A pet tracer targeting cbr receptor and a preparation method thereof

Abstract

The present application provides a radiolabeled compound targeting cannabinoid receptor type 1 with radionuclide 18F. The present application also provides a method for preparing the compound and its use as a positron emission tomography (PET) imaging agent.

Description

Technical Field

[0001] This invention belongs to the field of radiopharmaceuticals and nuclear medicine technology, specifically relating to a PET tracer targeting cannabinoid receptors, its preparation method, and its uses. Background Technology

[0002] Cannabinoids (CB) include endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Endocannabinoids play important physiological and biochemical functions in organisms, acting as key regulatory nodes in various diseases and neurological disorders, such as neuropathic pain, inflammation, autoimmune diseases, neurodegenerative diseases, cancer, ischemic stroke, gastrointestinal diseases, and cardiovascular diseases. Two cannabinoid receptors have been identified: CB1R (cannabinoid receptor type 1) and CB2R (cannabinoid receptor type 2). CB1R is primarily expressed in central nervous system regions such as the brain.

[0003] Positron emission tomography (PET) is currently the only novel imaging technology that can visualize biomolecular metabolism, receptors, 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; a single whole-body scan can obtain images of all areas of the body. PET is an imaging technique that reflects 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 clear 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.

[0004] PET tracers, also known as PET imaging agents, are radiopharmaceuticals labeled with positron-emitting nuclides. Once introduced into the body, these tracers can accumulate in target organs or tissues, and the emitted radiation is detected by imaging instruments to obtain an image of the drug's distribution within the body, used to diagnose various diseases. Glucose-based PET probes, such as 18-fluorodeoxyglucose (18F-FDG), are the most common positron emission tomography (PET) imaging agents used primarily in clinical research and have been extensively studied in tumor diagnosis and treatment. However, PET imaging also has inherent limitations; it has relatively low spatial resolution and cannot accurately locate lesions.

[0005] Although 18-fluoro-deoxyglucose ( 18 F-FDG) 18The application of F-NaF in cancer is becoming increasingly widespread, but 18-fluoro-deoxyglucose (F-NaF) is still being used. 18 F-FDG) 18 Currently, most clinically used tracers, such as F-NaF, are non-specific, making it difficult to perform specific imaging of specific regions or tissues. This invention provides a specific PET tracer that can bind to cannabinoid receptors in peripheral tissues, the brain, and other tissues. The distribution of this tracer can reflect the distribution of certain cells or molecules within the body, and it holds promise for the early diagnosis and treatment of inflammation, mental illnesses, and other conditions. Therefore, this contrast agent fills the technological gap in specific PET tracers.

[0006] A drug molecule targeting cannabinoid receptor type 1 (CB1R), namely SQKJ-2 shown in the figure below, was reported in the European Journal of Medicinal Chemistry 45 (2010) 1133-1139. It has high affinity and selectivity for cannabinoid receptor type 1.

[0007]

[0008] There is also a need in the field for radiolabeling of cannabinoid receptor type 1 with higher affinity and selectivity, and higher yield and stability. Summary of the Invention

[0009] The inventors have for the first time discovered and prepared an 18-fluorolabeled PET imaging agent that specifically targets cannabinoid receptor type 1. This invention also provides a method for the efficient preparation of said compound.

[0010] Specifically, the present invention provides a compound having the following structural formula:

[0011]

[0012] The compound exhibits high affinity and selectivity for cannabinoid receptor 1 (cannabinoid receptor type 1, CB1 receptor, CB1R). The compound is radioactive and can be used as a tracer, particularly as a PET tracer, and the tracer can target cannabinoid receptor type 1.

[0013] Furthermore, the radioactive compound can be used to prepare tracers for use in the diagnosis of mental illnesses, or it can be prepared by adding pharmaceutically acceptable excipients.

[0014] In another aspect of the invention, a method for preparing the following compounds is provided.

[0015]

[0016] The steps include:

[0017] 1) Compounds 1 and 2 were condensed in tetrahydrofuran as solvent under the action of n-butyllithium at 0–20°C for 2–3 hours. The condensation reaction was then quenched by saturated ammonium chloride aqueous solution, extracted, and concentrated to synthesize compound 3.

[0018]

[0019] 2) Compound 3 reacted with thionyl chloride in dichloromethane under reflux for 4 hours, and the mixture was concentrated to obtain compound 4.

[0020]

[0021] 3) Compounds 4 and 5 were reacted with acetonitrile as solvent under reflux for 12 hours with potassium carbonate as catalyst, and then concentrated to obtain compound 6.

[0022]

[0023] 4) Compound 6 was reacted with hydrochloric acid in 1,4-dioxane as solvent for 5 hours, then extracted with dichloromethane and concentrated to obtain compound 7.

[0024]

[0025] 5) Compound 7 and cyclohexane isocyanate were reacted in tetrahydrofuran as solvent at room temperature for 12 hours under N,N-diisopropylethylamine catalysis. After washing with brine and concentration, compound 9 was obtained.

[0026]

[0027] 6) Compound 9 reacted with 6,10-dioxaspiro[4.5]decadecane-7,9-dione and m-chloroperoxybenzoic acid in chloroform as solvent at room temperature for 2 hours. After treatment with sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate and concentrated to obtain compound 10.

[0028]

[0029] 7) Compound 10 and radioactive fluoride ions (18F-) were placed in a PET thermal synthesis module with acetonitrile as solvent. After a substitution reaction at 100-140℃, the mixture was purified and eluted to obtain the desired product. 18F -SQKJ-2.

[0030]

[0031] This invention also provides the use of the following compounds as PET developers:

[0032]

[0033] In one aspect of the invention, the compound is used as a tracer for CBR receptor type 1.

[0034] In one aspect of the present invention, the method of using the PET tracer includes:

[0035] 1) Administering the subject a radiopharmaceutical composition containing the PET tracer;

[0036] 2) To bind the PET tracer in the radiopharmaceutical composition to cannabinoid type 1 receptors in the subject;

[0037] 3) Detection 18 The signal emitted by F;

[0038] 4) Generate an image representing the position and / or quantity of the signal; and

[0039] 5) Determine the distribution and extent of cannabinoid type 1 receptor expression in the subject, wherein the expression is directly related to the signal.

[0040] The present invention also provides a radiopharmaceutical composition comprising the aforementioned compound as a PET tracer and a biocompatible carrier suitable for administration to mammals.

[0041] In one aspect of the invention, the radiopharmaceutical composition is used for the diagnosis of mental illnesses and inflammatory diseases.

[0042] 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).

[0043] After the administration step and before the detection step, the PET tracer binds to CBR receptor type 1. 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 CBR receptor type 1, a specific interaction occurs, making it more time-consuming to remove the PET tracer from tissue containing CBR receptor type 1 than from tissue containing little or no CBR receptor type 1, thereby enabling the detection of PET tracers specifically bound to CBR receptor type 1. 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 the expression of CBR receptor type 1, allowing for analysis by evaluating the generated images.

[0044] The "subject" in 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. In vivo imaging methods can be used in healthy subjects or in subjects who are known or suspected of having a pathological condition associated with abnormal expression of CBR receptor type 1. Therefore, it can be used as a method for diagnosing related conditions. Examples of conditions related to CBR receptor type 1 that are useful for in vivo imaging include mental illnesses and inflammatory diseases.

[0045] The present invention also provides a compound having the following structural formula:

[0046] Attached Figure Description

[0047] Figure 1 Preparation provided by the present invention 18 Mass spectrometry characterization of compound 10 using the F-SQKJ-2 method.

[0048] Figure 2 The PET tracer of this invention 18 HPLC chromatogram of F-SQKJ-2; signal is present under both radioactive and ultraviolet detectors. Detailed Implementation

[0049] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific examples. These embodiments are only for illustrating the present invention and not for limiting the present invention. Unless otherwise specified, the raw materials and equipment used in the present invention are all known products and can be obtained from commercially available products.

[0050] Example 1: Synthesis of a PET imaging agent specifically targeting cannabinoid receptor type 1

[0051] The paper (European Journal of Medicinal Chemistry 45(2010)1133-1139) reported the molecular structure of a drug targeting cannabinoid receptor type 1, namely SQKJ-2 in the figure below, which has high affinity and selectivity for cannabinoid receptor type 1.

[0052]

[0053] This invention designs, prepares, and verifies a novel PET developer molecule having the following molecular formula, denoted as [molecule name missing]. 18F -SQKJ-2,

[0054]

[0055] This invention provides preparation 18F The method for -SQKJ-2 is as follows:

[0056] 1) Compound 1 and Compound 2 were condensed in tetrahydrofuran as solvent under the action of n-butyllithium at 0-20°C for 2-3 hours, and then quenched, extracted and concentrated by saturated ammonium chloride aqueous solution to synthesize Compound 3.

[0057]

[0058] 2) Compound 3 and thionyl chloride were reacted under reflux for 4 hours with dichloromethane as solvent, and then concentrated to obtain compound 4.

[0059]

[0060] 3) Compound 4 and Compound 5 were reacted with acetonitrile as solvent under reflux for 12 hours with potassium carbonate as catalyst, and then concentrated to obtain Compound 6.

[0061]

[0062] 4) Compound 6 was reacted with hydrochloric acid in 1,4-dioxane as solvent for 5 hours, then extracted with dichloromethane and concentrated to obtain compound 7.

[0063]

[0064] 5) Compound 7 and cyclohexane isocyanate were reacted with tetrahydrofuran as solvent at room temperature for 12 hours under the catalysis of N,N-diisopropylethylamine. After washing with brine and concentration, compound 9 was obtained.

[0065]

[0066] 6) Compound 9 reacted with 6,10-dioxaspiro[4.5]decane-7,9-dione and m-chloroperoxybenzoic acid in chloroform as solvent at room temperature for 2 hours. After treatment with sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate and concentrated to obtain compound 10.

[0067] Its positive ion mode mass spectrometry characterization shows a molecular ion peak m / z = 7440.1176 and a characteristic fragment peak m / z = 572.0721. The characterization spectrum is shown in [reference needed]. Figure 1 .

[0068]

[0069] 6) Compound 10 and radioactive fluoride ions (18F-) were placed in a PET thermal synthesis module with acetonitrile as solvent. After a substitution reaction at 100-140℃, the mixture was purified and eluted to obtain the desired product. 18F -SQKJ-2.

[0070] radioactive products 18F The characterization spectrum of -SQKJ-2 is shown below. Figure 2 .

[0071]

[0072] by 18F -SQKJ-2 was used as a tracer in in vivo experiments on Sprague-Dawley (SD) rats using positron emission tomography / computed tomography (microPET / CT) to obtain... 18F Information on the distribution, aggregation, migration, and metabolism of -SQKJ-2 in vivo.

[0073] The results show that the 18F-labeled compound in this invention possesses PET imaging capabilities. Utilizing its extremely high sensitivity and strong penetrating power, it can be used for imaging analysis of the human body. In particular, the radioactive compound in this invention can target the CB1 receptor, exhibiting selectivity for the CB1 receptor and enabling high-quality imaging of the CB1 receptor. This compound can serve as a specific PET tracer for PET imaging, potentially filling the technological gap in the diagnosis of mental and inflammatory diseases and addressing the lack of PET tracers for these conditions.

[0074] 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 therefore fall within the scope of the invention.

Claims

1. A compound having the following structural formula:

2. Methods for preparing the following compounds, The steps include: 1) Compounds 1 and 2 were condensed in tetrahydrofuran as solvent under the action of n-butyllithium at 0–20°C for 2–3 hours. The condensation reaction was then quenched by saturated ammonium chloride aqueous solution, extracted, and concentrated to synthesize compound 3. 2) Compound 3 reacted with thionyl chloride in dichloromethane under reflux for 4 hours, and the mixture was concentrated to obtain compound 4. 3) Compounds 4 and 5 were reacted with acetonitrile as solvent under reflux for 12 hours with potassium carbonate as catalyst, and then concentrated to obtain compound 6. 4) Compound 6 was reacted with hydrochloric acid in 1,4-dioxane as solvent for 5 hours, then extracted with dichloromethane and concentrated to obtain compound 7. 5) Compound 7 and cyclohexane isocyanate were reacted in tetrahydrofuran as solvent at room temperature for 12 hours under N,N-diisopropylethylamine catalysis. After washing with brine and concentration, compound 9 was obtained. 6) Compound 9 reacted with 6,10-dioxaspiro[4.5]decadecane-7,9-dione and m-chloroperoxybenzoic acid in chloroform as solvent at room temperature for 2 hours. After treatment with sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate and concentrated to obtain compound 10. 7) Compound 10 and radioactive fluoride ion 18F- were placed in a PET thermal synthesis module with acetonitrile as solvent and a substitution reaction was carried out at 100-140℃. After purification and elution, the product was obtained. 18 F-SQKJ-2.

3. Use of the compound as defined in claim 1 for preparing a PET developer.

4. The use according to claim 3, wherein the compound is used as a tracer for CBR receptor type 1.

5. The use of claim 3, 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 1 receptors in the subject; 3) Testing 18 The signal emitted by F; 4) Generate an image representing the position and / or quantity of the signal; and 5) Determine the distribution and extent of cannabinoid type 1 receptor expression in the subject, wherein the expression is directly related to the signal.

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

7. A compound having the following structural formula:

Images