨8F]-AFM (5c), 4-[18F]-AFE (5d, respectively) ), 4-[i8F]-AFP ((iv), then 'purified by HPLC. Since the preparation steps of the ash-purifying agent contrast agent such as 4-[18F]-ADAM, 4-[18F]-AFM, 4-[18F]-AFE, 4-[18F]-AFP are cumbersome and are radiation, If it is prepared by manual operation, it is not only troublesome to operate, but also can be prepared in a small amount at a time, cannot be mass-produced, and the operator needs to be exposed to radiation for a long time, which will adversely affect its health. It can be seen that there are still many shortcomings in the above-mentioned conventional methods, which is not a good designer, and 亟 ^ to be improved. In view of the above-mentioned (four) methods of the female, the New Zealand-style method is a new method and has been painstakingly researched for many years. After the research, the method for manufacturing the serotonin operator contrast agent was successfully developed. Device. SUMMARY OF THE INVENTION The object of the present invention is to provide a method for producing a serotonin operator contrast agent, which is a method for manufacturing a serotonin operator contrast agent by an automated synthesis method, which simplifies the manufacturing process to meet clinical requirements. Research needs. 1329021 A second object of the present invention is to provide a device for producing a 18f positron radioisotope marker serotonin operator contrast agent, which is an automated device for manufacturing a serotonin carrier contrast agent to reduce the operator's exposure to radiation. . Automated synthesis of 18f positron radioisotope-labeled serotonin operator contrast agent 4_[18F]-ADAM, 4-[18F]-AFM, 4-[18F]-AFE, 4-[18F]-AFP reaction procedure and invention Humans have revealed the artificial operation of synthesizing the same room's, ie, the separation of ions; (2) nucleophilic substitution reaction of related precursors with ^ Κ [%] / Κ 2.2.2; (3) NaBH4 / Cu (OAc) 2 performing a reductive reaction; (4) purifying the product by HPLC; (5) formulating the formulation. A method for producing a 18F positronium radioisotope-labeled serotonin operator contrast agent capable of achieving the above object, comprising the steps of: Step 1: passing an aqueous solution of [18F] ions through a first separation device to adsorb the [i8F Ion; Step 2: The K^CXVKryptofiX2.2.2 solution is passed through the first separation device to carry out the [i8F] ions into a reaction device, and is dried by a blunt gas at an appropriate temperature and time; Step 3 Adding the precursor solution to the reaction device, and performing nucleophilic substitution reaction at a suitable temperature for a period of time, and then cooling to room temperature; φ Step 4: After adding water, the solution in the reaction device is passed through a first a separation device for adsorbing the intermediate product in the solution; Step 5: passing methylene chloride (CHfl2) through the second separation device to bring out the intermediate product to another reaction device and Drying at a temperature and time with an blunt gas; Step 6: sequentially adding ethanol, Cu(OAc)rH2 〇 saturated solution and NaBH4 solution to the reaction device and performing a reduction reaction at a suitable temperature for a period of time Thereafter, the mixture is injected into a third separation device for separation and purification; Step 7: collecting the product-containing solution into a water-containing collector; 1329021 Step 8: passing the solution in the collector through a fourth separation device, Soaking the product in the solution, and washing the fourth separation device with a cleaning solution to remove residual acetonitrile in the column; Step 9: passing ethanol through the fourth separation device to bring the product to A collector containing physiological saline is reserved. Wherein the [18f] ionic aqueous solution is prepared by a particle cyclotron with i8 〇 (p, ny8F nuclear reaction), wherein the concentration of the K2C03 solution is 20-50 mg/mL. wherein the Kryptofix 2.2.2 is dissolved in an acetonitrile solution. The concentration is 20-60 mg/mL. In a preferred embodiment, the precursor is j\^V-dimethyl-2-(2-nitro-4-bromophenylthio)benzylamine or A^V~dimethyl-2- (2,4-dinitrophenylthio) benzylamine ' is soluble in DMSO at a concentration of 4-20 mg/mL. In a preferred embodiment, the precursor is 2-[[4-((±1〇1*〇11) ^11^1)-2-nitrophenyljthioj-A^iV-dimethyl benzenemethanamine, soluble in acetonitrile at a concentration of 1-20 mg/mL °. In a preferred embodiment, the precursor is 4-[[2-( Dimethyl]i]]]]]]]]]]]]]]]]]]]] Methyl]phenyl]thio]-3-nitrobenzenepropanol 4-methylbenezenesulfonate, soluble in acetonitrile at a concentration of 1-20 mg/mL. The NaBHj solution is soluble in ethanol at a concentration of 10-20 mg/mL. The microporous membrane is a polytetrafluoroethylene membrane with a pore size of 0.22 μηη. 1329021 wherein the first separation device is an anion exchange resin; in a preferred embodiment, the first separation device is QMA. The second separating device is a resin having a C18 bonded stone molecule; in a preferred embodiment, the second separating device is a C18Sep-Pak pipe string, wherein the second separating device is half Preparing a semi-preparadve high performance liquid chromatography (HPLC) column and further connecting a radiation detector and an ultraviolet detector to the output column of the HPLC column; in a preferred embodiment, the The third separation device is a 10 X 250 mm NUCLEOSIL 100-5 C18 Nautilus column.

Wherein the fourth separation device is a resin having a C18 bonded ruthenium molecule; in a preferred embodiment, the fourth separation device is a tC18 Sep-Pak column. The appropriate temperature time in the step 2 is U5_13 (rc, 5-15 minutes. The appropriate temperature time in the step 3 is 12〇_13〇t, 51〇 minutes. The appropriate temperature time in the step 5 It is 65_75. 〇; 51 〇 minutes. The appropriate temperature time for the step ό is 75 85 < 1 (: ; ι〇 · 2 〇 minutes. The mixture of the step 6 can be further passed through a microporous membrane _ And injecting the first multiple separation device, wherein the cleaning liquid used in the step 8 is water. wherein the product of the step 9 can be further collected after a microporous membrane transition. In addition, the present hair duck-step provides - difficult to make 18ρ a device for positively displacing a serum-speed transconductant contrast agent includes a control relay and a reaction system; the control device is for automatically controlling a switch of each pipeline in the reaction system; the reaction system includes - - separation device, second separation device, - third separation device, - fourth separation device ... - reagent access device, - second reagent access device, - third reagent access device, - fourth reagent storage Take the device, 12 1329021 a first-inverse a device, a second reaction device, a -__ collector, a second collector, an aqueous solution storage device, and one or more waste liquid storage devices; the first separation device and the first solution access device Connecting 'to receive and separate the solution of the first reagent access device domain, and place the undesired solution in the aqueous solution storage device, and the required reagent is sent to the first reaction device wiper' The reaction device is connected to the second test device to receive the solution (4) when the second reagent access device is received, and the reaction is sent to the second separation device for separation, and the unnecessary solution is Will be placed in a waste storage device, and the required reagent is sent to the second reaction device, the second reaction device is connected to the third test device to receive the third test device. The bribe is mixed and reacted, and the solution of the counter-nucleus is sent to the second separation device for separation. The unnecessary liquid is placed in the waste liquid storage device, and the required reagent is sent to the first collector. , the first - the collector contains appropriate The reaction solution can be mixed with the reagent, the mixture will be sent to the fourth separation device for separation, the undesired solution will be placed in a waste liquid storage device, and the prepared product is sent to the second collector for use. The serotonin operator contrast agent labeled with the 18f positron radioisotope is a contrast agent which can be prepared by the following synthesizing program: (1 child! Separation of 8 ions; to K[I8F]/ K2.2·2 carries out nucleophilic substitution reaction on related precursors; (3) reduction reaction; (4) purification of products by HpLC; (5) formulation (Formulation); eg 4-[18F]-ADAM a serotonin operator contrast agent β such as 4-[18F]-AFM, .4-[18f]-afe, 4-[18F]-AFP, wherein the reaction system further comprises a vacuuming device, the vacuuming device The first reaction device or the second reaction device may be separately connected to drive the flow of the reaction solution in a vacuum manner or accelerate the evaporation process of the solution in the reaction device. The reaction system further includes a pressurizing device, and the pressurizing device can be respectively connected to the first reagent access device, the second reagent access device, the third reagent access device, and the fourth reagent storage device 13 1329021. The first reaction device, the second reaction device, the first collector, the second collector or the third separation device are connected to drive the flow of the reaction solution in a manner of filling the gas. Wherein the first separation device is an anion exchange resin; in a preferred embodiment, the first separation device is a QMA column. Wherein the second separation device is a resin having C18 bonded molecules; in a preferred embodiment, the second separation device is a C18 Sep-Pak column. Wherein the second separation device is an HPLC purification device comprising an HPLC column, a radiation debt detector, and a feed line spectrometer II, the H-ray and the ultraviolet fine doping are connected to the muscle C column In the preferred embodiment, the 6th second separation device is a 1〇χ25〇 匕 100 5(10) Nautilus column. Wherein the fourth sub-mixing system is - having a C18 calendar score only _; in the preferred embodiment, the fourth separating device is a tC18 Sep_pak column. Wherein the first reagent access device comprises more than one reagent accessor, and the outlet of each reagent accessor is provided with a switch to control the flow of the contents thereof. Wherein the first-touch access device stores a portion of the reagent required for the nucleophilic substitution reaction; in the preferred embodiment, 'containing an aqueous solution of [丨,] ions and a solution of the solution 22). The second reagent access device includes more than one reagent accessor, and the outlet of each reagent accessor is provided with a switch to control the flow of the contents thereof. 〇 The Violation of the 4th agent access device is the part of the reagents required for the nucleophilic substitution reaction. In a better implementation, the money is stored in the package, and the money is charged with 2α2). The second 5_ access device includes more than one reagent accessor, and each reagent accessor Uitj' controls the flow of the content. 1329021 wherein the third test device is a reagent for performing the reduction reaction; in a preferred embodiment, the <6> contains 6 alcohol, Cu(〇Ae)rH2(10) and hetero and NaBKj solutions. The fourth test age picking device comprises a reagent accessor on the __ gamma, and a flow outlet of each reagent accessor is provided with a switch to control the outflow of the contents thereof. Wherein the fourth reagent access device stores the reagents required for the formulation reaction; in a preferred embodiment, water and ethanol are included. Wherein the first reaction device comprises a reagent reactor and a temperature regulator. Wherein the second reaction cleavage comprises a reagent reactor and a temperature regulator. [Embodiment] Example - Automated synthesis device for serotonin operator of 18F positron carrier ** Please refer to Fig. 2 'Fig. 2 (b) - Manufacture of serotonin operator of Orthodox radioisotope A preferred embodiment of the contrast agent comprises a control device j and an anti-deer system 2; the control weaving S 1 system is automatically controlled to switch between the various lines in the anti-infrared system 2; the reaction system 2 comprises - a first separation device 3, a second separation device 32, a third separation device %, ♦ - a fourth separation device 34, a - reagent access device 2, a second reagent access device η, a J. a third reagent access device 23, a fourth reagent access device 24, a first reaction device 41, a first ... reaction device 42, a first collector 5, a second collection buffer 52, an aqueous solution storage device 61, Waste liquid storage devices 62, 63, 64, pressurizing devices 71, 72, 73, 74, 75, lv η Μ and a vacuuming device 8. The first reagent access device 21 comprises a reagent accessor (10) for storing an aqueous ion solution, and a reagent accessor 211 for containing a KaCCVKryptofix 222 solution; the outlet of the reagent accessor hi is provided with a switch 101 for controlling hOVKiyptofix 222 Whether the solution flows out or not; the 15 (.S) 1329021 reagent accessors 210, 211 are connected to the first separating device 31 by a three-way switch 110, which is by three-way m and the first - the reagent reactor 41a in the reaction device 41 and the aqueous solution storage device 01 are connected; the aqueous solution storage device is connected to the vacuuming device 8 via a switch (9), and the switch 12G can be opened to force the reagent. The [I8F] ion aqueous solution in the accessor 210 flows through the first separating device h; the first separating device • 31 series QMA f column, which can grasp the [18ρ] ion and prepare the aqueous solution through the three-way switch (1) Discharge to the aqueous solution storage device 61; the reagent reactor 41a is also connected to the vacuuming device 8 via a switch (2) to open the switch 21 and the switch 1〇1, that is, the reagent accessor can be forced by vacuuming Within 211 The K^OVKryptofix2·2·2 solution flows through the first separation device 31, carries out [18f] ions, and flows through the switch U1 to the reagent reactor 41a. The second reagent access device 22 includes a reagent accessor 221 for storing a precursor solution, a reagent accessor 222' for storing a buffer, and a reagent accessor 223 for storing a dichloromethane solution; the reagent accessor 22 The outlets of 222 and 223 are respectively provided with a switch 1〇2, 1〇3, 1〇4 to control the outflow or not of each solution; the reagent accessor 22 222, 223 and the first reaction device The reagent reactors 4la in 41 are connected; in order to reduce the number of tube configurations, the reagent accessors 222, 223 can be further combined with the reagent reactor 41a by a three-way switch 127; The input ports of the accessors 22, 222, and 223 are connected to the pressurizing device 71, and the switches 102 and 103 are respectively opened to force the solution in the reagent accessors 221 and 222 by filling the helium gas. Flowing into the reagent reactor 41a, and heating the reaction via the temperature regulator 41b in the first reaction device 41. Further, the reagent reactor 41a is further connected to the pressurizing device 73 via a switch 丨23 and a switch 124. 'Turn on the switches 123 and 124 to fill the helium gas' to force the test The solution in the reactor 41a passes through the switch 112 through the second separating device 32; the second separating device 32 is 1329021 by the three-way switch 113 and the reagent reactor 42a in the second reaction device 42 and the waste liquid storage The device 62 is connected; the second separating device 32 is a C18 Sep-Pak pipe string, which can pick up the intermediate product in the solution and discharge the unwanted solution to the waste liquid storage device 62 via the three-way switch 113; The switch 104 can force the solution in the reagent accessor 223 to flow to the reagent reactor 41a by filling the helium gas, and then flow through the second separation device 32 to bring out the intermediate product and pass the switch. 113 flows into the reagent reactor 42a. The third reagent access device 23 includes a reagent accessor 231 for storing alcohol, a reagent accessor 232 for storing a saturated solution of Cu(OAc)rH2, and a reagent for storing the NaBHt solution. The access device 233; the flow outlets of the reagent accessors 231, 232, 233 are respectively provided with a switch 1〇5, 106, 107′ to control the flow of each solution; the reagent accessors 231, 232, 233 Reacting with the reagent in the second reaction device 42 42a is connected; to reduce the number of tube configurations, the reagent accessors 232, 233 can be combined with the reagent reactor 42a by a three-way switch 128; the input of the reagent accessors 231, 232, 233 The mouth system is connected to the pressing device 71, and the switches 105, 106, 107 are respectively opened to force the solution in the reagent accessors 231 '232, 233 to flow to the reagent reactor 42a by filling the helium gas. The reaction can be warmed by the temperature regulator 42b in the second reaction unit 42. In addition, the reagent reactor 42a is further connected to the pressurizing device 73 via a switch 124. The switch 124 can be opened to force the solution in the reagent reactor 42a to pass through the switch 114 to the third separation by filling the helium gas. In the device 33, the third separating device 33 includes a microporous filter 33, an HPLC column 332, a radiation detector 333, an ultraviolet detector 334, and an HPLC flow washer accessor 335. The microporous membrane 331 is connected to the injection port of the HPLC column 332 to filter the injected solution, and the radiation detector 333 and the ultraviolet detector 334 are connected to the output end of the HPLC column 332 to detect Radiation and UV absorption of the flow-through wash fraction 17 1329021 spectrum; after the HPLC column 332, purification, and the light detector, such as the UV detector 334 side, the unwanted flow wash will be three-way The switch 115 is discharged to the waste liquid storage device, and the product containing the shampoo fragments flows through the three-way switch 115 to the contained first collector 51. • The first collector 51 is connected to the pressurizing device 74 via a switch 125, and is connected to the fourth separating device 34 via a three-way opening-closing 116 and a three-way switch 117; in addition, the fourth reagent access The device 24 includes a reagent accessor 241 for storing H2, and a reagent accessor 242 for storing ethanol, φ. The outlets of the reagent accessors 24 242 are respectively provided with -switches 108, 109 to control the flow of each solution. The reagent accessor 241 is also separated from the fourth via the three-way switch 116, ι7 The device 34 is connected to the reagent accessor 242 via the three-way switch 117 and is connected to the fourth separating device 34. Opening the switch 125, the solution in the first collector 51 is forced to pass through the third separating device 34 through the three-way switch U6, 117 by filling the helium gas; the fourth separating device is made by two directions The switch 118 is connected to the second collector 52 and the waste liquid storage device 64; the fourth separating device 34 is a tC18 Sep-Pak column, which can grab the product in the solution and pass the unwanted ® solution through the three The switch U8 is discharged to the waste liquid storage device 64; when the switch ι〇8 is opened, the solution in the reagent accessor 241 is forced to flow through the switch 116, ι17 by filling the helium gas. a separating device 34 for cleaning the residual solvent in the fourth separating device 34, and flowing to the waste liquid storage device 64 via the switch 118; and then opening the switch 1〇9 to fill the helium gas, forcing the reagent to be stored The solution in the extractor 242 flows through the fourth separating device 34 through the switch 117, and the product is taken out and then flows through the switch 118 to the second collector 52 to be mixed with the physiological saline. The second collector 52 can be further connected to the pressing device 74 through the three-way switch 126, and connected to a microporous filter 341 via a switch 119, and the microporous filter 341 is combined with the product to collect 1329021 collector 53 The switch 126 is opened to fill the helium gas, forcing the solution in the second collector 52 to pass through the microporous filter 341 through the switch 119, and then flow to the product collector 53 for use. Example 2 Serotonin Operator Contrast Agent 4^8F]_ADAM (Sa) Automatic Synthesis Referring to Figure 1 and Figure 2, the automatic synthesis of the serotonin contrast agent (5a) provided by the present invention mainly comprises the following steps: 1. The aqueous ion solution produced by the 180(p,n)18F nuclear reaction was transferred from the cyclotron to the reagent accessor 21 and filled with helium. 2. Open the switch ion water solution in the vacuum environment will be sucked out of the reagent accessor 210 ' and through the three-way switch 110 and (^ ^ pipe column 31, then through the three-way switch 1U, the last '180 will be recycled The aqueous solution storage device 6 will remain in the qMa column 31. 3. Open the switch 121 under vacuum, containing K2C〇3 (3mgK2c〇3 dissolved in l.lmlH2(7) and Kryptofix 2 2 2 ( A solution of 30 mg Kryptofix 2 2 2 dissolved in 9.9 ml CH3CN) is aspirated from the reagent accessor 211, through which the three-way switch 11A, the QMA column 31, and the three-way switch 111' remain The [18F] ions in the QMA column 31 are taken out by the solution and flowed into the reagent reactor 41a. 4. The solution is evaporated at 125 ° C for 10 minutes and dried by flowing helium gas. 5. The nitrite-based precursor jimethyl-2-(2,4-dinitrophenylthio)benzylamine (lb) (the precursor is dissolved in 0.5 ml of DMSO) is used to indirectly fill the helium gas. The method is added to the reagent reactor 41a containing the residue of K[18F]/Kryptofix 2.2.2(2). 6. The solution is applied at 125 ° C. After the clock, it was cooled to room temperature. 1329021 7. 10 ml of water in the reagent accessor 222 was added to the reagent reactor 41a under helium gas filling. 8. After opening the switch 123 and the switch 124, 'in the reagent reactor 41a The reactants pass through switch 112, C18 Sep-Pak column 32, and three-way switch 113' and then into waste storage device 62, while intermediate product A^, iV~dimethyl-2-(2-nitro-4-18F -fluorOphenylthio) benzylamine (3a) will remain in the C18 Sep-Pak column 32. 9. 5 ml of dichloromethane (CH2C12) in reagent accessor 223 is added to the reagent reactor 41a under helium gas filling. 10. After opening switch 123 and switch 124, the dichloromethane (CH2C12) eluent in reagent reactor 41a will pass through switch 112 under helium gas filling and will remain in the C18 Sep-Pak tube. The intermediate product y, _/v_dimethyl-2-(2-nitro-4-18F-fluoiOphenylthio)benzylamine (3a) in column 32 is washed out and collected in reagent reactor 42a via three-way switch 113. The methane (03⁄43⁄4) eluent was evaporated at 7 (TC for 5 minutes and dried by flowing helium). 12. Turn on switch 105 so that 0.5 ml of ethanol (EtOH) in reagent accessor 231 is added to reagent reactor 42a under helium gas filling. 13. Turn on the switch 106 to make a saturated solution of Cu(0Ac)rH20 in the reagent accessor 232 (about 20 mg of Cu(OAc):rH2〇 dissolved in 1 ml of ethanol), and add it to the reagent reactor 42a under helium gas filling. in. 14. Open switch 107' to allow NaBHt (about 8 mg dissolved in 0.6 ml of ethanol) in reagent accessor 233 to be added to reagent reactor 42a under helium gas filling. 15. The mixture in the reagent reactor 42a was heated at 80 ° C for 20 minutes. 16. The switch 124 and the switch 114 are opened, and the mixture in the reagent reactor 42a is filtered by a polytetrafluoroethylene (PTFE) microporous membrane 331 (millipore filter, 0.22 μηι) under helium gas filling, and then Injection into half to prepare high performance liquid chromatography column 1329021 332 (semi-preparative high performance liquid chromatography, HPLC » 10 x 250 mm, NUCLEOSIL 100-5 C18 Nautilus; flow wash for CH3CN: 0.1 M HCO2NH4 (3.0:70) ) contains 0·3 0/〇 (v/v) acetic acid; the flow rate is 10 ml/min). The flow through the HPLC column 332 passes through a radiation detector 333 and an ultraviolet detector 334, and then flows through the three-way switch 115 to the waste storage device 63. 18. By adjusting the three-way switch 115, the flow-washing section containing the product 4-[18F]-ADAM (5a) is collected into a first collector 51 containing 250 ml of water. 19. Turning the three-way switch 125 to the helium source, the collected product 4-[18F]-ADAM(5a) and 250 ml of water pass through a three-way switch 116 and a three-way switch 117 through a tC18 Sep-Pak column. 34 (tC18 Sep-Pak cartridge), and flows through the three-way switch 118 into the waste storage device 64. 20. The 10 ml of water in the open switch 108' reagent accessor 241 will flow through the tC18 Sep-Pak column 34 to the waste storage device 64 for cleaning to remove residual acetonitrile in the column 34. 21. Open switch 109 '1 ml of ethanol in reagent accessor 242 will flow through the three-way switch in, the tC18 Sep-Pak column 34 and the three-way switch 118' and flow to the first part containing 5 ml of physiological saline. The 4-[18F]-ADAM (5a) remaining in the tC18 Sep-Pak column 34 in the second collector 52 is flushed with the ethanol into the second collector 52. 22. Turn the three-way switch 126 to the helium source and turn on the switch 119. The 4-[F]-ADAM (5a) in the physiological saline solution will pass through a mixed fiber (Mixed Cellulose Ester, MCE) microporous membrane. Filtered by 341 (millipore filter, 〇·22 μιη) and then passed to product collector 53 for later use. Example 3 Automatic Synthesis of Serotonin Transmitter Contrast Agent 4-[18F]-ADAM Product Analysis and Animal Test The radiochemical yield of 4-[18ρ]_ΑΙ)ΑΜ synthesized by this method is 2.5% calibration efficiency (End 〇f Bombardment, EOB) 'Speciflc activity is 13_2 2 α/μιη〇 Synthesis time 21 1329021 is 120 minutes' radiochemical and chemical purity is higher than 95% and 98% individually; final formulation (final The solvent content of the formulation) is within the standards of the United States Pharmacopoeia (CH3CN <0.04%; C2H5 〇 H <3%; DMSO is not detected) and the final product is stable for 4 hours at room temperature. Above, and it is sterile without pyrogen; for example, after synthesis and purification of [18F] ions of 228 mCi from 3043 soil, it can obtain 39 7±7 8 mCi (n=9). 4-[18F]-ADAM. The serotonin operator contrast agent prepared in Example 2 was used for animal test. 'llMBq4-[18F]-ADAM and l〇5MBq4-[18F]-ADAM were injected into rats and monkeys respectively, and passed through 60 respectively. After -90 minutes and 210-240 minutes, by positron tomography (PET) analysis, the results showed that the serotonin-operator contrast agent 4-[18F]-ADAM synthesized in this method was shown in Figure 4 And monkeys (shown in Figure 3) bind to serotonin-rich regions in vivo - including midbrain, thalamus, striatum, caudate and putamen ( pUtamen), and its brain intake is sufficient to show the contrast signal, while in the serotonin-free cerebellum, the presence of serotonin is not detected; from the animal test results, the device provided by the present invention The serotonin contrast agent prepared by the manufacturing method can be applied to clinical tests. Example 4 Automatic Synthesis of Serotonin Operator Contrast Agent (5c) 4 Referring to Figure 1 and Figure 2, the automatic synthesis of the serotonin contrast agent (II) provided by the present invention mainly comprises the following steps: 1. O^P' n) The [18F] ion aqueous solution produced by the F nuclear reaction is moved from the particle cyclotron to the reagent accessor 21 and filled with helium. 2. Open the vacuum in the case of vacuum (4) UO'p8 aqueous solution will be sucked out of the test device 210' and pass the two-way switch 11 and the column 3 and then pass the three-way switch to the most 22 1329021, The 18 〇 will be recycled to the aqueous storage device 6 and the [呷] ions will remain in the qMA column 31. 3. Open switch 121 in an evacuated environment, and a solution containing K2C03 (3 mg K2C03 dissolved in 0.1 ml H2O) and Kryptofix η.2 (30 mg Kryptofix 2 2 2 dissolved in 〇·9 ml CH3CN) will be supplied from reagent accessor 211. After being sucked out, the [18F] ions remaining in the QMA column 31 through the three-way switch 11A, the QMA column 31, and the three-way switch 111' are taken out by the solution and flow to the reagent reactor. Within 41a. 4. The solution was evaporated at 125 ° C for 10 minutes and dried by flowing helium. 5. The vaporized methyl precursor in the reagent accessor 221 2-[[4-((:111〇|'〇11^%1> 2-nitrophenyl]thio]-N,N-dimethylbenzenemethanamine (1 c (The precursor is dissolved in 1 ml of acetonitrile) and added to the reagent reactor 41a containing the 2 2 2 (7) residue in a manner of indirectly filling the helium gas. 6. The solution is allowed to act at 80 ° C for 15 minutes, then cooled. To room temperature 7. Add 10 ml of water in the reagent accessor 222 to the reagent reactor 41a under helium gas filling. 8. After opening the switch 123 and the switch 124, the reactants in the reagent reactor 41a pass through the switch. 112, C18Sep-Pak column 32, and three-way switch 113, and then into the waste storage device 62, and the intermediate product 2-[[2-nitro-4-([18F]fluoromethyl)phenyl]thio]-A^ iV-dimethyl benzene-methanamine (;3c) will remain in the C18 Sep-Pak column 32. 9. Add 5 ml of dichlorodecane (CH2C12) in reagent accessor 223 to the helium gas fill. In the reagent reactor 41a. 10. After opening the switch 123 and the switch 124, the dichloromethane (CH2C12) eluent in the reagent reactor 41a passes through the switch 112 under helium gas filling and will remain in the C18. Sep-P The intermediate product in the ak column 32 2-[[2-ηίΐτο-4-([18Ρ]ί1ιιοΐΌη^1ΐ}4) ρ1ιεηγ1]ΐ1ιίο]-Λ^ iV- 23 1329021 dimethylbenzene-methanamine(3c) washed out, after three The switch 113 is collected into the reagent reactor 42a. H. The di-methane ((: 3⁄43⁄4) eluate is evaporated at 70 ° C for 5 minutes, and dried by flowing helium gas. 0.5 ml of ethanol (EtOH) in the reagent accessor 231 was added to the reagent reactor 42a under helium gas filling. 13. The switch 106 was opened to make a Cu(0Ac)2-H20 saturated solution in the reagent accessor 232. (about 20 mg of Cu(OAc)rH2〇 dissolved in 1 ml of ethanol) was added to the reagent reactor 42a under helium gas filling. 14. Open the switch 107' to dissolve NaBH4 in the reagent accessor 233 (about 8 mg dissolved). It was added to the reagent reactor 42a under helium gas filling in 0.6 ml of ethanol. 15_ The mixture in the reagent reactor 42a was heated at 80 ° C for 10 minutes.

16. Open switch 124 and switch 114' The mixture in reagent reactor 42a is filled with helium gas through a polytetrafluoroethylene (PTFE) microfiltration membrane 331 (millipore filter, 0.22 μιη) and then injected Semi-preparative high performance liquid chromatography (HPLC * 10 x 250 mm, NUCLEOSIL 100-5 C18 Nautilus; flow wash for CH3CN: 0.1 M HCO2NH4 (30:70) 0.3% (v/v) acetic acid; flow wash rate is l〇ml/min). 17_ The flow through the HPLC column 332 passes through a radiation detector 333 and an ultraviolet detector 334, and then flows through the three-way switch 115 to the waste storage device 63. 18. The flow-washing section containing the product 4-[18F]-AFM (5c) by adjusting the three-way switch 115' is collected into a first collector 51 containing 250 ml of water. 19. Transfer the three-way switch 125 to the helium source. The collected product 4-[18F]-AFM (5c) and 250 ml of water will pass through a three-way switch 116 and three-way switch 117 through a tC18 Sep-Pak column. 34 24 1329021 (tCl8Sep-Pak cartridge), and flows into the waste liquid storage device 64 via the three-way switch U8. 20. Open switch 108' A reagent reservoir 241, such as water, will flow through the busy 18 Sep pak column 34 to the waste storage device 64 to clean and remove residual acetonitrile in the column 34. 21. Open the switch 109 'I ml of ethanol in the reagent accessor 242 will flow through the three-way switch 117, the tCl8 Sep-Pak column 34 and the three-way switch 118, and flow to the first part containing 5 ml of physiological saline. Within the second collector 52, the river (8) remaining at the 4th point of the tC18 Sep-Pak column 34 will be flushed with the ethanol into the second collector 52. 22. Turn the three-way switch 126 to the helium source and turn on the switch 119. The 4-[18F]-AFM (5c) in the physiological saline solution will pass through a mixed fiber (MCE) microfiltration membrane 341 (mimp〇 Re 〇.22μηι) is filtered and then passed to product collector 53 for later use. Example 5 Automated synthesis of serotonin operator contrast agent 4_[i8F]_AFE (Sd) Referring to Figures - and Figure 2, the automatic synthesis of serotonin contrast agent (10) provided by the present invention mainly comprises the following steps: (P'n) The [18f] ion aqueous solution produced by the F nuclear reaction was transferred from the particle cyclotron to the reagent accessor 21 and filled with helium. 2. Opening the switch ion aqueous solution in an evacuated environment will be sucked out of the reagent accessor 210, and passed through the two-way switch 11 and the qma column 31, and then through the three-way switch m, and finally, 18 〇 will be recovered. The aqueous solution storage device 61, while the ions are retained in the column 31. 3_Open switch 121 under vacuum, containing K2c〇3 (3 mg K2C〇3 dissolved in 吒〇lml吒〇) and Kryptofix η·2 (30 mg Kryptofix η.2 dissolved in 〇_9 ml CHsCN) Then, the reagent accessor 211 is sucked out, and the [18F] ions remaining in the QMA column 31 through the three-way switch 11A, the QMA column 31, and the three-way switch 111' are combined by the solution. Bring out, 25 1329021 into the reagent reactor 41a. 4. The solution was evaporated at 125 ° C for 10 minutes and dried by flowing helium. 5. The 4-[[2-[(dimethylamino)methyl]phenyl]thio]-3-nitrobenzeneethanol 4-methyl benzenesulfonate (Id) in the reagent accessor 221 (the precursor system) Dissolved in 1 ml of acetonitrile) indirectly filled with helium • Add to reagent reactor 41a containing K[18F]/Kryptofix222 (2) residue. .6. The solution was allowed to act at 80 ° C for 15 minutes and then cooled to room temperature. 7. 10 ml of water in the reagent accessor 222 was added to the reagent reactor 41a under helium gas filling. 8. After opening switch 123 and switch 124, the reactants in reagent reactor 41a pass through switch 112, C18 Sep-Pak column 32, and three-way switch 113, and then into waste storage device 62, while intermediate product Z- fp-nitrcM-pf^FJfluoroethyUphenyllthio]-·/^ A^-dimethyl benzenemethanamine (3d) will remain in the C18 Sep-Pak column 32. 9. 5 ml of dioxane methane (CH2C12) in reagent accessor 223 is added to reagent reactor 41a under helium gas filling. After opening switch 123 and switch 124, the dioxane (CH2C12) eluent (eluent) in reagent reactor 41a will pass through switch 112 under helium gas filling and will remain in the C18 Sep-Pak tube. The intermediate product 2-[[2-nitro-4-(2-[18F]fluoroethyl)phenyl]thio]-#, iV· diraethylbenzenemethanamine (3d) in 杈32 was washed out and collected through a three-way switch 113 to the reagent reaction. In the device 42a. H. The dichloromethane (CH2C12) eluate was evaporated at 70 ° C for 5 minutes and dried by flowing helium. 12. The switch 105 was opened, and 0.5 ml of ethanol (EtOH) in the reagent accessor 231 was added to the reagent reactor 42a under helium gas filling. 26 1329021 13. Open switch 1〇6, so that the Cu(OAc)2_H2〇 saturated solution (about 20mg Cu(0Ac)2-H20 is dissolved in 1 ml of ethanol) in reagent accessor 232 is added under helium filling. The reagent is in reactor 42a. 14. Open switch 1〇7 to allow NaBHt (about 8 mg dissolved in 0.6 ml of ethanol) in reagent accessor 233, and add to reagent reactor 42a under helium gas filling. 15. The mixture in the reagent reactor 42a was heated at 80 ° C for 10 minutes. « • 16. Open switch 124 and switch 114, the mixture in reagent reactor 42a is filled with helium, - filtered through a polytetrafluoroethylene (PTFE) microfiltration membrane 331 (millipore filter, 0.22 μπι), Then, half of the preparative high performance liquid chromatography column 332 was injected (semi-preparative high • performance liquid chromatography, HPLC > 10 x 250 mm, NUCLEOSIL 100-5 C18 Nautilus; the flow wash was CH3CN: 0.1 MHCO2NH4 (30: 70) containing 0.3 ° / 〇 (v / v) acetic acid; flow washing rate of 10 ml / min) β 17. The flow through the HPLC column 332 is passed through a radiation detector 333 and an ultraviolet detector 334 Thereafter, it flows through the three-way switch 115 to the waste liquid storage device 63. 18. By adjusting the three-way switch 115, the flow-washing section containing the product 4-[18F]-AFE (5d) is collected into a first collector 51 containing 250 ml of water. Φ 19· Turn the three-way switch 125 to the helium source 'collected product 4-[l8F]-AFE (5d) and 250 ml. The water will pass through a three-way switch 116 and a three-way switch 117 through a tC18 Sep-Pak The column 34 (tC18 Sep-Pak cartridge) flows through the three-way switch 118 into the waste storage device 64. 20. Open switch 108 '10 ml of water in reagent accessor 241 will flow through the tC18 Sep-Pak column 34 to the waste storage device 64 to clean and remove residual acetonitrile in the column 34. 21_Open switch 109, 1 ml of ethanol in reagent accessor 242 will flow through three-way switch 117, tC18 Sep-Pak column 34 and three-way switch 118, and flow to 27 ml of physiological saline solution 1329021 In the first collector 52, the 4-[18F]-AFE (5d) remaining in the busy 18 Sep-Pak column 34 is flushed with the ethanol into the second collector 52. Turning the -to-switch 126 to the helium source and opening the switch 119, the 4_[F]-AFE (5d) in the physiological saline solution will pass through a mixed fiber (MCE) microporous membrane 341 (miUip〇re he er , 0.22 μηι) filtered and then flowed to the product collector. Example 6 Serotonin Operator Contrast Agent 4-[18F]-AFP(5e) Automatic Synthesis Referring to Figure 1 and Figure 2, the serotonin contrast agent 4-[18F]-AFP (5e) provided by the present invention The automatic synthesis mainly includes the following steps: 1. The [i8F] ion aqueous solution prepared by the i80(p,n)18F nuclear reaction is transferred from the particle cyclotron to the reagent accessor 21 and filled with helium gas. 2. After opening the switch 12〇 in an evacuated environment, the [i8F] ion aqueous solution will be sucked out of the reagent accessor 210, and passed through the three-way switch 110 and the QMA column 31, and then through the three-way switch m, and finally, 180. It will be recycled to the aqueous storage device 61, and the [1$] ions will remain in the qma column 31. 3. Open the switch 121 under vacuum, and the solution containing K2C03 (3mgK2C03 dissolved in l.lmlH2〇) and Kryptofix 2 2 2 (30 mg Kryptofix η.2 dissolved in 0.9 ml CHsCN) will be from the reagent accessor 211. The [18F] ions remaining in the QMA column 31 through the three-way switch no, the qma column 31, and the three-way switch 111' are taken out by the solution, and flow to the reagent reactor. Within 41a. 4. The solution was evaporated at 125 ° C for 1 minute and dried by flowing helium. 5. The precursor 4-[[2-(dimethylamino)methyl;| phenyl]thio]-3-nitrobenzenepropanol 4-methylbenezenesulfonate (le) in the reagent accessor 221 (the precursor is dissolved in 1 ml of acetonitrile) The method of indirectly filling the helium gas is added to the reagent reactor 41a containing the residue of 28 1329021 K [〗 8F] / Kjyptofix 2.2.2 (2). 6. The solution was allowed to act at 80 ° C for 15 minutes and then cooled to room temperature. 7. 10 ml of water in the reagent accessor 222 was added to the reagent reactor 41a under helium gas filling. 8. After opening switch 123 and switch 124, the reactants in reagent reactor 41a pass through switch 112, C18 Sep-Pak column 32, and three-way switch 113, and then into waste storage device 62, while intermediate product S- ^-nitrcM-pf^FJfluoropropyDphenyUthiol-A^iV-dimethylbenzenemethanamine (3e) will remain in the C18 Sep-Pak column 32. 9. 5 ml of dichlorodecane (CH2C12) in the reagent accessor 223 was added to the reagent reactor 41a under helium gas filling. 10. After opening switch 123 and switch 124, the two-gas calcination (CH2C12) eluent in reagent reactor 41a will pass through switch 112 under helium gas filling and will remain in the C18 Sep-Pak column. The intermediate product 2-[[2-nitro-4-(3-[18F]fluoropropyl)phenyl]thio]-iV, iV·dimethylbenzenemethanamine (3e) was washed out and collected through a three-way switch 113 to the reagent reactor 42a. in. 11. The dichlorodecane (CHfl2) eluate was evaporated at 7 Torr for 5 minutes and dried by flowing helium. 12. The switch 105 was opened, and 0.5 ml of ethanol (EtOH) in the reagent accessor 231 was added to the reagent reactor 42a under helium gas filling. The switch 106 is turned on, and a Cu(0Ac)2-H20 saturated solution (about 20 mg of Cu(〇Ac)2_H2〇 in 1 ml of ethanol) in the reagent accessor 232 is added to the reagent reactor under helium gas filling. 42a. 14. Open switch 1〇7' to allow NaBH4 (about 8 mg dissolved in 0.6 ml of ethanol) in reagent accessor 233 to be added to reagent reactor 42a under helium gas filling. The mixture in the reagent reactor 42a was heated at 8 (TC for 10 minutes. (S) 29 1329021

16. The switch 124 and the switch 114 are opened, and the mixture in the reagent reactor 42a is filtered under a helium gas, filtered through a polytetrafluoroethylene (PTFE) microfiltration membrane 331 (millipore filter, 0.22 μm), and then injected. Semi-preparative high performance liquid chromatography (HPLC) 10 x 250 mm, NUCLEOSIL 100-5 C18 Nautilus; flow wash for CH3CN: 0.1 M HCO2NH4 (30:70) containing 0.3 % (v/v) acetic acid; flow wash rate is i〇ml/min). 17. The flow through the HPLC column 332 will pass through the three-way switch 115 to the waste storage device 63 after passing through a radiation detector 333 and an ultraviolet detector 334. 18. By adjusting the three-way switch 115, the flow-washing section containing the product 4-[18F]-AFP (5e) is collected into a first collector 51 containing 250 ml of water. 19. Transfer the three-way switch 125 to the helium source. The collected products 4_[1$>^?(56) and 25〇1111 water will pass through a three-way switch 116 and a three-way switch in through a tC18 Sep-Pak The column 34 (tC18 Sep-Pak cartridge) flows through the three-way switch 118 into the waste storage device 64. 20. Open switch 108 '1 ml of water in reagent accessor 241 will flow through the tC18 Sep-Pak column 34 to the waste storage device 64 to clean and remove residual acetonitrile in the column 34. 〇 21. Open switch 109, 1 ml of ethanol in reagent accessor 242 will flow through three-way switch 117, tC18 Sep-Pak column 34 and three-way switch n8, and flow to 5 ml of physiological saline Within the first collector 52, the 4-[18F]-AFP (5e) remaining in the tci8 Sep-Pak column 34 is flushed with the ethanol into the second collector 52. 22_ Transfer the three-way _ 126 to the source of gas, and hit the customs off 119. 4_[1SF]-AFP (5e) in the physiological saline solution will pass through a mixed fiber (MCE) microporous membrane 341 (mimp〇re The button is filtered and then passed to the product collector 53 for use. 1329021 The invention provides a method for manufacturing a 18f positron radioisotope-labeled serotonin operator contrast agent and a device thereof, which have the following advantages when compared with the foregoing hydrazine technology: 1. The invention is manufactured by automatic synthesis. The serotonin operator contrast agent has less preparation time than manual operation and has higher production efficiency. 2. The company relies on the addition of special plugs, pipelines and blunt gas fillings, so operators do not need to manually operate, reduce the chance of exposure to radiation, and work safer - more secure. 3. The serotonin operator contrast agent produced by the method of the present invention has a radioactivity specific activity such as actmty and quality 敎' suitable for clinical trials and meets the needs of clinical research. 4. The serotonin transporting device provided by the present invention (four) angiography device can be used to automatically synthesize other serotonin in addition to the automatic serotonin serotonin. Runner contrast agents, such as: stern, 4 stern, sputum, and other contrast agents using the same synthetic procedure. 5. The hair supply provided by the hair ride (4) (4) (4) manufacturing equipment, because there is no operator exposed to the environment for a long time, can be used for high-dose serotonin contrast agent synthesis, if there are many people need Use, no need to batch waste time and resources; because a large number of serotonin can be prepared _, in the same - range _ positron tomography test ^ can support each other, #某-正子_scan test can not make When the heterocyclotron cyclotron accelerates the Wcyclotron to produce a positron contrast agent, it can be supported by other units, so that the positron tomography can be performed as scheduled to achieve resource efficiency. The detailed description above is for the specific system of the present invention, but the embodiment is not intended to be a patent of _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the scope. 31 1329021 '·', the above description 'this case is not only innovative in terms of method, but also can improve the above-mentioned multiple functions compared with the customary items' should have fully met the statutory requirements for new inspections and advances, and Newfa applied, I urge you to approve the application for this invention patent to encourage the invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view showing the reaction of a serotonin operator contrast agent 4-[i8F]-ADAM; FIG. 2 is a device for manufacturing a serotonin transport (4) according to the present invention. Schematic diagram of the device; Figure 3 shows the distribution of 4-[18F]-ADAM in the monkey brain; and Figure 4 shows the distribution of 4-[18F]-ADAM in the rat brain. [Main component symbol description] (la) N, iV-dimethyl-2-(2-nitro-4- bromophenylthio)benzylamine (lb) iV, A^-dimethyl-2-(2,4-dinitrophenylthio)benzylamine (1 c 2-[[4-(chloromethyI)-2-nitrophenyl]thio]-A^iV-dimethyIbenzenemethanamine (1 d) 4-[[2-(dimethylamino)methyl]phenyl]thio]-3-nitrobenzeneethanol 4-methylbenezenesulfonate ( 1 e) 4-[[2-(dimethylamino)methyl]phenyl]thio]-3-nitrobenzenepropanol

4-methylbenezenesulfonate (2) potassium [18F]fluoride / Kryptofix 2.2.2 (3a) AyV-dimethyl-2-(2-nitro-4-18F-fluorophenylthio) benzylamine (3c) 2-[[2-nitro-4-( [18F]fluoromethyl)phenyl]thio]-A^A^-dimethylbenzenemethanamine (3d) 2-[[2-nitro-4-(2-[18F]fluoroethyl)phenyl]thio]-A^TV-dimethylbenzenemethanamine (3e) 2-[[2-nitro-4-(3-[lsF]fluoropropyl)phenyl]thio]-//,//-dimethylbenzenemethanamine (4) NaBH4/Cu(OAc)2 (5a) 4-[,8F]-ADAM ( 5c) 4-[18F]-AFM (5d) 4-[I8F]-AFE (5e) 4-[18F]-AFP 1 control device 2 reaction system 101 switch 21 first reagent access device 32 1329021

102 switch 103 switch 104 switch 105 switch 106 switch 107 switch 108 switch 109 switch 110 three-way switch 111 three-way switch 112 switch 113 three-way switch 114 switch 115 three-way switch 116 three-way switch 117 three-way switch 118 three-way switch 119 switch 120 switch 121 switch 123 switch 124 switch 125 three-way switch 126 three-way switch 127 three-way switch 128 three-way switch 31 first separation device 32 second separation device 33 third separation device 331 microporous membrane 332 HPLC column 333 radiation Detector 334 UV detector 335 HPLC stream washer accessor 34 fourth separation device 210 reagent accessor 211 reagent accessor 22 second reagent access device 221 reagent accessor 222 reagent accessor 223 reagent Accessor 23 third reagent access device 231 reagent accessor 232 reagent accessor 233 reagent accessor 24 fourth reagent access device 241 reagent accessor 242 reagent accessor 41 first reaction device 41a reagent reaction 41b temperature regulator 42 second reaction device 42a reagent reactor 42b temperature regulator 51 first collector 52 second collector 61 aqueous solution storage device 62 waste liquid storage device 63 waste liquid storage device 64 waste liquid storage device 71 pressurizing device 72 pressurizing device 73 pressurizing device 74 pressurizing device 75 pressurizing device 8 vacuuming device 33 1329021 341 microporous filter [Reference] l.Storch, A., Ludolph, AC , Schwarz, J., 2004. Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration. J. Neural. Transm. Ill, 1267-86. 2. Mann, JJ, Huang, YY., Underwood, MD, Kassir, SA, Oppenheim, S., Kelly, TM, Dwork, AJ, Arango, V., 2000. A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch. Gen. Psychiatry. 57, 729 -738. 3. Meltzer, CC, Smith, G., DeKosky, ST, Pollock, BG, Mathis, CA, Moore, RY, Kupfer, DJ, Reynolds, CF, 1998. Serotonin in aging, late-life depression, and Alzheimer's disease: the emerging role of functional imaging. Neuropsychopharmacology 18, 407-430.

4. Suehiro, M., Greenberg, JH, Shiue, C.-Y., Gonzalez, C., Dembowski, B., Reivich, M.} 1996. Radiosynthesis and biodistribution of the S-[l8F]fluoroethyl analog of 5262McN Nucl. Med. Biol. 23, 407-412. 5. Zessin, J., Eskola, 0., Brust, P., Bergman, J., Steinbach, J., Lehikoinen, P., Solin„ 0., Johannsen, B., 2001. Synthesis of S-[18F]fluoromethyl-(+)-McN5652 as a potential PET ligand for the serotonin transporter. Nucl. Med. Biol. 29, 857-863. 6. Ferris, RM, Brieaddy , L., Mehta, N., Hollingsworth, E., Rigdon, G., Wang, C., Soroko, F., Wastile, W., Cooper, B., 1995. Pharmacological properties of 403U76 a new chemical class of 5-hydroxytryptamine- and noradrenaline-reuptake inhibitor. J. Pharm. Pharmacol. 47, 775-781. 7. Jilek, J., Sindelar, K” Pomykacek, J·, Kmonicek, V·, Sedivy, Z” Hrubantova, M Holubek,

J., Svatek, E., Ryska, M., Koruna, I., Valchar, M., Dlabac, A., Metysova, J., Dlohozkova, N., Protiva, M., 1989. Potential antidepressants: 2- (methoxy- and hydroxy-phenylthio)benzylamines as selective inhibitors of 5-hydroxy-tryptamine re-uptake in the brain. Collect. Czech. Chem. Commun. 54,3294-3338. 8. Acton, PD, Kung, M.- P., Mu, M., Plossl, K., Hou, C., Siciliano, M., Oya, S., Kung, HF, 1999. Single-photon emission tomography imaging of serotonin transporters in the non-human primate brain With the selective radioligand [123I]IDAM. Eur. J. Nucl. Med. 26, 854-861. 9. Acton, PD, Mu, M., Plossl, K., Hou, C., Siciliano, M., Zhuang , ZP, Oya, S., Choi, SR, Kung, HF, 1999. Single-photon emission tomography imaging of serotonin transporters in the non-human primate brain with [l23I]ODAM. Eur. J. Nucl. Med. 1359-1362. 10. Kung, MP, Hou, C., Oya, S., Mu, M., Acton, PD, Kung, HF, 1999. Characterization of 34 1329021 [123I] ID AM as a novel single-photon Emission tom Eurography J. Nucl. Med. 26, 844-853. 11. Oya, S., Kung, Μ-P., Acton, PD, Mu, M., Hou, C., Kung, HF, 1999. A new single photon emission computed tomography imaging agent for serotonin transporters: [123I]IDAM, 5-iodo-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol. J. Med. Chem . 42, 333-335. 12. Oya, S., Choi, SR., Hou, C., Mu, M., Kung, Μ-P., Acton, PD, Siciliano, M., Kung, HF2, 2000.-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand. Nucl. Med. Biol. 27, 249-254.

13. Huang, Y., Bae, SA, Zhu, Z., Guo, N., Hwang, DR, Sudo, Y., Ngo, K., Kegeles, L., Laruelle, M., 2001a. Synthesis and characterization Of a new pet ligand for the serotonin transporter: 11 C-5-bromo-2-{2-[(dimethylamino)-methylphenyl-sulfanyl]phenylamine. J. Nucl. Med. 42, 112P. 14. Huang, Y., Bae, SA, Zhu, Z., Guo, N., Hwang, DR, Laruelle, M., 2001b. Fluorinated analogues of adam as new pet radioligands for the serotonin transporter: synthesis and pharmacological evaluation. J. Labelled Compd. Radiopharm. 44 (Suppl. 1), S18-1120. 15. Jarkas, N., McConathy, J., Ely, T., Kilts, CD, Votaw, J., Goodman, MM, 2001. Synthesis and radiolabeling of new derivatives of J. Labelled Cpd. Radiopharm. 44 (Suppl. 1), S204-S206. 16. Shiue, C.-Y., Watanabe, M., Wolf, AP, Fowler, JS , Salvadori, P., 1984. Application of the nucleophilic substitution reaction to the synthesis of no-carrier-added [18F]fluorobenzene and other F-18 l Abeled aryl fluorides. J. Labelled Cpd. Radiopharm. 21, 533-547. 17. Wilson, AA·, Houle, S., 1999. Radiosynthesis of carbon-11 labelled N-methyl-2-(arylthio)benzylamines: potential radiotracers For the serotonin reuptake receptor. J. Labelled Compd. Radiopharm. 42, 1277-1288. 18. Kauppinen, TA, Bergstrom, KA, Heikman, P., Hiltunen, J., Ahonen, AK, 2003. Biodistribution and radiation dosimetry of [123I]ADAM in healthy human subjects: preliminary results. Eur J Nucl Med. 30, 132-136. 19. Newberg, AB, Amsterdam, JD, Wintering, N., Ploessl, K., Swanson, RL, Shults, J Alavi, A., 2005. 123I-ADAM binding to serotonin transporters in patients with major depression and healthy controls: A preliminary study. J. Nucl. Med. 46,973-977. 20. Lin, KJ., Liu, CY, Wey, SP, Hsiao, IT, Wu, J., Fu, YK, Yen, TC, 2006. Brain SPECT imaging and whole-body biodistribution with [l23I]ADAM- a serotonin transporter radiotracer in healthy human subjects. Nucl Med Biol. 33, 193-202. 35 1329 021 21. Booij. J., de Win, MML 2006. Brain kinetics of the new selective serotonin transporter tracer [l23I]ADAM in healthy young adults. Nucl Med Biol. 33, 185-191. 22. Ginovart, N., Wilson , AA, Meyer, JH, Hussey, D., Houle, S., 2001. Positron emission tomography quantification of [UC]-DASB binding to the human serotonin tranporter: modeling strategies. J. Cereb. Blood Flow Metab. 21, 1342 -1353. 23. Houle, S., Ginovart, N., Hussey, D., Meyer, JH, Wilson, AA, 2000. Imaging the serotonin transporter with positron emission tomography: initial human studies with [nC]DAPP and [UC ]DASB. Eur. J. Nucl. Med. 27,1719-1722.

24. Meyer, JH, Wilson, AA, Ginovart, N., 2001. Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [nC]DASB PET imaging study. Am. J. Psychiatry 158, 1843-1849. 25. Shiue, GG, Fang, P., Shiue, CY, 2003. Synthesis of N, N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine as a serotonin transporter imaging agent. Appl. Rad Isot. 58,183-191. 26. Shiue, GG·, Choi, SR” Fang, P” Hou, C” Acton, PD, Cardi, C” Saffer, JR, Greenberg, JH, Karp, JS, Kung, HF, Shiue, CY, 2003. N,N-Dimethy 1-2-(2-Amino-4-18F-Fluorophenylthio)-Benzylamine (4-18F-ADAM): An Improved PET Radioligand for Serotonin Transporters. J. Nucl. Med. 44,1890-1897. 27. Huang, Y., Bae, SA, Zhu, Z., Guo, N., Roth, BL, Laruelle, M., 2005. Fluorinated Diaryl Sulfides as Serotonin Transporter Ligands: Synthesis, Structure- Activity Relationship Study, and in Vivo Eualuation of Fluorine-18-Labeled Compounds as PET Imaging Agents. J. Med. Chem. 48, 25 59-2570. (S ) 36

Claims (1)

1 Announcement 1 Patent application scope: An automated manufacturing method for a serotonin operator contrast agent of the F-positive radioisotope, comprising the following two steps: 1. Depositing the [F] ion aqueous solution in the first reagent access device (9) In the reagent accessor (210), the K2C〇3/Krypt〇fix 2 22 solution is stored in the reagent accessor (211) of the first reagent access device (21); the reagent accessor (211) The outlet of the flow is provided with a switch (101) for controlling the flow of the K2C〇3/Kry_X 222 solution; the reagent accessor (210) and the reagent accessor (211) are connected by a three-way switch (10) and - a QMA column (31) connected by a three-way switch (called a reagent reactor (41a) in the first reaction unit (41) and an aqueous solution storage unit (61); The aqueous solution storage device (61) is connected to a vacuuming device (8) via a switch (12〇), and after the switch (12〇) is opened by a control device (1), the vacuum device can be evacuated to force the reagent accessor ( An aqueous solution of [18F] ions in 210) flows through the QMA column (31) to adsorb the [18F] fluoride ion, and the unwanted aqueous solution is passed through the Discharging the switch (111) to the aqueous solution storage device (61); Step 2: The reagent reactor (41a) is also connected to the vacuuming device (8) via a switch (121), when the control device (1) is opened When the switch (121) and the switch (1〇1), the K2C〇3/Krypt〇flx 22 2 solution in the reagent accessor (211) can be forced to flow through the QMA column (31). To carry out [18pj ion, then flow through the switch to the reagent reactor (41a), and dry at a suitable temperature and time by blunt gas; Step 3: The precursor solution is stored in the second reagent access device (22) in the reagent accessor (221); storing water (sputum) in the reagent accessor (222) of the second reagent access device (22), and storing the dichlorosilane (CHjCl2) solution In the reagent accessor (223) of the second reagent access device (22); the outlets of the reagent accessors (221), (222), and (223) are not provided with a switch (1〇2) , (1〇3), (1〇4), to control whether the solution in each reagent accessor flows out; the reagent accessors (221), (222), (223) and the first reaction device The reagent reactor (41a) in (41) is connected; The reagent accessors (222), (223) combine the tubes connected to the reagent reactor (4ia) by a three-way switch (127); the reagent accessors (221), (222), (223) The input port is connected to a helium gas pressing device (71), and the switch device (1〇2) and (103) can be sequentially opened by the control device (丨), which can be filled with disorderly gas, respectively And forcing the solution in the reagent accessors (221) and (222) to flow into the reagent reactor (4ia), and heating the reaction via a temperature regulator (4) in the first reaction device (41) Wherein the current flooding solution is added to the reagent reactor (41a) in the first reaction unit (41) from the s type reagent accessor (221) and is cooled to room temperature after reacting at an appropriate temperature for a period of time. And adding water from the reagent accessor (221) to the reagent reactor (41a) in the first reaction device (41); Step 4 the reagent reactor (41a) is further connected via a switch (123) and a switch ( 124) is connected with a helium gas pressure device (73). When the control device (1) opens the switches (123) and (124), the solution in the reagent reactor (41a) can be forced by filling the helium gas. Switch 112) Pass the C1S Sep-Pak column (32) to grab the intermediate product in the solution and drain the unwanted solution through a three-way switch (113) to a waste storage device (62); the C1S Sep-Pak tube The column (32) is connected to the reagent reactor (42a) in the second reaction device (42) by the three-way switch (113); when the control device (1) opens the switch (104), it can be filled with helium gas. In a manner, the solution 2 1329021 in the reagent accessor (223) is forced to flow to the reagent reaction (41 &) and then flows through the (^886 port 4> 31^ column (32), bringing out the middle The product is then passed through the three-way switch (113) to the reagent reactor (42a), and dried at a suitable temperature and time with pure gas; Step 5: storing the ethanol in the third reagent access device (23) a reagent accessor (231); a Cu(〇Ac)rH2〇 ethanol saturated solution is stored in the reagent accessor (232) of the third reagent access device (23), and the NaBH4 ethanol solution is stored in the third reagent access a reagent accessor (233) of the device (23); the flow outlets of the reagent accessors (231), (232), and (233) are respectively provided with a switch (105), (106), (107) ' Control each solution Whether the reagent accessor (231), (232), (233) is connected to the reagent reactor (42a) in the second reaction device (42); the reagent accessor (232), 233) The pipeline connected to the reagent reactor (42a) may be combined by a three-way switch (128); the input ports of the reagent accessors (231), (232), and (233) are coupled to the helium gas The pressing device (71) is connected, and when the control device (1) respectively opens the switches (]05), (1〇6), π〇η, the reagent can be sequentially stored by filling the helium gas. The solution in the extractors (231), (232), (233) flows into the reagent reactor (42a), and can be heated by the temperature regulator (42b) in the second reaction device (42). And after reacting at a suitable temperature and time, the mixture is injected into an HPLC purification device (33) for separation and purification; Step 6: the reagent reactor (42a) is further connected to the helium gas pressure device (73) via a switch (124). When the control device (1) opens the switch (124), the solution in the reagent reactor (42a) is forced to be switched (114) to an HPLC purification device (33) by filling the helium gas; the HPLC purification Device (3 3) comprising a microporous membrane (331), an HPLC column (332), a radiation detector (333), an ultraviolet detector (334), and a 3 1329021 HPLC flow washer accessor ( 335), the microporous membrane (331) is connected to the host α of the HpLc column (332) to filter the injection solution; the light shot extractor (tear) and the ultraviolet detector (334) Is connected to the output end of the HPLC column (332) to detect the radiation and ultraviolet absorption spectrum of the flow washing liquid segment; the HPLC flow washing liquid accessor (335) is respectively connected by a switch (129) The column (32) connection and the switch (13〇) are connected to the helium gas pressure device (72); when the control device (1) opens the switch (129), (13〇), the atmosphere can be filled with The method of forcing the flow wash in the HPLC flow wash accessor (335) to enter the HPLC column (10) via the switch (129), purifying via the HpLC New Zealand (332), and the light detector (333) and The ultraviolet ray device (33. After the measurement, the unwanted flow washing liquid will be discharged through the three-way operation) is discharged to the waste liquid storage device (63), and the flow-washing product containing the product flows through the three-way switch (10). To the first containing water ((10) (51); ° Step 7: The first-receiving grain-switch (10) is connected to the helium gas pressure device (74), and the 'two-way switch (116) and the two-way switch (117) and the tc^ column (4) storing the water (He) in the reagent accessing device (241) of the fourth reagent access device (24), and storing the ethanol in the reagent accessor_ of the fourth reagent access device (4); Test (4) take the) and (242) flow outlets respectively have a switch) (9) to control the outflow or not, the reagent accessor (mi) also via the three-way _ (116), (four) and The 'snap column (four) is connected, the reagent accessor (242) is connected to the 'kun tube column (34) via the three-way switch 〇 17), and when the control device (1) opens the switch (125), The helium-filled square 4 1329021 can be used to force the solution in the first collector (51) to pass through the three-way switch (1) 6), (1) 7) through the tC18 Sep-Pak column (34) to capture the solution. The product, and the unwanted solution is discharged to the waste storage device (64) via a three-way switch (Π8); The inlet ports of the Xuan β-type accessors (241) and (242) are connected to a helium gas pressurizing device (7 u, and when the control device (1) opens the switch (108), the filling port can be filled by In a gaseous manner, the solution in the reagent accessor (241) is forced to flow through the tCls Sqj-Pak column (34) through the switches (116), (117) to clean the tCl8 Sep_Pak column (34). Residual solvent flows through the switch (118) to the waste storage device (64); after the switch (1〇9) is opened by the control device (1), it can be forced by filling the helium gas The solution in the reagent accessor (242) flows through the tQ8 Sep_pak column (34) through the switch (117), and the product is taken out and flows through the switch (118) to the second collector (52). The physiological saline is mixed; and the step 8. s second collector (52) can further pass through the three-way switch (126) and the helium gas pressure device (cut-connected and via a switch (119) with a microporous membrane (341) connecting the microporous membrane (341) and connected to a product collector (53); when the control device (1) opens the three-way switch (126), the method of filling the helium gas is forced to force the first Solution in the second collector (52) After the switch (119) is filtered through the microporous membrane (341), it flows to the product collector (53) for use. 2. The 18F positron radioisotope marker serotonin according to claim 1 An automated manufacturing method of an operator contrast agent, wherein the aqueous fluoride ion solution is obtained by a particle cyclotron with a ruthenium (p, n) 18p nuclear reaction. 3. A chemical ion isotope marker as described in Patent Application No. W An automated manufacturing method for a clear-working contrast agent, wherein the K2C〇3 solution is dissolved in water at a concentration of 5 1329021 20-50 mg/mL. 4. The l8F positron radioisotope label as described in claim 1 An automated manufacturing method for a serotonin operator contrast agent, wherein the Kryptofix 2.2.2 solution is dissolved in an acetonitrile solution at a concentration of 20-60 mg/mL. 5. As described in claim 1 18f positron radioisotope label | An automated manufacturing method for serotonin operator contrast agent, wherein the precursor is W, iV-dimethyl-2-(2-nitro-4-bromophenylthio)benzylamine or MAMimethyl-2-(2) ,4-dinitro Phenylthio)benzylamine, soluble in DMSO at a concentration of 4-20 mg/mL. 6. An automated manufacturing method for a serotonin transmitter contrast agent of the 18f positron radioisotope marker as described in claim 1 of the patent application, wherein the precursor The compound is 2-[[4-(chloromethyl)-2-nitrophenyl]thio]-MiV-dimethylbenzenemethanamine, which is soluble in acetonitrile at a concentration of 1-20 mg/mL. 7-Automated manufacturing method of serotonin operator contrast agent of 18F positron radioisotope label as described in claim 1 wherein the precursor is 4-[[2-(dimethylamino) methyl]phenyl]t; ]-3-nitrobenzeneethanol 4-methylbenezenesulfonate, soluble in acetonitrile at a concentration of 1-20 mg/mL. 8. An automated method for producing a serotonin operator contrast agent of the l8F positron radioisotope label as described in claim 1, wherein the precursor is 4-[[2-(dimethylamino)methyl]phenyl]thio]- 3-nitrobenzenepropanol 4-methylbenezenesulfonate, soluble in acetonitrile at a concentration of 20 mg/mL. 9. An automated manufacturing method for a serotonin operator contrast agent of the 18f positron radioisotope marker as described in claim 1, wherein the NaBH4 solution is soluble in ethanol at a concentration of 10-20 mg/mL ° Ϊ329021 ι〇 For the automated manufacturing method of the serotonin operator contrast agent of the % positron emission _ 杂 杂 所述 所述 , , , , , , , , , Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu Cu 10-20 mg/mL. U. If you apply for the paste of the 丨 丨 丨 % 正 正 放 同位素 同位素 同位素 同位素 同位素 同位素 同位素 同位素 同位素 同位素 同位素 HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC U. For example, the application method is an automated manufacturing method for a contrast agent, wherein the appropriate temperature is 115-13 CTC, 5-15 minutes. For example, the method of applying the paste is summarized in the automated manufacturing method of the positive contrast agent, wherein the appropriate temperature is 120-130t, 5-10 minutes. Two U• If you apply for a special (four) 1 Gu Xu% positive son to secrete the automatic manufacturing method of the contrast agent with the Saskatchewan serum, which is the appropriate temperature scale °C, 5-10 minutes. '丨. The application of the patented detail IM 摘8f positron-released isotope-labeled red serum is an automated manufacturing method for the contrast agent, wherein the appropriate temperature at the step 5 is 〇C ' 10-20 minutes. π 1 = an automated manufacturing method for a serum contrast agent of the % positron-complementing isotope as described in the patent specification, wherein the microporous Duqingchuan of the step 6 is an ethylene filter having a pore size of 0.22 μm. '", come to the four gas Π · For example, apply for a patent to turn over the automatic manufacturing method of the 正 器 造影 造影 造影 造影 造影 放射性 放射性 , , , , , , , , , 造影 造影 造影 造影 造影 造影The ethylene filter membrane has a pore size of 0.22 μm. 8. An automatic device for automatically coating a serotonin running device contrast agent for each F-positive radioisotope, including a control device and a reaction system; the control device is used to automatically control the blessing and the various pipelines; «Integrated-QMA column, -Cl8Sep_Pak S column HPLC purification device, a ^ column, a first reagent access device, a second reagent access device, a third reagent access port, - fourth a reagent access device, a first reaction device, a second reaction device, a first collector, a second collector, an aqueous solution storage device, a vacuuming device, a plurality of pressurized devices, and more than one Waste liquid storage device '13⁄4 QMA胄(4)_帛—· Persimmon I! Lai, can be vacuumed by the control device to open and close the storage of the first reagent access device (4) The undesired surface is placed in the water-soluble interaction device, and the required test d is reached in the material-reaction device, and the first reaction device is connected to the second reagent access device' by means of the control device After the switch, the helium gas pressure device can be used to fill the wire. The method is to receive the solution stored in the second reagent access device and react, and the solution after the reaction is also controlled. After the switch is turned on, the helium gas pressing device sends the helium gas to the solution. Kunlun pipe column for separation, the unneeded solution will be placed in a waste liquid storage device' and the required reagents are also required to be opened by the control device after the switch is opened, and the helium gas pressure device is transported to the atmosphere by filling the atmosphere. In the second reaction device, the second reaction is placed and connected to the third reagent access device, and the switch device can be vacuumed after the switch is opened to receive the third reagent access device. The solution is reacted and reacted. After the reaction, the solution is also turned on by the control device, and then sent to the sail C purification device for separation and separation, and the undesired solution will be placed in a Waste liquid storage device, and the required reagents to the first collector, the first collector contains the appropriate reaction solution can be mixed with the reagent 1329021 ey 'mixture also waits for the control device to open the switch, said gas plus Pressure Place it in a nitrogen-filled manner and record it in the tc18 Sep-Pak tube (4). If the inspection is not carried out, it will be placed in a waste storage device. _The finished product is also to be controlled (4) _ after the atmosphere The gas addition and pressure device is sent to the second collector for filling with helium gas. • 19. The automatic production of 18f positron radioisotope labeled serotonin as described in claim 18 of the patent scope The automatic device for making the device, the 18F positron radioisotope marker - the serotonin operator contrast agent is a contrast agent which can be prepared by the following synthesis program, which is: (1) separation of [18F] ions; (2) The nucleophilic substitution reaction K3) reduction reaction of the relevant precursor is carried out in the town of 18.2; _ HPLC purification product; (3) 酉 hexamidine reaction (F_u on n). 20. The serotonin operator contrast imaging method for the automatic manufacture of 丨8ρ positrons radioisotope labeled as described in claim 18, wherein the serotoner operator contrast agent of the cap % positron radioisotope marker is 4-[ 18F]-ADAM, 4屮8F]-AFM, 4-[18F]-AFE, 4-[18F]-AFP and other serotonin transmitter contrast agents. 21. The automated device for automatically manufacturing an isF positronium radioisotope marker serotonin operator contrast agent according to claim 18, wherein the third separation device is an HpLC purification device comprising an HPLC column, a Han The emitter and the ultraviolet detector are connected to the HPLC column output to detect the flow of the washing liquid. The radiation and ultraviolet absorption spectrum of the fragment. 22. An automated device for automatically manufacturing a serotonin mobile contrast agent as described in claim 18, wherein the first reagent access device comprises more than one reagent accessor, each reagent accessing The outlet of the device is provided with a switch to control the flow of its contents. 23. The automated device for automatically producing a % positron radioisotope labeled 1329021 as described in claim 18, wherein the first reagent access device is required for storage of a nucleophilic substitution reaction. A part of the reagent, comprising an aqueous solution of fluoride ion and a K2C〇3/Kryptofix 2 2 2 solution. 24. The automated manufacturing of the serotonin operator contrast agent of the 丨8ρ positron radioisotope labeled as described in claim 18, wherein the second reagent access device comprises more than one reagent accessor, The outlet of each reagent accessor is provided with a switch to control the flow of its contents. 25. An automated device for the automated manufacture of a serotonin-operator contrast agent of the positron-emitting radioisotope marker as described in claim 1S, which allows the second reagent access device to be stored in a portion required for the reduction-nuclear substitution reaction Reagents, including precursors, water, and Erqijiayuan (Xun (5). 26. An automated device for automatically manufacturing a % positron radioisotope labeling serotonin operator contrast agent as described in claim 18, wherein The third reagent accessing skirt comprises one and the upper accessing access, and the outlet of each reagent accessor is provided with an opening to control the outflow of the contents thereof. As described in the application __18 From the _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ NaBH4 ethanol solution. 28. The automatic device for automatically manufacturing 18F positron radioisotope labeled with a monthly operating agent as described in claim 18 of the patent scope, wherein the fourth reagent access device comprises a In the above supplementary access device, a flow outlet of each reagent accessor is provided with a switch to control the outflow or not of the contents thereof. The patent for the automatic manufacture of the 18p positron radioisotope mark 10 S 1329021 An automated device for a serotonin operator contrast agent, wherein the fourth reagent access device stores reagents required for the formulation reaction, including water and ethanol. 30. Automated manufacturing as described in claim 18 % Orthotonic radioisotope is an automated device for the serotonin operator contrast agent, wherein the first reaction device comprises a reagent reactor and a temperature regulator. 3i • Automatic manufacturing as described in claim 18 An automated device for the serotonin operator contrast agent of the positron-positive radioisotope label, wherein the second reaction device comprises a reagent reactor and a temperature regulator.