Novel pet imaging agents targeting cannabinoid type 2 receptor and preparation method and application thereof

Abstract

The present invention provides a radiolabeled compound targeting cannabinoid receptor type 2 labeled with the radionuclide 18F. The present invention also provides a process for the preparation of said compound and its use as a positron emission tomography (PET) imaging agent.

Description

Novel PET Imaging Agents Targeting Cannabinoid Type 2 Receptors, Their Preparation Methods and Applications Technical Field

[0001] This invention relates to the field of medical technology. Specifically, this invention relates to a triarylsulfonamide derivative labeled with the radionuclide 18F, its preparation method, and its application as a positron emission tomography (PET) imaging agent with the ability to target cannabinoid type 2 receptors. Background Technology

[0002] Cannabinoids (CB) include endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Among them, endocannabinoids have important physiological and biochemical functions in organisms and play a key regulatory role in a variety of diseases and neurological disorders, such as neuropathic pain, inflammation, autoimmune diseases, neurodegenerative diseases, cancer, ischemic stroke, gastrointestinal diseases, and cardiovascular diseases.

[0003] Two cannabinoid receptors have been identified, namely CB1R and CB2R. CB1R is mainly expressed in central regions such as the brain, while CB2R is mainly expressed in peripheral cells and tissues derived from the immune system. Over the past few decades, researchers have found that drugs designed to target CB1R often cause significant psychiatric side effects, while drugs selectively targeting CB2R face fewer of these problems, and an increasing number of diseases are being found to have pathogenesis and mechanisms closely related to CB2R.

[0004] Typically, research on CB2R relies heavily on in vitro or ex vivo experiments, lacking methods for in vivo visualization of cannabinoid type 2 receptors. Positron emission tomography (PET) is currently the only novel imaging technique capable of displaying biomolecular metabolism, receptor activity, and neurotransmitter activity in vivo. It is now widely used in the diagnosis and differential diagnosis of various diseases, efficacy evaluation, organ function research, and new drug development. PET imaging technology boasts high sensitivity, high specificity, and strong penetration. Furthermore, it can provide whole-body imaging, allowing for images of all areas of the body in a single examination. PET is an imaging technique reflecting molecular metabolism. When a disease is in its early stages, at the molecular level, and the morphology and structure of the lesion area are not yet abnormal, and MRI and CT scans cannot provide a definitive diagnosis, PET examination can detect the lesion, obtain three-dimensional images, and perform quantitative analysis, enabling early diagnosis—a capability currently unmatched by other imaging examinations.

[0005] PET probes, also known as PET imaging agents, are radiopharmaceuticals that, once introduced into the body, can perform imaging of organs, tissues, or molecules. After introduction, these radiopharmaceuticals accumulate in target organs or tissues. Imaging instruments detect the emitted radiation, thus obtaining images of the drug's distribution within the body, which are used to diagnose various diseases. PET probes include glucose-based probes, primarily used in clinical research. For example, 18-fluorodeoxyglucose (18F-FDG) is the most common PET imaging agent and has been extensively studied in tumor diagnosis and treatment.

[0006] There is also a need in this field for radiolabeling with higher affinity and selectivity for cannabinoid type 2 receptors, as well as higher yield and stability. Summary of the Invention

[0007] The inventors have for the first time discovered and prepared an 18-fluoro-labeled triarylsulfonamide derivative compound and demonstrated its potential as a PET imaging agent specifically targeting cannabinoid type 2 receptors. This invention also provides a method for the efficient preparation of said compound.

[0008] Specifically, the present invention provides a compound having the following structural formula:

[0009]

[0010] This invention also provides a method for preparing the compound of formula I, which is a two-step synthetic process, and the synthetic process flow is as follows:

[0011]

[0012] In one aspect of the invention, the method includes the following steps:

[0013] (1) In the presence of a phase transfer catalyst, 2-bromoethyltrifluoromethane (BrCH2CH2OTf), o-dichlorobenzene and a radioactive fluorine source containing [18F]F ions are reacted in an alkaline solution at about 110°C to 150°C to generate [18F]FCH2CH2Br.

[0014] (2) Add the [18F]FCH2CH2Br obtained in step 1 to... In a polar aprotic solution, the reaction is carried out at approximately 100°C to 160°C to obtain

[0015] Specifically, the above method may include the following steps:

[0016] Oxy-octadecyl water containing [18F]F ions is adsorbed by an anion exchange resin to adsorb [18F]F ions. The [18F]F ions are then washed into the reaction flask using an eluent containing alkaline substances (e.g., a solution containing potassium carbonate, potassium acetate, cesium carbonate, tetraalkylammonium bicarbonate, etc.). Anhydrous acetonitrile solution is then added to the reaction flask. Depending on the composition of the eluent, a phase transfer catalyst (e.g., cryptether K222, 18-crown ether-6, etc.) can be selectively added to the reaction flask. The solvent in the reaction flask is removed by azeotropic distillation of water and acetonitrile at approximately 90-120°C, under normal or reduced pressure, to obtain a dry radioactive fluorine source containing [18F]F ions.

[0017] 2-Bromoethyltrifluoromethane (BrCH2CH2OTf) was prepared into a solution using o-dichlorobenzene reagent and added to the reaction flask of the previous step. The reaction was carried out in a sealed reaction flask at 110°C to 150°C for 3 to 20 minutes. Then, an inert gas was introduced into the reaction flask, and the generated [18F]FCH2CH2Br was distilled into a gas containing... In an anhydrous polar aprotic solvent (0.2 mg / mL to 40 mg / mL, solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc.), the solution is heated at approximately 100°C to 160°C for approximately 10 to 40 minutes to obtain a solution containing... The solution.

[0018] Optionally, the above-mentioned substances containing [specific substances] can be analyzed by high-performance liquid chromatography. The solution was separated and purified.

[0019] The present invention also provides another method for preparing the compound of formula I above, which is a one-step synthesis process, and the synthesis process flow is as follows:

[0020]

[0021] In one aspect of the invention, the method includes, in the presence of a phase-transfer catalyst, […]. A solution in a polar aprotic solvent reacts with a radioactive fluorine source containing [18F]F ions under alkaline conditions at approximately 90°C to 165°C to produce...

[0022]

[0023] Specifically, the above method may include the following steps:

[0024] Oxy-octadecyl water containing [18F]F ions is adsorbed by an anion exchange resin to adsorb [18F]F ions. The [18F]F ions are then washed into the reaction flask using an eluent containing alkaline substances (e.g., a solution containing potassium carbonate, potassium acetate, cesium carbonate, tetraalkylammonium bicarbonate, etc.). Anhydrous acetonitrile solution is then added to the reaction flask. Depending on the composition of the eluent, a phase transfer catalyst (e.g., cryptether K222, 18-crown ether-6, etc.) can be selectively added to the reaction flask. The solvent in the reaction flask is removed by azeotropic distillation of water and acetonitrile at approximately 90-120°C, under normal or reduced pressure, to obtain a dry radioactive fluorine source containing [18F]F ions.

[0025] Will A solution prepared using an anhydrous polar aprotic solvent (such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.) is added to the aforementioned reaction flask. The reaction is carried out in a sealed reaction flask at approximately 90°C to 165°C for approximately 5 to 40 minutes. The resulting product contains... The crude product solution.

[0026] Optionally, the above-mentioned substances containing [specific substances] can be analyzed by high-performance liquid chromatography. The solution was separated and purified.

[0027] The present invention also provides a precursor compound for preparing the compound of formula I above, having the following structural formula:

[0028]

[0029] The present invention also provides a method for preparing compounds of formula II above, said method by passing the compound... It is obtained by reacting with di(p-toluenesulfonate) ethylene glycol (TsOCH2CH2OTs).

[0030] In one aspect of the invention, the method includes: Dissolved in anhydrous organic solvents (acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, etc.), approximately 1.1 to 10 equivalents of base (cesium carbonate, potassium carbonate, potassium acetate, etc.) are added, along with approximately 0.9 to 3 equivalents of ethylene di-p-toluenesulfonate (TsOCH2CH2OTs). The reaction is carried out at room temperature for approximately 2 to 36 hours to obtain a product containing... The solution.

[0031] Optionally, the above-mentioned substances containing [specific substances] can be analyzed by extraction and chromatography. The solution was separated and purified, for example by diluting with ethyl acetate, extracting with equal volumes of water and saturated sodium chloride solution, retaining the organic layer, drying with anhydrous sodium sulfate, filtering, removing the solvent by rotary evaporation, and purifying with rapid chromatography (silica packing, ethyl acetate-petroleum ether washing system) to obtain purified TsO-EOTB.

[0032] The present invention also provides a compound having the following structural formula:

[0033]

[0034] The present invention also provides a method for preparing the above-described compound III, wherein the method involves passing the compound... It is obtained by reacting with fluoroethyl p-toluenesulfonate (FCH2CH2OTs).

[0035] The present invention also provides a radiopharmaceutical composition comprising the aforementioned compound of formula I as a PET tracer, and a biocompatible carrier suitable for administration to mammals.

[0036] "Biocompatible carriers" are generally fluids, especially liquids, in which the PET tracer of the present invention is suspended or dissolved, making the radiopharmaceutical composition physiologically tolerable, for example, administerable to mammals without toxicity or excessive discomfort. Suitable biocompatible carriers are injectable carrier liquids, such as sterile, pyrogen-free water for injection; aqueous solutions, such as saline (which can advantageously balance so that the final product for injection is isotonic or non-hypotonic); aqueous solutions of one or more stress-regulating substances (e.g., salts of plasma cations and biocompatible counter-charge ions), sugars (e.g., glucose or sucrose), sugar alcohols (e.g., sorbitol or mannitol), glycols (e.g., glycerol), or other nonionic polyol materials (e.g., polyethylene glycol, polypropylene glycol, etc.). Biocompatible carriers may also contain biocompatible organic solvents, such as ethanol. Such organic solvents can be used to solubilize more lipophilic compounds or formulations. Preferred biocompatible carriers are pyrogen-free water for injection, isotonic saline, or aqueous ethanol solutions. The pH range for biocompatible carriers used for intravenous injection is preferably 4.0-10.5.

[0037] Radiopharmaceutical compositions can be administered parenterally, i.e., by injection, preferably in aqueous solutions. Such compositions may optionally contain additional components, such as buffers; pharmaceutically acceptable solubilizers (e.g., cyclodextrins or surfactants, such as prullanic, Tween, or phospholipids); and pharmaceutically acceptable stabilizers or antioxidants (e.g., ethanol, ascorbic acid, 2,5-dihydroxybenzoic acid, or para-aminobenzoic acid).

[0038] The compound of formula I provided by this invention can be used as a PET tracer for detecting cannabinoid type 2 receptor expression in subjects in vivo. This invention also provides the use of the aforementioned compound of formula I as a PET tracer, wherein the compound is used as a tracer to determine the distribution and / or extent of cannabinoid type 2 receptor expression in subjects.

[0039] In one aspect of the present invention, the method of using the PET tracer may include:

[0040] 1) Administering the subject a radiopharmaceutical composition containing the PET tracer;

[0041] 2) To allow the PET tracer in the radiopharmaceutical composition to bind to cannabinoid type 2 receptors in the subject;

[0042] 3) Detection 18 The signal emitted by F;

[0043] 4) Generate an image representing the position and / or quantity of the signal; and

[0044] 5) Determine the distribution and extent of cannabinoid type 2 receptor expression in the subject, wherein the expression is directly related to the signal.

[0045] The administration of the PET tracer is preferably performed parenterally, and most preferably intravenously. The intravenous route represents the most efficient way to deliver the PET tracer throughout the subject's body, thus also crossing the blood-brain barrier (BBB) ​​and contacting the PBR expressed in the subject's central nervous system (CNS).

[0046] After the administration step and before the detection step, the PET tracer binds to cannabinoid type 2 receptors. For example, when the subject is a mammal, the PET tracer dynamically moves through the mammal's body, contacting various tissues therein. Once the PET tracer contacts the cannabinoid type 2 receptors, a specific interaction occurs, making it take longer to remove the PET tracer from tissues containing cannabinoid type 2 receptors than from tissues containing few or no cannabinoid type 2 receptors, thereby enabling the detection of PET tracers specifically bound to cannabinoid type 2 receptors. The signal emitted by 18F contained in the PET tracer can be detected by a detector sensitive to the signal (i.e., a PET camera). A reconstruction algorithm can be applied to the obtained signal data by computer to obtain a dataset. This dataset is then processed to produce an image showing the location and / or amount of the signal emitted by 18F. The emitted signal is directly correlated with PBR expression, allowing for analysis by evaluating the generated images.

[0047] The "subject" of this invention can be any human or animal subject. Preferably, the subject of this invention is a mammal. In a particularly preferred embodiment, the subject of this invention is a human. The in vivo imaging method can be used in healthy subjects or in subjects with known or suspected pathological conditions associated with abnormal expression of cannabinoid type 2 receptors. Thus, it can be used as a method for diagnosing related conditions. Examples of conditions related to cannabinoid type 2 receptors that are useful for in vivo imaging include neuropathic pain, inflammation, autoimmune diseases, neurodegenerative diseases, cancer, ischemic stroke, gastrointestinal diseases, cardiovascular diseases, etc. The PET tracer of this invention is particularly suitable for in vivo imaging of the CNS due to its good brain absorption. Attached Figure Description

[0048] Figure 1 shows the gamma signal spectrum of the 18F-EOTB product purified by liquid chromatography in an exemplary two-step synthesis process of 18F-EOTB using the auxiliary group method provided by the present invention.

[0049] Figure 2 shows an exemplary proton NMR spectrum of TsO-EOTB obtained by the process of preparing TsO-EOTB from HOTB provided by the present invention.

[0050] Figure 3 shows one of the quality control methods for the 18F-EOTB prepared according to the present invention. Figure 3 is an analytical liquid chromatogram of a mixture of 18F-EOTB and 19F-EOTB.

[0051] Figure 4 shows the stability analysis of 18F-EOTB prepared in this invention in rat serum. Figure 4 is an analytical liquid chromatogram of 18F-EOTB in rat serum.

[0052] Figure 5 shows a microPET / CT image of 18F-EOTB prepared in this invention as a tracer in rats. The PET data were reconstructed into a three-dimensional sine wave to obtain the enrichment and distribution of the tracer probe in rats during a 90-minute scan. Detailed Implementation

[0053] The following will further illustrate the essence and beneficial effects of the present invention with reference to embodiments. These embodiments are only used to illustrate the present invention and are not intended to limit the present invention.

[0054] Unless otherwise specified, the raw materials and equipment used in the following examples are all known products and can be obtained from commercially available products, such as those purchased from Sigma-Aldrich of Merck, Germany.

[0055] Example 1: Design and synthesis scheme of PET imaging agent specifically targeting cannabinoid type 2 receptor

[0056] The paper (Journal of Medicinal Chemistry, 2013, vol. 56, #5, pp. 2045-2058) reported a series of drug molecular structures targeting cannabinoid type 2 receptors. Among them, the following compound (referred to as MOTB) was reported, exhibiting high affinity and selectivity for cannabinoid type 2 receptors:

[0057]

[0058] This invention designs a novel PET developer molecule: N-(4-(diethylamino)benzyl)-4-(2-(18-fluoro)ethoxy)-N-(p-tolyl)benzenesulfonamide, denoted as 18F-EOTB, with the following molecular structure:

[0059]

[0060] This invention provides two methods for preparing 18F-EOTB, including processes for precursor synthesis and radioactive synthesis, namely a two-step synthesis process using a cofactor method and a one-step synthesis process using a direct nucleophilic substitution method.

[0061] Synthesis process one is a two-step auxiliary group method, and the process route is as follows:

[0062]

[0063] The starting compound used, (4-(diethylamino)benzyl)-4-hydroxy-N-(p-tolyl)benzenesulfonamide, denoted as HOTB, has the following structural formula:

[0064]

[0065] The synthesis of HOTB can be found in the paper [Applied Radiation and Isotopes, 2014, vol. 90, p. 181-186].

[0066] Synthesis process two is a direct nucleophilic substitution method, and the process route is as follows:

[0067]

[0068] The starting compound used, 2-(4-(N-(4-(diethylamino)benzyl)-N-(p-tolyl)sulfonamide)phenoxy)ethyl-4-methylbenzenesulfonate, denoted as TsO-EOTB, has the following structural formula:

[0069]

[0070] TsO-EOTB can be prepared by various processes, one of which is a synthetic process starting with HOTB:

[0071]

[0072] Example 2: Two-step synthesis of 18F-EOTB via a prosthetic group method

[0073] The prosthetic route for the two-step synthesis of 18F-EOTB using HOTB as the starting compound is as follows:

[0074]

[0075] Process route for preparing 18F-EOTB from HOTB via a cofactor method

[0076] The synthesis of 18F-EOTB was carried out according to the above route, including the following main experimental steps:

[0077] A cyclotron produces oxo-octadecyl water containing [18F]F ions. The [18F]F ions are adsorbed by an anion exchange resin. The [18F]F ions are then washed into the reaction flask using an eluent containing alkaline substances (such as a solution containing potassium carbonate, potassium acetate, cesium carbonate, tetraalkylammonium bicarbonate, etc.; potassium carbonate was used in this experiment). Anhydrous acetonitrile solution is then added to the reaction flask. Depending on the composition of the eluent, a phase transfer catalyst (such as cryptether K222, 18-crown ether-6, etc.; cryptether K222 was used in this experiment) can be selectively added to the reaction flask. The solvent in the reaction flask is removed by azeotropic distillation of water and acetonitrile at 90-120°C and under normal or reduced pressure. Anhydrous acetonitrile solution is added 1 to 4 times during this process to ensure complete solvent removal, yielding a dry radioactive fluorine source containing [18F]F ions.

[0078] 1 mg to 15 mg of 2-bromoethyltrifluoromethane (BrCH2CH2OTf) was dissolved in 0.1 mL to 2 mL of o-dichlorobenzene reagent and added to a reaction flask. The reaction was carried out in a sealed reaction flask at 110°C to 150°C for 3 to 20 minutes. Then, an inert gas was introduced into the reaction flask, and the generated [18F]FCH2CH2Br was distilled into the solution of the next reaction flask at 130°C. The solution in the next reaction flask was prepared using 1 mg to 20 mg of HOTB (prepared according to the method described in the paper [Applied Radiation and Isotopes, 2014, vol. 90, pp. 181-186]) and anhydrous polar aprotic solvent (0.2 mg / mL to 40 mg / mL, including acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc., with acetonitrile used in the experiment). After the radioactivity of the solution reaches its maximum, the reaction mixture is heated at 100°C to 160°C for 10 to 40 minutes to obtain a crude product solution containing 18F-EOTB.

[0079] The crude product solution was diluted using the mobile phase solution of high-performance liquid chromatography (HPLC), followed by separation and purification of the product using semi-preparative HPLC. The fraction containing high-purity 18F-EOTB was collected. Its gamma signal spectrum is shown in Figure 1. The solvent was further removed by vacuum distillation, and the product was redissolved in 4.5 mL of saturated saline solution containing 10 mg ascorbic acid and 0.5 mL of ethanol. The solution was then filtered through a sterile membrane with a particle size of 0.22 μm to obtain the final 18F-EOTB solution. The entire process took 78 to 85 minutes. The yield was calculated to be approximately 16% to 38% using the following formula: Radioactive uncorrected yield = (Activity of the purified product / Activity of the fluorine source at the start of synthesis) * 100%.

[0080] Example 3: One-step synthesis of 18F-EOTB via direct nucleophilic substitution

[0081] The nucleophilic substitution process for the one-step synthesis of 18F-EOTB using TsO-EOTB as the starting compound is as follows:

[0082]

[0083] The starting compound TsO-EOTB was provided. The main steps in preparing TsO-EOTB in this experiment are as follows:

[0084] One equivalent of HOTB was dissolved in an anhydrous organic solvent (acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, etc., acetonitrile was used in the experiment). 1.1 to 10 equivalents of alkali (cesium carbonate, potassium carbonate, potassium acetate, etc., potassium carbonate was used in the experiment) were added to the HOTB solution, and the mixture was stirred at room temperature for 15 minutes to 1 hour. The mixture was cooled to 0°C (down to -20°C), and 0.9 to 3 equivalents of ethylene di-p-toluenesulfonate (TsOCH2CH2OTs) were slowly added to the mixture while stirring. After the addition was complete, the mixture was gradually brought back to room temperature and stirred for 2 to 36 hours. After the reaction was complete, ethyl acetate was added for dilution, and the mixture was extracted twice each with equal volumes of water and saturated sodium chloride solution. The organic layer was retained, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The purified TsO-EOTB was obtained by rapid chromatography (silica packing material, ethyl acetate-petroleum ether washing system).

[0085] The synthesized TsO-EOTB was confirmed using 1H NMR spectroscopy and mass spectrometry. The 1H NMR data of the prepared TsO-EOTB are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.82(d,J=8.3Hz,2H),7.55(d,J=8.8Hz,2H),7.36(d,J= 8.0Hz,2H),7.00(d,J=8.1Hz,4H),6.82(dd,J=8.6,2.8Hz,4H),6.50(d,J=8.3Hz,2H),4 .56(s,2H),4.39(dd,J=5.7,3.5Hz,2H),4.22(dd,J=5.6,3.5Hz,2H),3.28(q,J=7.0Hz ,4H),2.46(s,3H),2.27(s,3H),1.10(t,J=7.0Hz,6H).ESI-MS([M+H]+)(m / z=623.22).

[0086] The synthesis of 18F-EOTB was carried out according to the aforementioned nucleophilic substitution synthetic route, including the following main experimental steps:

[0087] A radioactive fluorine source containing [18F]F ions was prepared using the same method as in Example 2. Specifically, a cyclotron produced oxooctadecyl hydroxide containing [18F]F ions. The [18F]F ions were adsorbed onto an anion exchange resin. The [18F]F ions were then washed into a reaction flask using an eluent containing an alkaline substance (such as a solution containing potassium carbonate, potassium acetate, cesium carbonate, tetraalkylammonium bicarbonate, etc.; potassium carbonate was used in this experiment). Anhydrous acetonitrile solution was then added to the reaction flask. Depending on the composition of the eluent, a phase transfer catalyst (such as cryptether K222, 18-crown ether-6, etc.; cryptether K222 was used in this experiment) could be selectively added to the reaction flask. The solvent in the reaction flask was removed by azeotropic distillation of water and acetonitrile at 90-120°C, under normal or reduced pressure. Anhydrous acetonitrile solution was added 1 to 4 times during this process to ensure complete solvent removal, resulting in a dry radioactive fluorine source containing [18F]F ions.

[0088] 1 mg to 30 mg of TsO-EOTB was dissolved in 0.1 mL to 2 mL of anhydrous polar aprotic solvent (including acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.; anhydrous acetonitrile was used in the experiment) and added to the reaction flask. The reaction was carried out in a closed reaction flask at 90°C to 165°C for 5 to 40 minutes. A crude product solution containing 18F-EOTB was obtained.

[0089] The crude product solution was processed using the same method as in Example 2. The crude product solution was diluted with the mobile phase solution of high-performance liquid chromatography (HPLC), and then the product was separated and purified using semi-preparative HPLC. The fraction containing high-purity 18F-EOTB was collected, and the solvent was removed by vacuum distillation. The solution was then redissolved in 4.5 mL of saturated saline solution containing 10 mg ascorbic acid and 0.5 mL of ethanol, and filtered through a sterile membrane with a particle size of 0.22 micrometers to obtain the final 18F-EOTB solution.

[0090] The entire process takes 55 to 65 minutes, and the final yield, calculated using radioactive uncorrected yield, is approximately 31% to 61%.

[0091] Example 4: Quality control of 18F-EOTB using a high-performance liquid chromatography system

[0092] 1. N-(4-(diethylamino)benzyl)-4-(2-(fluoro)ethoxy)-N-(p-tolyl)benzenesulfonamide (denoted as 19F-EOTB) was used as a non-radioactive comparison standard:

[0093]

[0094] The synthetic route of 19F-EOTB is as follows:

[0095]

[0096] The synthesis process of TsO-EOTB from HOTB in Example 3 was followed, except that the raw material di(p-toluenesulfonate) (TsOCH2CH2OTs) was replaced with fluoroethyl(p-toluenesulfonate) (FCH2CH2OTs).

[0097] The synthesis of 19F-EOTB was confirmed using 1H NMR spectroscopy and mass spectrometry. The 1H NMR data of the prepared 19F-EOTB are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.66–7.59(m,2H),7.21(dt,J=7.4,1.0Hz,2H) ,7.14–7.05(m,5H),7.05–7.01(m,1H),6.86–6.79(m,2H),4.84(t,J=1.0Hz, 2H),4.72(t,J=7.1Hz,1H),4.60(t,J=7.1Hz,1H),4.27(t,J=7.1Hz,1H),4.2 1(t,J=7.1Hz,1H),3.24(q,J=8.0Hz,4H),2.34(s,3H),1.13(t,J=8.0Hz,6H).

[0098] 2. Quality control of 18F-EOTB:

[0099] (1) By mixing 1 mCi of 18F-EOTB injection (red peak line) with 1 mg of non-radioactive 19F-EOTB (black peak line) and diluting with 1 mL of eluent (0.6 mL acetonitrile, 0.4 mL water), the solution was analyzed by analytical high-performance liquid chromatography (Waters 2695, Sunfire C18 column). (5μm, 4.6mm x 250mm). The retention time difference between products 18F-EOTB and 19F-EOTB was confirmed to be within 0.1 minutes. Simultaneously, the radiochemical purity of 18F-EOTB was detected to exceed 99%. This demonstrates the successful preparation of 18F-EOTB and that the purity meets the requirements. See Figure 3 for the results.

[0100] (2) A small amount of the prepared 18F-EOTB injection solution was added to 10 times its volume of rat serum and stirred at 37°C (550 rpm) for 0, 30, 90, and 180 minutes. At each time point, 1 / 10 volume of the solution was taken out, diluted with 10% ethanol saline solution, and analyzed for radiochemical purity using a high-performance liquid chromatography system equipped with a radioactive gamma ray detection probe. The results are shown in Figure 4. This demonstrates that the 18F-EOTB injection solution maintains extremely high stability (radiochemical purity higher than 98%) throughout the 180-minute period.

[0101] Example 5: MicroPET / CT using 18F-EOTB as a tracer in animals

[0102] The first in vivo experiment using 18F-EOTB as a tracer was conducted. Positron emission tomography / computed tomography (microPET / CT) was performed on Sprague-Dawley (SD) rats to obtain information on the distribution, aggregation, migration, and metabolism of 18F-EOTB in vivo.

[0103] SD rats were anesthetized with 2%-2.5% isoflurane in O2 at a flow rate of 1.5 L / min. 18F-EOTB (500 μL, 22 MBq-33 MBq) was injected into the SD rats via the tail vein. A 90-minute dynamic scan was performed using a Super-Argus micro PET / CT (Sedecal, Spain). After the experiment, the PET data were reconstructed into a three-dimensional sine wave, ultimately revealing the enrichment and distribution of the probe during the 90-minute scan.

[0104] The results are shown in Figure 5. The results indicate that the imaging agent was highly uptaken in the liver, intestine, and spleen, and minimally uptaken in the bladder, kidney, and brain. Furthermore, no bone uptake was observed during the scanning process, verifying that the probe did not undergo radioactive defluorination in live SD rats, meaning that 18F-EOTB maintains extremely high metabolic stability in vivo.

[0105] The above results demonstrate that the 18F-EOTB provided by this invention successfully labeled radionuclides while retaining affinity for cannabinoid type 2 receptors. 18 F, when the research target is related to cannabinoid type 2 receptors, can be used as a PET imaging agent for visualization in animals. The novel PET imaging agent provided by this invention can play an important role in disease diagnosis, pathological research, and efficacy evaluation, and can significantly reduce the consumption of human and material resources, and accelerate research progress or drug development.

[0106] The foregoing description of the present invention should not be construed as limiting it. Unless otherwise indicated, the present invention will be practiced using conventional techniques such as organic chemistry, polymer chemistry, and biotechnology, and it is obvious that the invention can be implemented in other ways besides those specifically described in the foregoing description and examples. Other aspects and modifications within the scope of the invention will be apparent to those skilled in the art. Many changes and variations are possible based on the teachings of the present invention and are therefore within its scope.

Claims

1. A compound having the following structural formula:

2. A method for preparing the compound as defined in claim 1, the method comprising the following steps: (1) In the presence of a phase transfer catalyst, BrCH2CH2OTf, o-dichlorobenzene and containing 18 The radioactive fluorine source of F ions reacts in an alkaline solution at 110°C to 150°C to generate 18 FCH2CH2Br; (2) The product obtained in step 1 18 FCH2CH2Br was added to In a polar aprotic solution, the reaction is carried out at 100°C to 160°C to obtain 3. A method for preparing the compound as defined in claim 1, the method comprising the following steps: contain 18 F-ion-containing oxoadecane is adsorbed by anion exchange resin. 18 F ions, using a rinsing solution containing alkaline substances to... 18 F ions are flushed into the reaction flask, and then anhydrous acetonitrile solution is added. Depending on the composition of the eluent, a phase transfer catalyst may be selectively added to the reaction flask. The solvent in the reaction flask is removed by azeotropic distillation of water and acetonitrile at 90-120°C, under normal or reduced pressure, yielding a dry product containing... 18 A radioactive fluorine source for F ions; BrCH2CH2OTf is prepared into a solution using o-dichlorobenzene reagent and added to the reaction flask of the previous step, reacting in a sealed reaction flask at 110°C to 150°C for 3 to 20 minutes; then an inert gas is introduced into the reaction flask, and the generated ions are reacted at 130°C. 18 FCH2CH2Br was introduced into a solution via distillation. In an anhydrous polar aprotic solvent solution, heating at 100°C to 160°C for 10 to 40 minutes yields a solution containing... The solution, optionally, can be analyzed by high-performance liquid chromatography (HPLC) to detect the above-mentioned substances containing... The solution was separated and purified.

4. A method for preparing the compound as defined in claim 1, the method comprising, in the presence of a phase transfer catalyst, […]. polar aprotic solutions and solutions containing 18 The radioactive fluorine source of F ions reacts in an alkaline solution at temperatures between 90°C and 165°C to generate F ions.

5. A method for preparing the compound as defined in claim 1, the method comprising the following steps: contain 18 F-ion-containing oxoadecane is adsorbed by anion exchange resin. 18 F ions, using a rinsing solution containing alkaline substances to... 18 F ions are flushed into the reaction flask, and then anhydrous acetonitrile solution is added. Depending on the composition of the eluent, a phase transfer catalyst may be selectively added to the reaction flask. The solvent in the reaction flask is removed by azeotropic distillation of water and acetonitrile at 90-120°C, under normal or reduced pressure, yielding a dry product containing... 18 A radioactive fluorine source for F ions; A solution prepared with an anhydrous polar aprotic solvent was added to the aforementioned reaction flask, and the reaction was carried out in a sealed reaction flask at 90°C to 165°C for 5 to 40 minutes to obtain a product containing... The crude product solution, optionally, can be analyzed by high-performance liquid chromatography (HPLC) to determine the presence of the above-mentioned components. The solution was separated and purified.

6. A precursor compound for preparing the compound defined in claim 1, having the following structural formula:

7. A method for preparing the compound as defined in claim 6, said method by passing the compound... It is obtained by reacting with di(p-toluenesulfonate) ethylene glycol TsOCH2CH2OTs.

8. A method for preparing the compound as defined in claim 6, the method comprising: Will Dissolved in an anhydrous organic solvent, 1.1 to 10 equivalents of base were added, along with 0.9 to 3 equivalents of ethylene di-p-toluenesulfonate. The mixture was reacted at room temperature for 2 to 36 hours to obtain a product containing... A solution containing; optionally, the above-mentioned solution can be obtained by extraction and chromatography. The solution was separated and purified by dilution with ethyl acetate, followed by extraction with equal volumes of water and saturated sodium chloride solution, retaining the organic layer, drying with anhydrous sodium sulfate, filtering, removing the solvent by rotary evaporation, and purifying by rapid chromatography to obtain the purified product.

9. A compound having the following structural formula:

10. Methods for preparing the following compounds, The method uses compounds It is obtained by reacting with fluoroethyl p-toluenesulfonate.

11. A radiopharmaceutical composition comprising a compound as defined in claim 1 as a PET tracer, and a biocompatible carrier suitable for administration to mammals.

12. Use of the compound as defined in claim 1 in the preparation of a PET tracer, wherein the compound is used as a tracer for determining the distribution and / or extent of cannabinoid type 2 receptor expression in a subject.

13. The use of claim 12, wherein the method of using the PET tracer comprises: 1) Administering the subject a radiopharmaceutical composition containing the PET tracer; 2) To bind the PET tracer in the radiopharmaceutical composition to cannabinoid type 2 receptors in the subject; 3) To detect 18 F) emits a signal; 4) generates an image representing the location and / or amount of the signal; and 5) determines the distribution and extent of cannabinoid type 2 receptor expression in the subject, wherein the expression is directly related to the signal.

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