Benzamidophenylpiperazine radio compounds, methods of making and using the same

Abstract

The application discloses benzamide phenylpiperazine radioactive compounds and a preparation method and application thereof, and belongs to the field of radioactive drugs. 18 The F-labeled compound is simple in preparation method. The benzamide phenylpiperazine radioactive compound can be used as a dopamine D3 receptor targeted radioactive probe, and has the characteristics of excellent biological performance, high chemical purity and high specific activity.

Description

Technical Field

[0001] This invention belongs to the field of radiopharmaceuticals and relates to benzamide-phenylpiperazine radioactive compounds, their preparation methods, and applications. Background Technology

[0002] Dopamine is an important neurotransmitter that regulates various physiological functions of the central nervous system. Its effects in vivo are mediated by five major dopamine receptor subtypes. The specific distribution of dopamine D3 receptors (D3Rs) in the mesolimbic region has drawn widespread attention in research on schizophrenia and substance abuse. Changes in the quantity of D3Rs in the brain are closely related to the occurrence and development of diseases. Autopsy results of schizophrenia patients show a significantly elevated number of D3Rs in their brains compared to normal individuals. Quantitative analysis of D3Rs in the brain at the in vivo level is of great significance for understanding disease research. Positron emission tomography (PET) imaging can display changes in the quantity and distribution of D3Rs in vivo, playing an important role in disease diagnosis, pathogenesis research, and drug development. However, the key to achieving this goal is the development of highly selective D3R radioactive probes. Early D3R radioactive probes focused on structures such as aminotetrahydronaphthalenes and tetrahydropyrrolidines, but often had poor selectivity for dopamine receptor subtypes.

[0003] Over the years, researchers have developed D3R ligands and summarized certain patterns from their structure-activity relationships. Specifically, an aryl or aryl-substituted amide (①) is linked to an aryl piperazine structure (③) through a functionalized hydrocarbon moiety (②), resulting in the D3R radioactive probe structure, with the general formula as follows: Figure 1 As shown. Ligands with this type of structure often exhibit good subtype selectivity and D3R affinity, such as the D3R partial agonist BP897:

[0004]

[0005] The structure of arylpiperazine D3R ligands such as BP897 was chemically modified and then... 18 F radioactive labeling, thus obtaining D3R radioactive probes, such as [ 18F]FTP (refer to Mach RH, Tu ZD, Xu JB, Li SH, Jones LA, Taylor M, Luedtke RR, Derdeyn CP, Perlmutter JS, Mintun M A.Endogenousdopamine(DA) competes with the binding of a radiolabeled D3 receptor partialagonist in vivo:A positron emission tomography study.Synapse,2011,65(8):724-732),[ 18 F]5 (refer to Hocke C, Cumming P, Maschauer S, et al. Biodistribution studies of two 18F-labeled pyridinylphenyl amides as subtype selective radioligands for the dopamine D3 receptor [J]. Nuclear Medicine and Biology, 2014, 41 (3): 223-228).

[0006] Currently, the most effective radioactive probe in this arylpiperazine structure is [ 18 F]FTP, its molecular structure is as follows:

[0007]

[0008] PET results showed that after the tranquilizer lorazepam inhibited dopamine secretion, there was significant specific uptake in D3R-rich areas of the rhesus monkey brain, such as the striatum and thalamus. However, subsequent clinical trial results showed that the D3R inhibitor perphenazine inhibited […]. 18 F]FTP showed no significant difference in the D3R enrichment region, therefore further optimization and exploration of radioactive probes with this type of structure are needed to develop D3R-specific radioactive probes with high affinity and selectivity in the human body.

[0009] Because the number of D3Rs in the brain is extremely small, interference from non-specific signals has a more significant impact on PET imaging. Therefore, a radioactive probe has been proposed. 18 F]5, its molecular structural formula is as follows:

[0010]

[0011] Excessive lipid solubility often leads to significant nonspecific binding, affecting radioactive probes. 18 F]5 (logP = 5.27) showed uniform uptake throughout the rat brain in autoradiography. Although its in vitro binding and inhibition experiments demonstrated good D3R affinity and specificity, its high lipid solubility still severely contaminated PET images, making it difficult to distinguish brain regions. Summary of the Invention

[0012] To address the problems existing in the prior art, the present invention aims to provide a benzamide-phenylpiperazine radioactive compound, its preparation, and its application as a dopamine D3 receptor-targeting radioactive probe. This benzamide-phenylpiperazine radioactive compound is simple to prepare and, when used as a dopamine D3 receptor-targeting radioactive probe, exhibits excellent biological properties, high chemical purity, and high specific activity.

[0013] To achieve the above objectives, the present invention adopts the following technical solution:

[0014] In a first aspect, the present invention proposes radioactive compounds of the benzamide-phenylpiperazine class, including FBPC, FBPB, or FBNPB classes. 18 F-labeled compounds; among which,

[0015] FBPC class 18 The general molecular structural formula of F-labeled compounds is as follows:

[0016]

[0017] FBPB class 18 The general molecular structural formula of F-labeled compounds is as follows:

[0018]

[0019] FBNPB class 18 The general molecular structural formula of F-labeled compounds is as follows:

[0020]

[0021] Wherein, group R carries 18 F mark.

[0022] Furthermore, FBPC class 18 F-labeled compounds include [ 18 F]FBPC01、[ 18 F]FBPC02 or [ 18 F]FBPC03, where, [ 18 In the molecular structural formula of F]FBPC01, R is CH2CH2 18 F, [ 18In the molecular structural formula of F]FBPC02, R is (CH2CH2O)2CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPC03, R is CH2CHOHCH2 18 F.

[0023] Furthermore, FBPB class 18 F-labeled compounds include [ 18 F]FBPB01、[ 18 F]FBPB02 or [ 18 F]FBPB03, where, [ 18 In the molecular structural formula of F]FBPB01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPB02, R is (CH2CH2O)2CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPB03, R is CH2CHOHCH2 18 F.

[0024] Furthermore, the FFBNPB class 18 F-labeled compounds include [ 18 F]FBNPB01 or [ 18 F]FBNPB03, where, [ 18 In the molecular structural formula of F]FBNPB01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBNPB03, R is CH2CHOHCH2 18 F.

[0025] Secondly, the present invention also provides a method for preparing benzamide-phenylpiperazine radioactive compounds, comprising the following steps:

[0026] First, synthesize phenylpiperazine precursor compounds containing p-toluenesulfonyl substituents (OTs), including FBPC, FBPB, or FBNPB precursor compounds;

[0027] Then the precursor compound and [ 18 F]F - Nucleophilic substitution reaction was carried out to prepare the following product: 18 F-labeled benzamide-phenylpiperazine radioactive compounds, including FBPC, FBPB, or FBNPB types. 18 F-labeled compounds; among which,

[0028] The general molecular structural formulas of FBPC precursor compounds are as follows:

[0029]

[0030] The general molecular structural formulas of FBPB-type precursor compounds are as follows:

[0031]

[0032] The general molecular structural formulas of FBNPB-type precursor compounds are as follows:

[0033]

[0034] FBPC class 18 The general molecular structural formula of F-labeled compounds is as follows:

[0035]

[0036] FBPB class 18 The general molecular structural formula of F-labeled compounds is as follows:

[0037]

[0038] FBNPB class 18 The general molecular structural formula of F-labeled compounds is as follows:

[0039]

[0040] In the FBPC, FBPB, or FBNPB precursor compounds, R3 and R4 in the general molecular formula are the groups to be labeled. 18 In the general formula of F-labeled compounds, R represents the symbol with the radical "R". 18 F-labeled groups.

[0041] Furthermore, the FBPC precursor compounds include precursor compounds 5a, 5b or 6c, wherein R3 in the molecular structure of precursor compound 5a is CH2CH2OTs, R3 in the molecular structure of precursor compound 5b is (CH2CH2O)3Ts, and R4 in the molecular structure of precursor compound 6c is CH2CH(OTHP)CH2OTs.

[0042] Prepared FBPC class 18 F-labeled compounds include [ 18 F]FBPC01、[ 18 F]FBPC02 or [ 18 F]FBPC03, where, [ 18 In the molecular structural formula of F]FBPC01, R is CH2CH2 18 F, [ 18In the molecular structural formula of F]FBPC02, R is (CH2CH2O)2CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPC03, R is CH2CHOHCH2 18 F.

[0043] Furthermore, the FBPB class precursor compounds include precursor compounds 9a, 9b or 10c, where R3 in the molecular structure of precursor compound 9a is CH2CH2OTs, R3 in the molecular structure of precursor compound 9b is (CH2CH2O)3Ts, and R4 in the molecular structure of precursor compound 10c is CH2CH(OTHP)CH2OTs.

[0044] Prepared FBPB class 18 F-labeled compounds include [ 18 F]FBPB01、[ 18 F]FBPB02 or [ 18 F]FBPB03, where, [ 18 In the molecular structural formula of F]FBPB01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPB02, R is (CH2CH2O)2CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPB03, R is CH2CHOHCH2 18 F.

[0045] Furthermore, the FBNPB class of precursor compounds includes precursor compounds 14a or 15c, where R3 in the molecular structure of precursor compound 14a is CH2CH2OTs and R4 in the molecular structure of precursor compound 15c is CH2CH(OTHP)CH2OTs.

[0046] Prepared FBNPB class 18 F-labeled compounds include [ 18 F]FBNPB01 or [ 18 F]FBNPB03, where, [ 18 In the molecular structural formula of F]FBNPB01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBNPB03, R is CH2CHOHCH2 18 F.

[0047] Furthermore, the steps for preparing FBPC precursor compounds 5a, 5b, or 6c include:

[0048] Trans-4-hydroxycinnamic acid was dissolved in an aqueous NaOH solution. Then, an aqueous solution of 2-bromoethanol, 2-[2-(2-chloroethoxy)ethoxy]ethanol, or 3-chloro-1,2-propanediol was slowly added dropwise under heating and stirring. After the reaction was complete, the solution was cooled and diluted, acidified with dilute hydrochloric acid, and then filtered, washed, and purified to obtain compounds 3a, 3b, or 3c, with the following molecular structures:

[0049]

[0050] Compounds 3a, 3b, or 3c were dissolved in DMF, and EDCI and HOBt were added and stirred under an ice-water bath. Then, DIPEA and 4-amino-1-(4-(2-methoxyphenyl)piperazine)2-butanol were added. The mixture was removed from the ice-water bath and stirred at room temperature. After the reaction was complete, the solution was adjusted to alkalinity with saturated sodium bicarbonate solution, followed by DCM extraction, drying, extraction, and purification to obtain compounds 4a, 4b, or 4c, with the following molecular structures:

[0051]

[0052] Compounds 4a, 4b, or 4c were dissolved in DCM, and triethylamine was added under ice bath conditions. For compound 4c, Bu2SnO was also added. Then, p-toluenesulfonyl chloride was added in portions. The mixture was allowed to rise to room temperature naturally and then stirred. After the reaction was completed, ice water was added to terminate the reaction. The mixture was then extracted with DCM, washed, dried, filtered, and purified to obtain compounds 5a, 5b, or 5c, where compounds 5a and 5b were precursor compounds 5a and 5b.

[0053] Compound 5c was dissolved in DCM, PPTs and DHP were added, and the mixture was heated and stirred. After the reaction was completed, the mixture was cooled, washed, collected, dried, filtered, and purified to obtain the precursor compound 6c.

[0054] Furthermore, the steps for preparing FBPC precursor compounds 9a, 9b, or 10c include:

[0055] Benzofuran carboxylic acid was dissolved in an aqueous NaOH solution. Then, an aqueous solution of 2-bromoethanol, 2-[2-(2-chloroethoxy)ethoxy]ethanol, or 3-chloro-1,2-propanediol was slowly added dropwise under heating and stirring. After the reaction was complete, the solution was cooled and diluted, acidified with dilute hydrochloric acid, filtered, and the precipitate was collected, washed, and purified to obtain compounds 7a, 7b, or 7c, with the following molecular structures:

[0056]

[0057] Compounds 7a, 7b, or 7c were dissolved in DMF, and EDCI and HOBt were added and stirred in an ice-water bath. Then, DIPEA and 4-amino-1-(4-(2-methoxyphenyl)piperazine)2-butanol were added. The mixture was removed from the ice-water bath and stirred at room temperature. After the reaction was complete, the solution was adjusted to alkalinity with saturated sodium bicarbonate solution, followed by DCM extraction, drying, extraction, and purification to obtain compounds 8a, 8b, or 8c, with the following molecular structures:

[0058]

[0059] Compounds 8a, 8b, or 8c were dissolved in DCM, and triethylamine was added under ice bath conditions. For compound 8c, Bu2SnO was also added. Then, p-toluenesulfonyl chloride was added in portions. The mixture was allowed to rise naturally to room temperature and then stirred. After the reaction was completed, ice water was added to terminate the reaction. The mixture was then extracted with DCM, washed, dried, filtered, and purified to obtain compounds 9a, 9b, or 9c, where compounds 9a and 9b were precursor compounds 9a and 9b.

[0060] Compound 9c was dissolved in DCM, PPTs and DHP were added, and the mixture was heated and stirred. After the reaction was completed, the mixture was cooled, washed, collected, dried, filtered, and purified to obtain precursor compound 10c.

[0061] Furthermore, the steps for preparing FBNPB-type precursor compounds 14a or 15c include:

[0062] Benzofuran carboxylic acid was dissolved in an aqueous NaOH solution. Then, an aqueous solution of 2-bromoethanol or 3-chloro-1,2-propanediol was slowly added dropwise under heating and stirring to initiate the reaction. After the reaction was complete, the solution was cooled and diluted, acidified with dilute hydrochloric acid, filtered to collect the precipitate, and washed and purified to obtain compound 7a or 7c, with the following molecular structure:

[0063]

[0064] N-(4-bromobutyl)phthalimide, 1-(3-cyanophenyl)piperazine, K2CO3, and NaI were dissolved in anhydrous 1,4-dioxane and stirred under reflux. After the reaction was completed, the mixture was cooled to room temperature, filtered, and purified to obtain compound 11, with the following molecular structure:

[0065]

[0066] Compound 11 and hydrazine hydrate were dissolved in ethanol and stirred at room temperature. After the reaction was complete, the solution was removed, the filter residue was diluted, ultrasonically shaken, and then extracted with dichloromethane. The organic phases were combined, washed, dried, and extracted again to obtain compound 12, with the following molecular structure:

[0067]

[0068] Compound 7a or 7c was dissolved in DMF, and EDCI and HOBt were added and stirred under an ice-water bath. Then, DIPEA and compound 12 were added, and the mixture was removed from the ice-water bath and stirred at room temperature. After the reaction was complete, the solution was adjusted to alkalinity with saturated sodium bicarbonate solution. Compound 13a or 13c was obtained by DCM extraction, drying, extraction, and purification, with the following molecular structure:

[0069]

[0070] Compound 13a or 13c was dissolved in DCM, and triethylamine was added under ice bath conditions. For compound 13c, Bu2SnO was also added. Then, p-toluenesulfonyl chloride was added in portions, and the mixture was allowed to rise naturally to room temperature before stirring. After the reaction was completed, ice water was added to terminate the reaction. After extraction with DCM, washing, drying, filtration, and purification, compound 14a or 14c was obtained. Compound 14a is the precursor compound 14a.

[0071] Compound 14c was dissolved in DCM, PPTs and DHP were added, and the mixture was heated and stirred. After the reaction was completed, the mixture was cooled, washed, collected, dried, filtered, and purified to obtain precursor compound 15c.

[0072] Furthermore, the precursor compound is combined with [ 18 F]F - The steps involved in a nucleophilic substitution reaction include:

[0073] Cyclotron bombards oxygen-rich water (H2) 18 O yields radioactive nuclides [ 18 F]F - The anion exchange column is used to [ 18 F]F - Captured on the column and reacted with K2CO3 and phase-transfer catalyst K 222 The rinsing solution will [ 18 F]F - After rinsing, you get [ 18 F]KF solution; under heating conditions, water is removed by blowing nitrogen and adding anhydrous acetonitrile in an azeotropic manner;

[0074] The precursor compound was dissolved in an anhydrous polar aprotic solution, and then [[ 18 F]F - Nucleophilic substitution reaction was carried out; for precursors with DHP protecting groups, hydrochloric acid solution was added after the reaction to carry out deprotection reaction; after cooling to room temperature, saturated sodium bicarbonate solution was added to neutralize the solution;

[0075] After the reaction was completed, the mixture was cooled and diluted, and excess water was removed by C18 solid-phase extraction column extraction. 18 F]F -The column was rinsed with water again, the radiolabeled product was eluted with acetonitrile, the solution was concentrated and diluted with the appropriate proportion of high performance liquid chromatography (HPLC) mobile phase, and then separated and purified by semi-preparative HPLC.

[0076] The fraction purified by HPLC was diluted, and acetonitrile was removed by C18 solid-phase extraction. The column was washed again with water, and the radiolabeled product was eluted with ethanol and then prepared with physiological saline to obtain... 18 F-labeled benzamide phenylpiperazine radioactive compounds.

[0077] Furthermore, a synthesizer module is used for automatic synthesis. 18 F-labeled benzamide phenylpiperazine radioactive compounds.

[0078] Further, standard compounds 4d, 4e, 4f, 8d, 8e, 8f, 13d, and 13f, corresponding to the precursor compounds and containing p-toluenesulfonyl substituents, were synthesized. 18 The F-labeled benzamide-phenylpiperazine radioactive compounds were compared with corresponding standard compounds to determine... 18 The synthesis of F-labeled benzamide-phenylpiperazine radioactive compounds was correct; among them...

[0079] The molecular structural formulas of standard compounds 4d, 4e, and 4f are as follows:

[0080]

[0081] In the molecular structures of 4d, 4e, and 4f, R2 is CH2CH2F, (CH2CH2O)2CH2CH2F, and CH2CHOHCH2F, respectively.

[0082] The molecular structural formulas of standard compounds 8d, 8e, and 8f are as follows:

[0083]

[0084] In the molecular structures of 8d, 8e, and 8f, R2 is CH2CH2F, (CH2CH2O)2CH2CH2F, and CH2CHOHCH2F, respectively.

[0085] The molecular structural formulas of standard compounds 13d and 13f are as follows:

[0086]

[0087] In the molecular structures of 13d and 13f, R2 is CH2CH2F and CH2CHOHCH2F, respectively.

[0088] Thirdly, this invention also proposes the application of benzamide-phenylpiperazine radioactive compounds as radioactive probes targeting dopamine D3 receptors, specifically in nuclear medicine dopamine D3 receptor PET imaging. As a radioactive probe, it is injected into the body via intravenous injection and specifically binds to dopamine D3 receptors in the brain. Information on the uptake and distribution of dopamine D3 receptors in the brain is obtained through PET imaging.

[0089] The advantages of this invention include:

[0090] 1. In terms of probe design, since part ① of the D3R radioactive probe structure is a secondary pharmacophore that binds to the D3R secondary structure site, its impact on the overall structure-activity relationship may be smaller than that of modifying the main pharmacophore in part ③. Therefore, this invention attempts to modify the aromatic ring in this part while preserving the structure of part ③ to the greatest extent possible. Different hydrophilic side chains (fluoroethoxy, fluoropolyethylene glycol group, 1-fluoro-2-hydroxy-3-propoxy) are introduced into the aromatic ring in part ① to facilitate the labeling of radionuclides at the chain ends via nucleophilic substitution reactions. Furthermore, the introduction of these side chains can reduce the lipophilicity of the compound, potentially resulting in less nonspecific uptake during PET imaging.

[0091] 2. On the benzene ring 18 F-labeling reaction conditions are often complex or yield low results; therefore, this invention chooses to carry out the reaction on an alkyl chain. 18 The F mark. The structural design of this invention allows for very simple marking conditions and steps. 18 F undergoes a nucleophilic substitution reaction with the OTs substituents on the side chain of the precursor molecule, thereby... 18 F was introduced into the compound to obtain the final radioactive probe, and a high radiochemical labeling yield was obtained.

[0092] 3. The product prepared by this invention 18 F-labeled benzamide-phenylpiperazine radioactive compounds, when used as probes, all exhibit high dopamine D3 receptor affinity and high D3R / D2R selectivity.

[0093] 4. This invention can be implemented through a synthesizer module. 18 The automated synthesis of F-labeled benzamide-phenylpiperazine radioactive compounds all exhibited high specific activity, yielding radiolabeled products with high specific activity for subsequent clinical applications.

[0094] 5. The product prepared by this invention 18F-labeled benzamide-phenylpiperazine radioactive compounds, used as radioactive probes targeting dopamine D3 receptors, showed significant specific uptake in rat brain regions where dopamine D3 receptors are present, such as the pituitary gland and ventricles, according to preliminary PET imaging results. The eight probes designed and synthesized in this invention have suitable lipid-water ratios, and most probes showed no non-specific uptake in the rat brain on PET imaging, enabling quantitative analysis of dopamine D3 receptor levels in the brain.

[0095] 6. The product prepared by this invention 18 F-labeled benzamide-phenylpiperazine radioactive compounds exhibit good chemical stability, showing no visible decomposition after 4 hours at room temperature. High-performance liquid chromatography (HPLC) analysis reveals radiochemical purity exceeding 97%, with radiochemical yields all above 20%. The lipid-water partition coefficient (logP) is between 2 and 4, theoretically allowing for easy brain penetration and moderate lipid solubility. In vitro binding experiments demonstrate that the probe possesses nanomolar to sub-nanomolar D3R affinity and appropriate D3R / D2R selectivity. Attached Figure Description

[0096] Figure 1 This is a general structural diagram of a D3R radioactive probe.

[0097] Figure 2 This is the synthetic route for 4-amino-1-(4-(2-methoxyphenyl)piperazine)2-butanol.

[0098] Figure 3 This is a synthetic route diagram for FBPC precursor compounds and standard compounds.

[0099] Figure 4 This is a synthetic route diagram for FBPB-type precursor compounds and standard compounds.

[0100] Figure 5 This is a synthetic route diagram for FBNPB-type precursor compounds and standard compounds.

[0101] Figure 6 yes[ 18 F]FBPC01 radioactive HPLC peak (red) and standard compound UV peak (black) diagram.

[0102] Figure 7 yes[ 18 F] FBPC03 radioactive HPLC peak (red) and standard compound ultraviolet peak (black) diagram.

[0103] Figure 8 yes[ 18 Radioactive HPLC chromatogram of the separation and purification process of the F]FBPC01 synthesizer module.

[0104] Figure 9 yes[18 Radioactive HPLC chromatogram of the separation and purification process of the F]FBPC03 synthesizer module.

[0105] Figure 10 yes[ 18 F]FBPC03 and [ 18 [F] Average PET / CT image between 10 and 30 minutes after FBPC01 injection.

[0106] Figure 11 The uptake of nutrients in the fourth ventricle, lateral ventricle, striatum, cerebellar white matter, and pituitary gland in the normal and inhibited groups of rats […]. 18 F]FBPC03(a,b) and [ 18 Time-radioactivity curve of F]FBPC01(c,d).

[0107] Figure 12 This is a schematic diagram of the TRACERlab FX2 N synthesizer module. Detailed Implementation

[0108] The present invention will now be described in further detail with reference to the accompanying drawings. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0109] This invention prepares benzamide-phenylpiperazine radioactive compounds by modifying the structures of parts ①②③ in the D3R radioactive probe, resulting in different combinations and the synthesis of eight radioactive compounds in three classes (FBPC, FBPB, and FBNPB). 18 F]FBPC01、[ 18 F]FBPC02、[ 18 F]FBPC03、[ 18 F]FBPB01、[ 18 F]FBPB02、[ 18 F]FBPB03、[ 18 F]FBNPB01、[ 18 F]FBNPB03).

[0110] For FBPCs, 2-methoxyphenylpiperazine is selected at part ③, a 3-OH group is introduced into the butyl chain at part ②, and a small-ring cinnamamide is selected at part ①, with an alkyl side chain at the para-position of the benzene ring. 18 F]Fluoroethoxy, [ 18 F]Fluoropolyethylene glycol group, 1-[ 18 F]F-2-hydroxy-3-propoxy corresponds to [ 18 F]FBPC01、[ 18 F]FBPC02、[ 18 F]FBPC03. Figure 3This is the synthetic route for FBPC precursor compounds and standard compounds.

[0111] For FBPB-type compounds, 2-methoxyphenylpiperazine is selected at part ③, a 3-OH group is introduced into the butyl chain at part ②, and a benzofuran amide with a heteroaromatic ring structure is selected at part ①, with an alkyl side chain introduced at position 5. 18 F]Fluoroethoxy, [ 18 F]Fluoropolyethylene glycol group, 1-[ 18 F]F-2-hydroxy-3-propoxy corresponds to [ 18 F]FBPB01、[ 18 F]FBPB02、[ 18 F]FBPB03. Figure 4 This is the synthetic route for FBPB-type precursor compounds and standard compounds.

[0112] For FBNPB class, 3-cyanophenylpiperazine is selected at part ③, butyl chain is selected at part ②, benzofuranamide is selected at part ①, and an alkyl side chain is introduced at position 5. 18 F]fluoroethoxy, 1-[ 18 F]F-2-hydroxy-3-propoxy corresponds to [ 18 F]FBNPB01、[ 18 F]FBNPB03. Figure 5 This is the synthetic route for FBNPB-type precursor compounds and standard compounds.

[0113] The technical solution of the present invention will be described in detail below through examples. Since the above three types of compounds have many commonalities in synthesis, the following examples will describe the synthesis stages with different commonalities together to avoid repetition.

[0114] The synthesis of 1,2-(2-(ethylene oxide)ethyl)isoindoline-1,3-dione (compound 1), as follows: Figure 2 As shown.

[0115] Potassium o-phenylimine (2.77 g, 15 mmol) was dissolved in 10–15 mL of anhydrous DMF and reacted with 2-(2-bromoethyl)oxocycloane (2.27 g, 15.0 mmol) at 55 °C with stirring for 12 h. After cooling to room temperature, the solid was filtered off, diluted with ethyl acetate (30 mL), and washed with H₂O (2 × 15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to give the crude product of compound 1 (2.99 g, 92% yield, pale yellow waxy solid), which did not require further purification.

[0116] The synthesis of 2,4-amino-1-(4-(2-methoxyphenyl)piperazine)2-butanol (compound 2), as follows: Figure 2 As shown.

[0117] A mixture of compound 1 (0.56 g, 2.6 mmol) and 1-(2-methoxyphenyl)piperazine (0.50 g, 2.6 mmol) was refluxed and stirred overnight in 2-PrOH (30–40 mL). The solvent was removed by rotary evaporation, and the product was purified by silica gel chromatography with hexane / ethyl acetate (v / v = 1 / 2) to give 0.72 g (70% yield). This product (0.409 g, 1 mmol) was dissolved in 15 mL of ethanol, and hydrazine hydrate (0.097 g, 3.02 mmol) was added. The mixture was refluxed and stirred for 5–10 h, cooled to room temperature, and the solvent was evaporated. The reaction mixture was diluted with 20% K₂CO₃ aqueous solution (20 mL) and extracted with CH₂Cl₂ (20 mL × 2). The organic phase was collected, and the solvent was removed by rotary evaporation to give compound 2 (0.18 g, 65% yield, colorless oil), which required no further purification.

[0118] 1 HNMR(500MHz, CDCl3)δ7.20–6.68(m,1H),7.20–6.58(m,4H),5.30(s,1H),3.86(s,3H) ,3.46–2.74(m,8H),2.56(d,J=61.2Hz,2H),2.30(d,J=92.3Hz,3H),1.65–1.50(m,2H).

[0119] The synthesis of 3.2-(4-(4-(3-cyanophenyl)piperazin-1-yl)butyl)isoindoline-1,3-dione (compound 11), as follows: Figure 5 As shown.

[0120] N-(4-bromobutyl)phthalimide (0.141 g, 0.5 mmol), 1-(3-cyanophenyl)piperazine (0.0935 g, 0.5 mmol), K₂CO₃ (1.932 g, 14 mmol), and NaI (0.2235 g, 1.5 mmol) were dissolved in 3–5 mL of anhydrous 1,4-dioxane and stirred under reflux for 15–24 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove the precipitate, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (elution buffer: DCM / MeOH / Et₃N: 18 / 1 / 0.01) to give compound 11 (0.17 g, 90% yield, solid).

[0121] Synthesis of 4,3-(4-(4-aminobutyl)piperazin-1-yl)cyanobenzene (compound 12), as follows: Figure 5 As shown.

[0122] Compound 11 (0.15 g, 0.4 mmol) and hydrazine hydrate (0.06 g, 1.2 mmol) were dissolved in 6 mL of ethanol and stirred at room temperature for one day. After the reaction was complete, the solution was removed by filtration. The residue was diluted with 20% potassium carbonate aqueous solution (4 mL), sonicated for 1–4 h, and then extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with 3 mL of saturated brine, dried over Na₂SO₄, and the solvent was removed by rotary evaporation to give product 12 (0.077 g, 75% yield, solid), which did not require further purification.

[0123] 1 H NMR (500MHz, D2O) δ7.45–7.16(m,4H),3.12(s,4H),2.61(dd,J=16.1,9.2Hz,6H),2.42–2.24(m,2H),1.56–1.28(m,4H).

[0124] LC-MS(ESI): m / z calcd for C 15 H 23 N4[M+H] + :259.18; found:259.08.

[0125] 5. Synthesis of compounds 3a-3f and 7a-7f, such as Figure 3 , Figure 4 As shown.

[0126] For the synthesis of compounds 3a-3f, trans-4-hydroxycinnamic acid (1 equivalent) was dissolved in a 3 mol / L aqueous solution of NaOH; for the synthesis of compounds 7a-7f, benzofuranic acid (1 equivalent) was dissolved in a 3 mol / L aqueous solution of NaOH. The mixture was then stirred at 50°C for 3–4 hours. The corresponding R1-substituted compounds (2-bromoethanol or 2-[2-(2-chloroethoxy)ethoxy]ethanol, 3-chloro-1,2-propanediol, fluoroethyl p-toluenesulfonate, 2-(2-(2-fluoroethoxy)ethoxy)ethyl-4-p-toluenesulfonic acid or 1-chloro-3-fluoro-2-propanol, 1.5 equivalent) were dissolved in an appropriate amount of water and slowly added dropwise to the above solution. The reaction was carried out at 90°C for 8–10 hours. After cooling, the mixture was poured into ice-cold deionized water and acidified to pH 3-4 with 1 mol / L dilute hydrochloric acid. The precipitate was collected by filtration and washed with a small amount of water. The crude product was purified by silica gel column chromatography to obtain compounds 3a-3f and 7a-7f.

[0127] Example 1:

[0128] Trans-4-hydroxycinnamic acid (0.82 g, 5 mmol) was dissolved in 4 mL of 3 mol / L NaOH aqueous solution and stirred at 50 °C for 3 hours. 2-bromoethanol (0.937 g, 7.5 mmol) was dissolved in 1 mL of water and slowly added dropwise to the above solution. The reaction was carried out at 90 °C for 8 hours. After cooling, 5 mL of ice-cold deionized water was added, and the solution was acidified to pH 3-4 with 1 mol / L dilute hydrochloric acid. The precipitate was collected by filtration and washed with a small amount of water. The crude product was purified by silica gel column chromatography to give compound 3a (0.46 g, 45% yield, solid).

[0129] 1 HNMR(500MHz,MeOD)δ7.63(t,J=12.7Hz,1H), 7.55(d,J=8.7Hz,2H), 7.00(t,J=1 0.1Hz,2H), 6.41–6.24(m,1H), 4.19–4.02(m,2H), 3.86(dd,J=26.2,21.6Hz,2H).

[0130] Example 2:

[0131] Benzofuranic acid (0.534 g, 3 mmol) was dissolved in 3 mL of 3 mol / L NaOH aqueous solution and stirred at 50 °C for 3 hours. 1-Chloro-3-fluoro-2-propanol (0.495 g, 45 mmol) was dissolved in 0.5 mL of water and slowly added dropwise to the above solution. The reaction was carried out at 90 °C for 8 hours. After cooling, 5 mL of ice-cold deionized water was added, and the solution was acidified to pH 3-4 with 1 mol / L dilute hydrochloric acid. The precipitate was collected by filtration and washed with a small amount of water. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate / methanol / acetic acid: 10 / 1 / 0.01) to give compound 7c (0.34 g, 45% yield, solid).

[0132] 6. Synthesis of compounds 4a-4f, 8a-8f, 13a, 13c, 13d, and 13f, such as... Figure 3 , Figure 4 , Figure 5 As shown.

[0133] For the synthesis of compounds 4a-4f and 8a-8f, compounds 3a-3f and 7a-7f (1 equivalent) were dissolved in DMF, and EDCI (1.15 equivalent) and HOBt (1.05 equivalent) were added under an ice-water bath and stirred for 45 minutes. Then, DIPEA (1.2 equivalent) and compound 2 were added, and the mixture was removed from the ice-water bath and stirred at room temperature for 8 hours. For the synthesis of compounds 13a, 13c, 13d, and 13f, compounds 7a, 7c, 7d, and 7f (1 equivalent) were dissolved in DMF, and EDCI (1.15 equivalent) and HOBt (1.05 equivalent) were added under an ice-water bath and stirred for 45 minutes. Then, DIPEA (1.2 equivalent) and compound 12 (1 equivalent) were added, and the mixture was removed from the ice-water bath and stirred at room temperature for 5–10 hours. After the reaction was complete, the pH was adjusted to 9 with saturated sodium bicarbonate solution. Extracted three times with DCM, the organic phase was mixed, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The resulting product was purified by silica gel column chromatography to obtain compounds 4a-4f, 8a-8f, 13a, 13c, 13d, and 13f. Among these, 4d, 4e, 4f, 8d, 8e, 8f, 13d, and 13f are respectively […]. 18 F]FBPC01、[ 18 F]FBPC02、[ 18 F]FBPC03、[ 18 F]FBPB01、[ 18 F]FBPB02、[ 18 F]FBPB03、[ 18 F]FBNPB01、[ 18 F]FBNPB03 is a standard compound.

[0134] Example 3:

[0135] Compound 3d (0.298 g, 1 mmol) was dissolved in 10 mL of anhydrous DMF. EDCI (0.22 g, 1.15 mmol) and HOBt (0.14 g, 1.05 mmol) were added under an ice-water bath, and the mixture was stirred for 45 minutes. Then, DIPEA (0.155 g, 1.2 mmol) and compound 2 (0.208 g, 1 mmol) were added. The mixture was removed from the ice-water bath and stirred at room temperature for 8 hours. After the reaction was complete, the pH was adjusted to 9 with saturated sodium bicarbonate solution. The mixture was extracted three times with DCM, and the organic phases were mixed, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The solution was purified by silica gel column chromatography (eluent: DCM / MeOH: 10 / 1) to give compound 4d (55% yield, solid).

[0136] 1HNMR(500MHz, CDCl3) δ7.56(d,J=15.6Hz,1H), 7.45(d,J=8.7Hz,2H), 7.07–6.98(m ,1H), 6.97–6.78(m,4H), 6.52(s,1H), 6.27(d,J=15.6Hz,1H), 4.86–4.68(m,2H), 4. 31–4.17(m,2H), 3.95–3.80(m,3H), 3.75(ddd,J=28.6,14.1,7.1Hz,1H), 3.45–3.3 0 (m, 1H), 3.15 (s, 3H), 2.92 (d, J = 36.4Hz, 2H), 2.74 (s, 2H), 2.51 (q, J = 12.5Hz, 2H).

[0137] LC-MS (ESI): m / zcalcd for C 26 H 35 FN3O4[M+H] + :471.25; found:472.27.

[0138] Example 4:

[0139] Compound 7d (0.224 g, 1 mmol) was dissolved in 10 mL of anhydrous DMF. EDCI (0.22 g, 1.15 mmol) and HOBt (0.14 g, 1.05 mmol) were added under an ice-water bath, and the mixture was stirred for 45 minutes. Then, DIPEA (0.155 g, 1.2 mmol) and compound 2 (0.208 g, 1 mmol) were added. The mixture was removed from the ice-water bath and stirred at room temperature for 8 hours. After the reaction was complete, the pH was adjusted to 9 with saturated sodium bicarbonate solution. The mixture was extracted three times with DCM, and the organic phases were mixed, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The solution was purified by silica gel column chromatography (eluent: DCM / MeOH: 20 / 1) to give compound 8d (56% yield, solid).

[0140] 1 HNMR (500MHz, CDCl3) δ7.49 (s, 1H), 7.46–7.35 (m, 2H), 7.10 (d, J = 2.4Hz, 1H),

[0141] 7.09–6.98(m,2H), 6.97–6.90(m,2H), 6.87(d,J=7.7Hz,1H), 4.92–4.66(m,2H), 4.36–4.15(m,2H), 3.86(d,J=10.7Hz,3H), 3.60–3.46(m ,1H), 3.12(s,4H), 2.89(s,2H), 2.63(d,J=10.1Hz,2H), 2.52–2.33(m,2H), 2.29–2.09(m,1H), 2.01(d,J=6.1Hz,1H), 1.96–1.73(m,2H).

[0142] LC-MS(ESI): m / zcalcdforC 26 H 33 FN3O5[M+H] + :486.23; found:486.20.

[0143] Example 5:

[0144] Compound 7d (0.224 g, 1 mmol) was dissolved in 10 mL of anhydrous DMF. EDCI (0.22 g, 1.15 mmol) and HOBt (0.14 g, 1.05 mmol) were added under an ice-water bath, and the mixture was stirred for 30–50 minutes. Then, DIPEA (0.155 g, 1.2 mmol) and compound 12 (0.258 g, 1 mmol) were added. The mixture was removed from the ice-water bath and stirred at room temperature for 5–10 hours. After the reaction was complete, the pH was adjusted to 9 with saturated sodium bicarbonate solution. The mixture was extracted three times with DCM, and the organic phases were mixed, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The solution was purified by silica gel column chromatography (eluent: DCM / MeOH: 20 / 1) to give compound 13d (65% yield, solid).

[0145] 1 HNMR (500MHz, CDCl3) δ7.43–7.29(m,3H), 7.13–7.03(m,5H), 6.89(s,1H), 4.89–4.68(m,2H), 4.24(ddd,J=20.9,12.6 ,4.2Hz,2H), 3.52(dd,J=12.4,6.3Hz,2H), 3.34–3.11(m,4H), 2.62(s,4H), 2.47(t,J=6.8Hz,2H), 1.83–1.67(m,4H).

[0146] LC-MS (ESI): m / zcalcd for C 26 H 30 FN4O3[M+H] +:465.22; found:465.17.

[0147] 7. Synthesis of compounds 5a-5c, 9a-9c, 14a, and 14c, such as... Figure 3 , Figure 4 , Figure 5 As shown.

[0148] Compounds 4a-4c, 8a-8c, and 13a (1 equivalent) were dissolved in DCM. Triethylamine (Et3N, 3 equivalents) was added under ice bath conditions. For the synthesis of compounds 5c, 9c, and 14c, 0.2 equivalents of Bu2SnO were also added. Then, p-toluenesulfonyl chloride (TsCl, 2 equivalents) was added in portions. The mixture was allowed to rise naturally to room temperature and then stirred. The reaction progress was monitored by TLC. After the reaction was completed, ice water was added to terminate the reaction. The mixture was extracted three times with DCM, and the organic phases were mixed, washed with saturated sodium bicarbonate solution, and then washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified compounds were then purified by silica gel column chromatography to obtain compounds 5a-5c, 9a-9c, 14a, and 14c, of which 5a, 5b, 9a, 9b, and 14a were […]. 18 F]FBPC01、[ 18 F]FBPC02、[ 18 F]FBPB01、[ 18 F]FBPB02、[ 18 F]FBNPB01 precursor compound.

[0149] Example 6:

[0150] Compound 4a (0.469 g, 1 mmol) was dissolved in DCM, and triethylamine (0.3035 g, 3 mmol) was added under ice bath conditions. Then, TsCl (0.3814 g, 2 mmol) was added in portions. The mixture was allowed to rise naturally to room temperature and then stirred. The reaction progress was monitored by TLC. After the reaction was completed, ice water was added to terminate the reaction. The mixture was extracted three times with DCM, and the organic phases were mixed. The organic phases were washed with saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified compound 5a (0.37 g, 60% yield, solid) was obtained by silica gel column chromatography (eluent: DCM / MeOH: 15 / 1).

[0151] 1HNMR (500MHz, CDCl3) δ7.81(d,J=8.2Hz,2H), 7.54(d,J=15.6Hz,1H), 7.41(d,J=8.7Hz,2H), 7.34(d,J=8.1Hz ,2H), 7.07–6.99(m,1H), 6.93(dd,J=8.5,5.9Hz,2H), 6.87(d,J=8.0Hz,1H), 6.76(d,J=8.7Hz,1H), 6.53(s,1 H), 6.27(d,J=15.6Hz,1H), 4.41–4.34(m,2H), 4.20–4.13(m,2H), 3.87(s,3H), 3.80–3.68(m,2H), 3.42(d,J= 7.8Hz,1H), 3.14(s,4H), 2.94(s,2H), 2.72(s,2H), 2.51(s,1H), 2.45(s,3H), 2.26–2.16(m,1H), 1.77(s,2H).

[0152] LC-MS (ESI): m / zcalcd for C 33 H 42 N3O7S[M+H] + :624.27; found:624.41.

[0153] Example 7:

[0154] Compound 4c (0.5 g, 1 mmol) was dissolved in DCM. Triethylamine (0.15 g, 2 mmol) and Bu₂SnO (0.05 g, 0.2 mmol) were added in an ice bath, followed by the addition of TsCl (0.198 g, 1 mmol) in portions. The mixture was allowed to rise naturally to room temperature and then stirred. The reaction was monitored by TLC. After the reaction was complete, ice water was added to terminate the reaction. The mixture was extracted three times with DCM, and the organic phases were mixed, washed with saturated sodium bicarbonate solution, and then washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to obtain compound 5c (0.58 g, 90% yield, solid), which could be used directly in the next step without further purification.

[0155] 1HNMR(500MHz, CDCl3) δ7.79(d,J=8.3Hz,2H), 7.55(d,J=15.6Hz,1H), 7.48–7.37( m,2H), 7.34–7.27(m,2H), 7.07–6.71(m,6H), 6.28(d,J=15.6Hz,1H), 4.21(td,J= 11.8,4.1Hz,3H), 3.99(dd,J=13.6,4.8Hz,2H), 3.87(s,3H), 3.40(s,2H), 3.11(s ,4H), 2.89(s,2H), 2.65(s,2H), 2.43(d,J=18.0Hz,4H), 2.34(s,1H), 1.77(s,2H).

[0156] LC-MS (ESI): m / zcalcd for C 34 H 44 N3O8S[M+H] + :654.28; found:654.41.

[0157] 8. Synthesis of compounds with 6c, 10c, and 15c structures, such as... Figure 3 , Figure 4 , Figure 5 As shown.

[0158] Compounds 5c, 9c, and 14c (1 equivalent) were dissolved in DCM, and pyridine p-toluenesulfonate (PPTs, 8 equivalents) and 3,4-dihydro-2H-pyran (DHP, 40 equivalents, which became OTHP protecting group after reaction) were added. The mixture was stirred at 40°C for 20–24 hours. After the reaction was completed and cooled, the mixture was washed with saturated sodium bicarbonate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain products 6c, 10c, and 15c, respectively. 18 F]FBPC03、[ 18 F]FBPB03、[ 18 F]FBNPB03 precursor compound.

[0159] Example 8:

[0160] Compound 5c (0.2 g, 0.3 mmol) was dissolved in 60 mL of DCM, and PPTs (0.6 g, 2.4 mmol) and DHP (1.0 g, 12 mmol) were added. The mixture was stirred at 40 °C for 1 day. After the reaction was completed and cooled, the mixture was washed with saturated sodium bicarbonate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (eluent: DCM / n-hexane / methanol: 10 / 5 / 0.5) to give 6c (0.094 g, 38%, solid).

[0161] 1HNMR (500MHz, CDCl3) δ7.76 (s, 2H), 7.55 (d, J = 15.3Hz, 1H), 7.38 (d, J = 41.5Hz, 2H), 7.27 ( s,2H), 6.90(dd,J=75.4,46.0Hz,5H), 6.52(s,1H), 6.27(d,J=15.0Hz,1H), 4.74(d,J=37.9H z,1H), 4.12(dd,J=90.9,45.2Hz,5H), 3.87(s,3H), 3.78(s,2H), 3.44(d,J=36.0Hz,2H), 3.1 3(s,4H), 2.91(s,2H), 2.68(s,2H), 2.44(d,J=41.0Hz,4H), 2.22(s,1H), 1.96–1.44(m,8H).

[0162] LC-MS(ESI): m / zcalcdforC44H60N3O10S[M+H]+:822.39; found:822.56.

[0163] 9. Preparation of Benzamide-Phenylpiperazine Radioactive Compounds

[0164] a. Cyclotron bombarding oxygen-rich water (H2) 18 O yields radioactive nuclides [ 18 F]F - The anion exchange column is used to [ 18 F]F - Captured on the column and reacted with K2CO3 and a phase transfer catalyst (K 222 The rinsing solution will [ 18 F]F - After rinsing, [ 18 The F]KF solution was dried with nitrogen at 120°C to remove moisture. After drying, 0.5 mL of anhydrous acetonitrile was added three times in batches to further remove water using an azeotropic method.

[0165] b. Then, dissolve the synthesized precursor compound (4 mg / mL) in an anhydrous polar aprotic solution (such as acetonitrile or DMSO) and add it to the reaction flask. React at 100-120°C for 5-20 min with […]. 18 F]F - Nucleophilic substitution reaction is carried out. For precursors with DHP protecting groups, hydrochloric acid solution is added after the reaction and reacted at 100°C for 10 min to carry out deprotection reaction. After cooling to room temperature, saturated sodium bicarbonate solution is added to neutralize the solution.

[0166] c. After the reaction is complete and the solution has cooled slightly, dilute it with 10 mL of water and remove excess solution using a C18 solid-phase extraction column.18 F]F - The column was rinsed again with 10 mL of water, and the radiolabeled product was washed off with 2 mL of acetonitrile. The solution was concentrated and diluted with the appropriate proportion of HPLC mobile phase, and then purified by semi-preparative HPLC.

[0167] d. Dilute the HPLC-collected fraction with twice its volume of water, remove acetonitrile using a C18 solid-phase extraction column, rinse the column again with 10 mL of water, and then extract the purified fraction with 2 mL of ethanol. 18 F-labeled benzamide-phenylpiperazine radioactive compounds were eluted, and the concentrated solution was prepared with physiological saline for subsequent in vitro and in vivo evaluation.

[0168] As a preferred embodiment, the anion exchange column used in step a above is a Sep-Pak lightweight QMA column (Waters, USA). The eluent is prepared as follows: 6 mg K₂CO₃ dissolved in 0.5 mL of water, 11.1 mg K₂CO₃... 222 Dissolve in 1 mL of acetonitrile, and mix the two solutions thoroughly to obtain the rinsing solution.

[0169] In a preferred embodiment, the concentration of hydrochloric acid used in step b above is 2 mol / L, and the volume used is 0.2 mL.

[0170] In a preferred embodiment, the HPLC mobile phase used for separation and purification in step c above is as follows: Phase A: water + 0.1% TFA; Phase B: acetonitrile + 0.1% TFA. The flow rate is 5 mL / min.

[0171] Example 9:

[0172] The [generated by the cyclotron] 18 F]F - Adsorbed on a QMA column using K2CO3 / K 222 The rinsing solution will [ 18 F]F - Rinse the solution into a 10 mL penicillin bottle, dry the solvent by purging with nitrogen at 120 °C, and add 0.5 mL of acetonitrile for azeotropic dehydration. Dissolve 4 mg of FBPC01 precursor (5a) in 1 mL of anhydrous DMSO and add it to the penicillin bottle. Cap the bottle at 120 °C and react for 5 minutes. After the reaction is complete and slightly cooled, add 10 mL of water and remove excess water using a C18 solid-phase extraction column. 18 F]F -The column was rinsed again with 10 mL of water, and the crude product was eluted with 2 mL of acetonitrile. The solvent was concentrated to 200 μL, diluted with 370 μL of water, and then purified by HPLC (mobile phase ratio 0-30 min: 35% B, 5 mL / min). The collected fraction was diluted with twice its volume of water, and the acetonitrile was removed by C18 solid-phase extraction. The column was rinsed again with 10 mL of water, and the radiolabeled product was eluted with 2 mL of ethanol. The solution was concentrated, and physiological saline was added to prepare the final radioactive compound. 18 F]FBPC01, with a radiochemical yield of 25% after attenuation correction.

[0173] Figure 6 yes[ 18 The HPLC peak (red) of the F]FBPC01 radioactive compound and the ultraviolet peak (black) of the standard compound are compared. (See diagram for reference.) Figure 6 The HPLC analysis results showed that the radiochemical purity was greater than 99%. The retention time in HPLC was 8.25 min. The HPLC conditions for analyzing the final radioactive products were: HITACHI (D-2000) high-performance liquid chromatograph; Kromaisl C18 column 250 × 4.6 mm, 5 μm. Phase A is water (0.1% TFA), and Phase B is methanol (0.1% TFA); the elution gradient is: 0-15 min: 35% Phase B; 15-25 min: 35%-100% Phase B; 25-30 min: 100% Phase B; flow rate 1 mL / min.

[0174] Example 10:

[0175] The [generated by the cyclotron] 18 F]F - Adsorbed on a QMA column using K2CO3 / K 222 The rinsing solution will [ 18 F]F - Rinse the solution into a 10 mL penicillin bottle, purge the solvent with nitrogen at 120 °C, and add 0.5 mL of acetonitrile for azeotropic dehydration. Dissolve 4 mg of FBPC03 precursor (6c) in 1 mL of anhydrous DMSO and add it to the penicillin bottle. Cap the solution at 120 °C for 5 minutes. After cooling to 100 °C, add 0.2 mL of 2M HCl and cap the solution for 8 minutes. After the reaction is complete and slightly cooled, adjust the pH to 7-8 with saturated sodium bicarbonate solution, add 10 mL of water to dilute the solution, and remove excess solution using a C18 solid-phase extraction column. 18 F]F -The column was rinsed again with 10 mL of water, and the crude product was eluted with 2 mL of acetonitrile. The solvent was concentrated to 200 μL, diluted with 370 μL of water, and then purified by HPLC (mobile phase ratio 0-30 min: 35% B, 5 mL / min). The collected fraction was diluted with twice its volume of water, and the acetonitrile was removed by C18 solid-phase extraction. The column was rinsed again with 10 mL of water, and the radiolabeled product was eluted with 2 mL of ethanol. The solution was concentrated, and physiological saline was added to prepare the final radioactive compound. 18 F]FBPC03, with a radiochemical yield of 45% after attenuation correction.

[0176] Figure 7 yes[ 18 The HPLC peak (red) of the F]FBPC03 radioactive compound and the ultraviolet peak (black) of the standard compound are compared. (See diagram for reference.) Figure 7 The HPLC analysis showed that the radiochemical purity was greater than 99%. The retention time in HPLC was 7.89 min. The HPLC conditions for analyzing the final radioactive products were: HITACHI (D-2000) high-performance liquid chromatograph; Kromaisl C18 column 250 × 4.6 mm. Phase A is water (0.1% TFA), and Phase B is methanol (0.1% TFA); the elution gradient is: 0-15 min: 35% Phase B; 15-25 min: 35%-100% Phase B; 25-30 min: 100% Phase B; flow rate 1 mL / min.

[0177] 8. The synthesizer module automates the synthesis of benzamide-phenylpiperazine radioactive compounds.

[0178] a. Before synthesis, the materials required for the reaction process are sequentially loaded into the respective storage bottles of the synthesizer module. The following examples specifically use the existing TRACERlab FX2 N synthesizer module, whose structure is as follows: Figure 12 As shown, this is a device capable of automated synthesis.

[0179] b. The PETtrace840 (GE, USA) accelerator produces [ 18 F]F - Transmitted to the synthesizer module (GE, USA) [ 18 F]F - Once the transfer is complete in the collection bottle, click the start button on the computer interface of the synthesizer module to begin automatic synthesis. The automatic synthesis program is described below.

[0180] c.[ 18 F]F - Captured on a QMA column, eluted with eluent from Vial01 to REACTOR 1, and azeotropically dried.

[0181] d. The first reaction tube was cooled to 60°C, and the precursor solution in Vial O3 was added to carry out a nucleophilic substitution reaction.

[0182] e. After the reaction is complete, dilute with the HPLC mobile phase from Vial 06, transfer the mixture to TUBE 2, and purify with Al2O3 to remove excess [unspecified substance]. 18 F]F - .

[0183] f. The mixture in the second reaction tube is transferred to the quantitative loop of the synthesizer module HPLC and purified by HPLC preparative column.

[0184] The components collected by g.HPLC were placed in a flask, diluted, and purified at C18 2. The product was washed again with water at Vial14, and the purified labeled product was rinsed off with ethanol at Vial13. The product was then formulated with physiological saline at Vial12 to obtain the final product.

[0185] Example 11:

[0186] Before synthesis, load the materials required for the reaction into the synthesizer module. Vial01: 6 mg K₂CO₃ / 0.5 mL water + 11.1 mg K 222 / 1mL acetonitrile; Vial 03: 4mg FBPC01 precursor (5a) dissolved in DMSO; Vial 06: 1.5mL HPLC mobile phase; Vial 12: 20mL physiological saline; Vial 13: 2mL ethanol; Vial 14: 10mL water; Add 20mL water to the round-bottom flask; Install a QMA column between V10 and V11; Install an Al2O3 column between VX2 and VZ1; Install a C18 column between V17 and V15; Prepare 800mL of HPLC mobile phase (40% acetonitrile / 60% water / 0.1% TFA) in the mobile phase solvent bottle. 18 F]F - Captured on a QMA column, the sample was eluted to the first reaction tube with Vial 01 eluent and azeotropically dried under vacuum and helium at 90°C. After drying, the first reaction tube was cooled to 60°C, and a Vial 03 precursor solution was added. A nucleophilic substitution reaction was then carried out at 120°C for 5 min. After the reaction, 1.5 mL of HPLC mobile phase was added for dilution, and the mixture was transferred to the second reaction tube. En route, the mixture was purified using an Al2O3 column to remove excess […]. 18 F]F - The mixture from the second reaction tube was transferred to the quantitative loop of the HPLC in the synthesizer module and purified by HPLC preparative column separation at a flow rate of 10 mL / min. The components collected by HPLC were then transferred to a flask (e.g., Figure 8 The following is a list of […] 18[F] Radioactive HPLC chromatogram of the separation and purification process of FBPC01), the liquid in the round-bottom flask was purified by passing it through a C18 column, then washed with water by Vial 14, the product was eluted with ethanol by Vial 13, and the product was formulated with physiological saline by Vial 12 to obtain the product. 18 F]FBPC01. Obtained from automated production [ 18 The total synthesis time of F]FBPC01 was 55.9 minutes, with high radiochemical yield and specific activity of 26.4% and 112 GBq / μmol, respectively.

[0187] Example 12:

[0188] Before synthesis, load the necessary materials for the reaction into the synthesizer module. Vial01: 6 mg K₂CO₃ / 0.5 mL water + 11.1 mg K 222 / 1mL acetonitrile; Vial 03: 4mg FBPC03 precursor (6c) dissolved in DMSO; Vial 04: 0.2mL 1M hydrochloric acid; Vial 05: 0.5mL saturated sodium bicarbonate; Vial 06: 1.5mL HPLC mobile phase; Vial 12: 20mL physiological saline; Vial 13: 2mL ethanol; Vial 14: 10mL water; Add 20mL water to the round-bottom flask; Install a QMA column between V10 and V11; Install an Al2O3 column between VX2 and VZ1; Install a C18 column between V17 and V15; Prepare 800mL of HPLC mobile phase (30% acetonitrile / 70% water / 0.1% TFA) in the mobile phase solvent bottle. 18 F]F - Captured on a QMA column, the solution was eluted to the first reaction tube with eluent from Vial 01 and azeotropically dried under vacuum and helium at 90°C. After drying, the first reaction tube was cooled to 60°C, and a precursor solution of Vial 03 was added. A nucleophilic substitution reaction was carried out at 120°C for 5 min, followed by cooling to 100°C. Hydrochloric acid from Vial 04 was added to the first reaction tube, and the reaction was carried out for 8 min. After cooling to 40°C, a saturated sodium bicarbonate solution from Vial 05 was added for neutralization. After the reaction was complete, 1.5 mL of HPLC mobile phase was added for dilution, and the mixture was transferred to the second reaction tube. During the transfer, the mixture was purified by an Al2O3 column to remove excess […]. 18 F]F - The mixture from the second reaction tube was transferred to the quantitative loop of the HPLC in the synthesizer module and purified by HPLC preparative column separation at a flow rate of 10 mL / min. The components collected by HPLC were then transferred to a flask (e.g., Figure 9 The following is a list of […] 18 [F] Radioactive HPLC chromatogram of the separation and purification process of FBPC03), the liquid in the flask was purified by passing it through a C18 column, then washed with water by Vial 14, the product was eluted with ethanol by Vial 13, and the product was prepared by physiological saline by Vial 12 to obtain the product.18 F]FBPC03. Obtained from automated production [ 18 The total synthesis time of F]FBPC03 was 63 minutes, and it had a high radiochemical yield and specific activity of 22.8% and 135 GBq / μmol, respectively.

[0189] This invention uses phenylpiperazine compounds containing p-toluenesulfonyl (OTs) substituents as precursors, and [ 18 F]F - Eight novel nucleophilic substitution reactions were carried out to prepare them. 18 F-labeled benzamide-phenylpiperazine radioactive compounds. All compounds exhibited good chemical stability, showing no visible decomposition after 4 hours at room temperature. HPLC analysis revealed radiochemical purity exceeding 97%, radiochemical yields exceeding 20%, and lipid-water partition coefficients (logP) between 2 and 4, theoretically indicating easy brain penetration and moderate lipid solubility. In vitro binding experiments showed that the probes possessed high D3R affinity (nanomolar to subnanomolar) and appropriate D3R / D2R selectivity. See Table 1 below, where the reference compounds are NGB2904 and 7-OH-DPAT.

[0190] Table 1 shows the in vitro receptor binding data for 4d-4e, 8d-8e, 13d, and 13f.

[0191]

[0192] Because the number of D3R receptors is very small, the receptor binding sites are prone to saturation, leading to PET imaging failure. Therefore, probes need to have high specific activity. This invention produces probes with high specific activity of over 100 GBq / μmol using a synthesizer module, which can meet the requirements of PET imaging.

[0193] 10. Applications of Benzamide-Phenylpiperazine Radioactive Compounds

[0194] This invention uses [ 18 F]FBPC01 and [ 18 PET imaging of rats using F]FBPC03 showed very clear PET images of the pituitary gland and ventricles. 18 F]FBPC03 and [ 18 PET / CT imaging of F]FBPC01 rats showed significant specific uptake in the pituitary gland, which is rich in D3R, as well as in the fourth ventricle (4V) and lateral ventricles (LV). Uptake decreased significantly after inhibition with the D3R inhibitor BP897, but no significant changes were observed in the cerebellar white matter (cbw), which contains almost no D3R. The lack of significant uptake of the two probes in the striatum (ST), which is rich in D2R, indicates no significant binding with D2R. Figure 10 , Figure 11As shown. Among them Figure 10 for[ 18 F]FBPC03 and [ 18 Average PET / CT images between 10 and 30 minutes after F]FBPC01 injection. Figure 11 For the normal group and the inhibited group, the uptake of nutrients in the fourth ventricle, lateral ventricle, striatum, cerebellar white matter and pituitary gland of the rat brain was measured. 18 F]FBPC03(a,b) and [ 18 Time-radioactivity curves of F]FBPC01(c,d) (radioactivity is expressed as standard uptake value SUV).

[0195] Although specific embodiments of the invention have been disclosed for illustrative purposes and to aid in understanding and implementing the invention, those skilled in the art will understand that various substitutions, variations, and modifications are possible without departing from the spirit and scope of the invention and the appended claims. Therefore, the invention should not be limited to the content disclosed in the preferred embodiments, and the scope of protection claimed by the invention is defined by the claims.

Claims

1. A benzamide-phenylpiperazine radioactive compound, characterized in that, Including FBPC, FBPB, or FNPB classes 18 F-labeled compounds; among which, FBPC class 18 The general molecular structural formula of F-labeled compounds is as follows: FBPB class 18 The general molecular structural formula of F-labeled compounds is as follows: FBNPB class 18 The general molecular structural formula of F-labeled compounds is as follows: Among them, FBPC class 18 F-labeled compounds include [ 18 F]FBPC01、[ 18 F]FBPC02 or [ 18 F]FBPC03, where, [ 18 In the molecular structural formula of F]FBPC01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPC02, R is (CH2CH2O)2CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPC03, R is CH2CHOHCH2 18 F; FBPB class 18 F-labeled compounds include [ 18 F]FBPB01、[ 18 F]FBPB02 or [ 18 F]FBPB03, where, [ 18 In the molecular structural formula of F]FBPB01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPB02, R is (CH2CH2O)2CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPB03, R is CH2CHOHCH2 18 F; FBNPB class 18 F-labeled compounds include [ 18 F]FBNPB01 or [ 18 F]FBNPB03, where, [ 18 In the molecular structural formula of F]FBNPB01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBNPB03, R is CH2CHOHCH2 18 F.

2. A method for preparing benzamide-phenylpiperazine radioactive compounds, characterized in that, Includes the following steps: First, synthesize phenylpiperazine precursor compounds containing p-toluenesulfonyl substituents, including FBPC, FBPB, or FBNPB precursor compounds; Then the precursor compound and [ 18 F]F - Nucleophilic substitution reaction was carried out to prepare the following product: 18 F-labeled benzamide-phenylpiperazine radioactive compounds, including FBPC, FBPB, or FBNPB types. 18 F-labeled compounds; among which, The general molecular structural formulas of FBPC precursor compounds are as follows: or The general molecular structural formulas of FBPB-type precursor compounds are as follows: or The general molecular structural formulas of FBNPB-type precursor compounds are as follows: or FBPC class 18 The general molecular structural formula of F-labeled compounds is as follows: FBPB class 18 The general molecular structural formula of F-labeled compounds is as follows: FBNPB class 18 The general molecular structural formula of F-labeled compounds is as follows: Among them, the FBPC precursor compounds include precursor compounds 5a, 5b, or 6c. In the molecular structure of precursor compound 5a, R3 is CH2CH2OTs; in the molecular structure of precursor compound 5b, R3 is (CH2CH2O)3Ts; and in the molecular structure of precursor compound 6c, R4 is CH2CH(OTHP)CH2OTs. The prepared FBPC-type... 18 F-labeled compounds include [ 18 F]FBPC01、[ 18 F]FBPC02 or [ 18 F]FBPC03, where, [ 18 In the molecular structural formula of F]FBPC01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPC02, R is (CH2CH2O)2CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPC03, R is CH2CHOHCH2 18 F; FBPB-type precursor compounds include precursor compounds 9a, 9b, or 10c. In the molecular structure of precursor compound 9a, R3 is CH2CH2OTs; in the molecular structure of precursor compound 9b, R3 is (CH2CH2O)3Ts; and in the molecular structure of precursor compound 10c, R4 is CH2CH(OTHP)CH2OTs. The prepared FBPB-type... 18 F-labeled compounds include [ 18 F]FBPB01、[ 18 F]FBPB02 or [ 18 F]FBPB03, where, [ 18 In the molecular structural formula of F]FBPB01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPB02, R is (CH2CH2O)2CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBPB03, R is CH2CHOHCH2 18 F; FBNPB-type precursor compounds include precursor compounds 14a or 15c. In the molecular structure of precursor compound 14a, R3 is CH2CH2OTs, and in the molecular structure of precursor compound 15c, R4 is CH2CH(OTHP)CH2OTs. The prepared FBNPB-type... 18 F-labeled compounds include [ 18 F]FBNPB01 or [ 18 F]FBNPB03, where, [ 18 In the molecular structural formula of F]FBNPB01, R is CH2CH2 18 F, [ 18 In the molecular structural formula of F]FBNPB03, R is CH2CHOHCH2 18 F.

3. The preparation method according to claim 2, characterized in that, The steps for preparing FBPC precursor compounds 5a, 5b, or 6c include: Trans-4-hydroxycinnamic acid was dissolved in an aqueous NaOH solution. Then, an aqueous solution of 2-bromoethanol, 2-[2-(2-chloroethoxy)ethoxy]ethanol, or 3-chloro-1,2-propanediol was slowly added dropwise under heating and stirring. After the reaction was complete, the solution was cooled and diluted, acidified with dilute hydrochloric acid, and then filtered, washed, and purified to obtain compounds 3a, 3b, or 3c, with the following molecular structures: Compounds 3a, 3b, or 3c were dissolved in DMF, and EDCI and HOBt were added and stirred under an ice-water bath. Then, DIPEA and 4-amino-1-(4-(2-methoxyphenyl)piperazine)2-butanol were added. The mixture was removed from the ice-water bath and stirred at room temperature. After the reaction was complete, the solution was adjusted to alkalinity with saturated sodium bicarbonate solution, followed by DCM extraction, drying, extraction, and purification to obtain compounds 4a, 4b, or 4c, with the following molecular structures: Compounds 4a, 4b, or 4c were dissolved in DCM, and triethylamine was added under ice bath conditions. For compound 4c, Bu2SnO was also added. Then, p-toluenesulfonyl chloride was added in portions. The mixture was allowed to rise to room temperature naturally and then stirred. After the reaction was completed, ice water was added to terminate the reaction. The mixture was then extracted with DCM, washed, dried, filtered, and purified to obtain compounds 5a, 5b, or 5c, where compounds 5a and 5b were precursor compounds 5a and 5b. Compound 5c was dissolved in DCM, PPTs and DHP were added, and the mixture was heated and stirred. After the reaction was completed, the mixture was cooled, washed, collected, dried, filtered, and purified to obtain the precursor compound 6c.

4. The preparation method according to claim 2, characterized in that, The steps for preparing FBPB-type precursor compounds 9a, 9b, or 10c include: Benzofuran carboxylic acid was dissolved in an aqueous NaOH solution. Then, an aqueous solution of 2-bromoethanol, 2-[2-(2-chloroethoxy)ethoxy]ethanol, or 3-chloro-1,2-propanediol was slowly added dropwise under heating and stirring. After the reaction was complete, the solution was cooled and diluted, acidified with dilute hydrochloric acid, filtered, and the precipitate was collected, washed, and purified to obtain compounds 7a, 7b, or 7c, with the following molecular structures: Compounds 7a, 7b, or 7c were dissolved in DMF, and EDCI and HOBt were added and stirred in an ice-water bath. Then, DIPEA and 4-amino-1-(4-(2-methoxyphenyl)piperazine)2-butanol were added. The mixture was removed from the ice-water bath and stirred at room temperature. After the reaction was complete, the solution was adjusted to alkalinity with saturated sodium bicarbonate solution, followed by DCM extraction, drying, extraction, and purification to obtain compounds 8a, 8b, or 8c, with the following molecular structures: Compounds 8a, 8b, or 8c were dissolved in DCM, and triethylamine was added under ice bath conditions. For compound 8c, Bu2SnO was also added. Then, p-toluenesulfonyl chloride was added in portions. The mixture was allowed to rise naturally to room temperature and then stirred. After the reaction was completed, ice water was added to terminate the reaction. The mixture was then extracted with DCM, washed, dried, filtered, and purified to obtain compounds 9a, 9b, or 9c, where compounds 9a and 9b were precursor compounds 9a and 9b. Compound 9c was dissolved in DCM, PPTs and DHP were added, and the mixture was heated and stirred. After the reaction was completed, the mixture was cooled, washed, collected, dried, filtered, and purified to obtain precursor compound 10c.

5. The preparation method according to claim 2, characterized in that, The steps for preparing FBNPB-type precursor compounds 14a or 15c include: Benzofuran carboxylic acid was dissolved in an aqueous NaOH solution. Then, an aqueous solution of 2-bromoethanol or 3-chloro-1,2-propanediol was slowly added dropwise under heating and stirring to initiate the reaction. After the reaction was complete, the solution was cooled and diluted, acidified with dilute hydrochloric acid, filtered to collect the precipitate, and washed and purified to obtain compound 7a or 7c, with the following molecular structure: N-(4-bromobutyl)phthalimide, 1-(3-cyanophenyl)piperazine, K2CO3, and NaI were dissolved in anhydrous 1,4-dioxane and stirred under reflux. After the reaction was completed, the mixture was cooled to room temperature, filtered, and purified to obtain compound 11, with the following molecular structure: Compound 11 and hydrazine hydrate were dissolved in ethanol and stirred at room temperature. After the reaction was complete, the solution was removed, the filter residue was diluted, ultrasonically shaken, and then extracted with dichloromethane. The organic phases were combined, washed, dried, and extracted again to obtain compound 12, with the following molecular structure: Compound 7a or 7c was dissolved in DMF, and EDCI and HOBt were added and stirred under an ice-water bath. Then, DIPEA and compound 12 were added, and the mixture was removed from the ice-water bath and stirred at room temperature. After the reaction was complete, the solution was adjusted to alkalinity with saturated sodium bicarbonate solution. Compound 13a or 13c was obtained by DCM extraction, drying, extraction, and purification, with the following molecular structure: Compound 13a or 13c was dissolved in DCM, and triethylamine was added under ice bath conditions. For compound 13c, Bu2SnO was also added. Then, p-toluenesulfonyl chloride was added in portions, and the mixture was allowed to rise naturally to room temperature before stirring. After the reaction was completed, ice water was added to terminate the reaction. After extraction with DCM, washing, drying, filtration, and purification, compound 14a or 14c was obtained. Compound 14a is the precursor compound 14a. Compound 14c was dissolved in DCM, PPTs and DHP were added, and the mixture was heated and stirred. After the reaction was completed, the mixture was cooled, washed, collected, dried, filtered, and purified to obtain precursor compound 15c.

6. The preparation method according to any one of claims 3-5, characterized in that, The precursor compound and [ 18 F]F - The steps involved in a nucleophilic substitution reaction include: Cyclotron bombards oxygen-rich water (H2) 18 O yields radioactive nuclides [ 18 F]F - The anion exchange column is used to [ 18 F]F - Captured on the column and reacted with K2CO3 and phase-transfer catalyst K 222 The rinsing solution will [ 18 F]F - After rinsing, you get [ 18 F]KF solution; under heating conditions, water is removed by blowing nitrogen and adding anhydrous acetonitrile in an azeotropic manner; The precursor compound was dissolved in an anhydrous polar aprotic solution, and then [[ 18 F]F - Nucleophilic substitution reaction was carried out; for precursors with DHP protecting groups, hydrochloric acid solution was added after the reaction to carry out deprotection reaction; after cooling to room temperature, saturated sodium bicarbonate solution was added to neutralize the solution; After the reaction was completed, the mixture was cooled and diluted, and excess water was removed by C18 solid-phase extraction column extraction. 18 F]F - The column was rinsed with water again, the radiolabeled product was eluted with acetonitrile, the solution was concentrated and diluted with the appropriate proportion of high performance liquid chromatography (HPLC) mobile phase, and then separated and purified by semi-preparative HPLC. The fraction purified by HPLC was diluted, and acetonitrile was removed by C18 solid-phase extraction. The column was washed again with water, and the radiolabeled product was eluted with ethanol and then prepared with physiological saline to obtain... 18 F-labeled benzamide phenylpiperazine radioactive compounds.

7. The preparation method according to any one of claims 2-5, characterized in that, Use a synthesizer module for automatic synthesis 18 F-labeled benzamide phenylpiperazine radioactive compounds.

8. The preparation method according to claim 2, characterized in that, Standard compounds 4d, 4e, 4f, 8d, 8e, 8f, 13d, and 13f, containing p-toluenesulfonyl substituents, corresponding to the precursor compounds, were synthesized. 18 The F-labeled benzamide-phenylpiperazine radioactive compounds were compared with corresponding standard compounds to determine... 18 The synthesis of F-labeled benzamide-phenylpiperazine radioactive compounds was correct; among them... The molecular structural formulas of standard compounds 4d, 4e, and 4f are as follows: In the molecular structures of 4d, 4e, and 4f, R2 is CH2CH2F, (CH2CH2O)2CH2CH2F, and CH2CHOHCH2F, respectively. The molecular structural formulas of standard compounds 8d, 8e, and 8f are as follows: In the molecular structures of 8d, 8e, and 8f, R2 is CH2CH2F, (CH2CH2O)2CH2CH2F, and CH2CHOHCH2F, respectively. The molecular structural formulas of standard compounds 13d and 13f are as follows: In the molecular structures of 13d and 13f, R2 is CH2CH2F and CH2CHOHCH2F, respectively.

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