MAGL inhibitors

Abstract

The present invention provides novel reversible MAGL inhibitors useful for the treatment or prevention of diseases or conditions associated with monoacylglycerol lipase (MAGL). The reversible MAGL inhibitors according to the present invention may also be labeled with a radioisotope and thus are useful for medical imaging such as positron emission tomography (PET) and / or autoradiography.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to organic compounds useful for the treatment or prevention of diseases or symptoms related to MAGL in mammals, particularly monoacylglycerol lipase (MAGL) inhibitors for treating or preventing MAGL-related diseases or symptoms in mammals. The present invention further relates to radiolabeled MAGL inhibitors useful for medical imaging such as positron emission tomography (PET) and / or autoradiography. [Background technology]

[0002] Background of the Invention Monoacylglycerol lipase (MAGL) is a serine hydrolase highly expressed in the central nervous system (CNS) and several peripheral organs (Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C. cDNA Cloning, Tissue Distribution, and Identification of the Catalytic Triad of Monoglyceride Lipase. J Biol Chem. 1997;272:27218-27223; Dinh TP, Carpenter D, Leslie FM, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci. 2002;99:10819-10824). MAGL plays a fundamental role in regulating endocannabinoid and lipid levels in physiological and pathological symptoms (Blankman JL, Simon GM, Cravatt BF. A Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2-Arachidonoylglycerol. Chem Biol. 2007;14:1347-1356). As a result, MAGL inhibitors are of great interest and represent potential therapeutic agents for the treatment of multiple diseases, including neurodegeneration, psychiatric disorders, and cancer (Gil-Ordonez A, Martin-Fontecha M, Ortega-Gutierrez S, Lopez-Rodriguez ML. Monoacylglycerol lipase (MAGL) as a promising therapeutic target. Biochem Pharmacol. 2018;157:18-32).

[0003] Positron emission tomography (PET), as a non-invasive imaging technique, supports drug discovery and development by providing valuable information on drug-target engagement, drug access, and procedure monitoring (Hou L, Rong J, Haider A, et al. Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development. 2020; 6). Early developed MAGL radioligands were mainly irreversible, for example, [ 11 C]MA-PB(Ahamed M, Attili B, van Veghel D, et al.Synthesis and preclinical evaluation of [ 11 C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase(MAGL).Eur J Med Chem.2017;136:104-113), [ 11 C]SAR127303(Wang L,Mori W,Cheng R,et al.Synthesis and Preclinical Evaluation of Sulfonamido-based [ 11 C-Carbonyl]-Carbamates and Ureas for Imaging Monoacylglycerol Lipase.Theranostics.2016;6:1145-1159), [ 11 C]PF-06809247(Zhang L,Butler CR,Maresca KP,et al.Identification and Development of an Irreversible Monoacylglycerol Lipase(MAGL)Positron Emission Tomography(PET)Radioligand with High Specificity.J Med Chem.2019;62:8532-8543), and [ 18F]PF-06795071 (Chen Z, Mori W, Fu H, et al. Design, Synthesis, and Evaluation of 18 F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes. J Med Chem. 2019;62:8866-8872), and these could hardly provide comprehensive quantification of drug-target interactions in pharmacokinetic modeling (Hou L, Rong J, Haider A, et al. Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development. J Med Chem. 2021;64:123-149).

[0004] 18 F]T-401 is currently the most representative case as a reversible MAGL PET radiotracer (Hattori Y, Aoyama K, Maeda J, et al. Design, Synthesis, and Evaluation of (4R)-1-{3-[2-( 18 F)Fluoro-4-methylpyridin-3-yl]phenyl}-4-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]pyrrolidin-2-one( 18 F] T-401) as a Novel Positron-Emission Tomography Imaging Agent for Monoacylglycerol Lipas. J Med Chem. 2019;62:2362-2375). However, 18 ​F]T-401 exhibits low brain uptake and the presence of CNS-penetrating radiopharmaceutical metabolites. These characteristics hinder the visualization of MAGL in the brain and complicate the quantification of specific binding signals in dynamic modeling (Pike VW, PET radiotracers: crossing the blood-brain barrier and surviving metabolism. Trends Pharmacol Sci. 2009;30:431-440). Due to the lack of a suitable reversible MAGL PET tracer, MAGL occupation due to therapeutic intervention or MAGL changes under pathological symptoms have not been reported in the preclinical stage. In summary, reversible PET tracers continue to be needed to verify the target involvement of therapeutic MAGL inhibitors and to examine MAGL expression levels under healthy and diseased conditions (Hou L, Rong J, Haider A, et al. Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development. J Med Chem. 2021;64:123-149). [Overview of the project]

[0005] In the first aspect, the present invention is [ka] The present invention provides a compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, wherein the compound optionally contains a radiolabel.

[0006] In a further embodiment, the present invention provides compounds described herein for use as therapeutically active substances.

[0007] In a further embodiment, the present invention provides compounds described herein for use in the treatment or prevention of diseases or symptoms related to MAGL.

[0008] In a further embodiment, the present invention provides radiolabeled compounds described herein for use in monoacylglycerol lipase (MAGL) occupancy tests.

[0009] In a further embodiment, the present invention provides radiolabeled compounds described herein for use in diagnostic imaging of monoacylglycerol lipase (MAGL).

[0010] In a further embodiment, the present invention provides a pharmaceutical composition comprising a radiolabeled compound described herein and a pharmaceutically acceptable carrier. [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 shows in vitro autoradiograms of [11C]-I (Cx=cortex; Hp=hippocampus; Cb=cerebellum; St=striatum; Th=thalamus) and MAGL mRNA expression in mouse brains recovered from mouse.brain-map.org (experiment: 69015242). [Figure 2] Figure 2 shows averaged representative PET images of [11C]-I in the brains of MAGL knockout (KO) mice and wild-type (WT) mice from 9.0 min to 52.5 min. [Figure 3] The time-activated curves (TACs) of the whole brain in MAGL KO mice and WT mice for [18F]-II and [18F]-III are shown. [Figure 4] Figure 4 shows receptor occupancy by [18F]-II, which was calculated by molar activity per injection and included in the saturation function. SUV0 to 90 minutes was fitted to the saturation function and the data was transferred to receptor occupancy. ○ represents [18F]-II with PF-06795071, and ● represents [18F]-II alone (baseline). [Figure 5] This shows the X-ray cocrystal structure of compound-II reversibly bound to human MAGL. [Modes for carrying out the invention]

[0012] Detailed description of the invention definition Features, integers, characteristics, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless they are incompatible. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process so so disclosed may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the embodiments described above. The present invention extends to any novel features or any novel combination of features disclosed herein (including any appended claims, abstract, and drawings), or any novel steps or any novel combination of any method or process so so disclosed.

[0013] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and especially hydrochloric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. These salts may also be prepared by adding inorganic or organic bases to free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyimine resins.

[0014] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably in this specification.

[0015] The term "mammal" includes humans, non-human primates such as chimpanzees and other apes and monkey species, domestic animals such as cattle, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats, and laboratory animals such as rodents such as rats, mice and guinea pigs. In certain embodiments, mammal is human. The term mammal does not imply a specific age or sex.

[0016] The terms "radioactive label" and "radioactive isotope" can be used interchangeably. 11 C, 13 N, 15 O, and18 This refers to radionuclides such as F that are useful for PET imaging.

[0017] The terms “pharmaceutically acceptable additive” and “therapeutically inactive additive” are interchangeable and refer to any pharmaceutically acceptable component in a pharmaceutical composition that does not have therapeutic activity and is nontoxic to the target of administration, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the manufacture of pharmaceutical products.

[0018] The term “treatment,” as used herein, includes: (1) suppressing a condition, disorder, or situation (e.g., in the case of maintenance treatment, stopping, reducing, or delaying the onset or recurrence of at least one clinical symptom or asymptomatic disease); and / or (2) alleviating a situation (i.e., causing regression of a condition, disorder, or situation, or at least one of its clinical symptoms or asymptomatics). The benefit to the treated patient is either statistically significant or at least recognizable to the patient or physician. However, it will be understood that when a medicine is administered to a patient to treat a disease, the outcome does not necessarily have to be an effective treatment.

[0019] As used herein, the term “prevention” includes, in mammals, preventing or delaying the onset of clinical symptoms of a condition, disorder or condition that develops in humans who are suffering from or susceptible to a condition, disorder or condition but have not yet experienced or shown any clinical symptoms or asymptomatic symptoms of that condition, disorder or condition.

[0020] As used herein, the term “neuroinflammation” refers to acute and chronic inflammation of nerve tissue, which is the major tissue component of the two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branched peripheral nerves of the peripheral nervous system (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Acute neuroinflammation usually occurs immediately after injury to the central nervous system, for example, as a result of traumatic brain injury (TBI).

[0021] The term "traumatic brain injury" (also known as "TBI" or "intracranial injury") refers to brain damage resulting from external mechanical forces such as rapid acceleration or deceleration, impact, blast, or penetration by a projectile.

[0022] The term “neurodegenerative disease” refers to diseases that involve the progressive loss of structure or function of neurons, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

[0023] The term “mental disorder” (also called mental illness or psychiatric disorder) relates to behavioral or mental patterns that may cause distress or dysfunction in life. Such features may occur as persistent, recurrent, and remittent episodes, or as single episodes. Examples of mental disorders include, but are not limited to, anxiety disorders and depression.

[0024] The term “pain” refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy-induced neuropathy, phantom limb pain, and psychogenic pain. A specific example of pain is neuropathic pain, which is caused by injury or disease affecting any part of the nervous system involved in bodily feelings (i.e., the somatosensory system). In one embodiment, “pain” is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, “pain” is chemotherapy-induced neuropathy.

[0025] The term "neurotoxicity" relates to toxicity in the nervous system. This occurs when exposure to naturally occurring or artificially produced toxic substances (neurotoxins) alters the normal activity of the nervous system and causes damage to nerve tissue. Examples of neurotoxicity include, but are not limited to, exposure to substances used in chemotherapy, radiation therapy, drug therapy, drug abuse, and organ transplantation, as well as neurotoxicity resulting from exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some naturally occurring substances.

[0026] The term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor resulting from the abnormal and uncontrolled proliferation of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, colon carcinogenesis, and ovarian cancer.

[0027] The compound of the present invention In one embodiment, the present invention is [ka] The present invention provides a compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, wherein the compound optionally contains a radiolabel.

[0028] In one embodiment, the radioactive label is 11 C, 13 N, 15 O, and 18 Selected from F.

[0029] In a preferred embodiment, the radioactive label is 11 C and 18 Selected from F.

[0030] In a preferred embodiment, the present invention is [ka] The present invention provides a radiolabeled compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment, the radiolabeled compound according to the present invention is [ka] or a pharmaceutically acceptable salt thereof.

[0032] In one embodiment, the radiolabeled compound according to the present invention is [ka] or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, the radiolabeled compound according to the present invention is [ka] or a pharmaceutically acceptable salt thereof.

[0034] Use of the compound of the present invention The compounds of the present invention are potent, reversible MAGL inhibitors that can be used for the treatment or prevention of diseases or symptoms associated with MAGL. Examples of diseases or symptoms that may be associated with MAGL include neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraines, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

[0035] Accordingly, in one embodiment, the present invention provides a method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorders, migraines, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain in mammals, the method comprising administering a therapeutically effective amount of a compound of formula I, II, or III or a pharmaceutically acceptable salt thereof to the mammal.

[0036] In further embodiments, the present invention provides compounds of formula I, II, or III or pharmaceutically acceptable salts thereof for use in methods of treatment or prevention described herein.

[0037] In a further embodiment, the present invention provides the use of compounds of formula I, II, or III or pharmaceutically acceptable salts thereof in methods of treatment or prevention described herein.

[0038] In a further embodiment, the present invention provides the use of compounds of formula I, II, or III or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorders, migraines, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

[0039] The compounds of the present invention can be radiolabeled and used, for example, as non-covalent reversible PET tracers to verify the target involvement of therapeutic MAGL inhibitors and to examine MAGL levels under normal and diseased conditions.

[0040] Therefore, in one embodiment, the present invention is a method for imaging monoacylglycerol lipase (MAGL) in the mammalian brain, (a) Administering to a mammal a detectable amount of the radiolabeled compound described herein or a pharmaceutical composition containing a detectable amount of the radiolabeled compound described herein, (b) If associated with MAGL, detect the radiolabeled compound. This provides a method that includes [something].

[0041] In a further embodiment, the present invention provides a pharmaceutical composition comprising a radiolabeled compound described herein or a pharmaceutically acceptable salt thereof, or a radiolabeled compound described herein, for use in a monoacylglycerol lipase (MAGL) occupancy test.

[0042] In one embodiment, the monoacylglycerol lipase (MAGL) occupancy test comprises contacting MAGL with a radiolabeled compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0043] In a further embodiment, the present invention provides a pharmaceutical composition comprising a radiolabeled compound described herein or a pharmaceutically acceptable salt thereof, or a radiolabeled compound described herein, for use in imaging diagnostic methods of monoacylglycerol lipase (MAGL) in the brain of mammals.

[0044] In a further embodiment, the present invention provides the use of a radiolabeled compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a radiolabeled compound described herein, in a method for imaging monoacylglycerol lipase (MAGL) in the brain of a mammal.

[0045] In a further embodiment, the present invention provides the use of radiolabeled compounds described herein or pharmaceutically acceptable salts thereof for preparing pharmaceuticals for imaging diagnostics of monoacylglycerol lipase (MAGL) in the brain of mammals.

[0046] In one embodiment, the diagnostic imaging is positron emission tomography (PET).

[0047] In one embodiment, the imaging diagnosis of monoacylglycerol lipase (MAGL) in the brain of a mammal includes contacting the monoacylglycerol lipase (MAGL) with a radiolabeled compound disclosed herein or a pharmaceutically acceptable salt thereof. [Examples]

[0048] Example 1 - Synthesis of Intermediates 1-4 [ka]

[0049] Scheme 1. Synthesis of intermediates 2-4. a) Triethylamine, tetrabutylammonium iodide, 3-iodoaniline, CH3CN / toluene, 50°C, overnight, 24%; b) Concentrated hydrochloridic acid, CH3CN, 50°C, 4-5 hours, 85%; c) Sodium borohydride cyanohydride, fran-2-yl(piperazine-1-yl)methanone, acetic acid, anhydrous THF, room temperature, overnight, 49%.

[0050] Step a - Synthesis of 1-(4-iodophenyl)-4-methoxy-1,5-dihydro-2H-pyrrole-2-one (2).

[0051] Compound 1 (4.12 g, 25.0 mmol), 4-iodoaniline (4.00 g, 18.3 mmol), tetrabutylammonium iodide (67.5 mg, 0.18 mmol), and triethylamine (2.80 mL, 20.1 mmol) were dissolved in acetonitrile (15 mL). After stirring in an ice bath for 10 minutes, the reaction mixture was heated at 50 °C for 14 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to 3 by adding 1 M HCl. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. To the residue, toluene (10 mL) and acetic acid (1 mL) were added, and the mixture was heated at 50 °C for 4 hours. The reaction mixture was concentrated, and the product was crystallized with methanol / diisopropyl ether (1:1). After washing with diisopropyl ether, the desired product was obtained as a white powder (1.46 g, 25%). 1 ¹H NMR (400 MHz, chloroform-d) δ 7.61 (d, J=9.0 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H), 5.16 (s, 1H), 4.21 (s, 2H), 3.85 (s, 3H).C 11 H 11 INO2 + [M+H] + The calculated HRMS (ESI) value for this was 315.9829 m / z, while the measured value was 315.9828 m / z.

[0052] Step b- Synthesis of 4-hydroxy-1-(4-iodophenyl)-1,5-dihydro-2H-pyrrole-2-one (3).

[0053] Compound 2 (1.30 g, 4.14 mmol) was dissolved in 10 mL of acetonitrile containing 6 mL of concentrated HCl. After monitoring by LC-MS and confirming that compound 2 had been consumed, the solvent was removed under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The crude product was applied directly to the next step without further purification.

[0054] Step c - Synthesis of 4-(4-(furan-2-carbonyl)piperazin-1-yl)-1-(4-iodophenyl)pyrrolidine-2-one (4)

[0055] Compound 3 (570 mg, 1.89 mmol) and furan-2-yl(piperazine-1-yl)methone (409 mg, 2.27 mmol) were stirred in 10 mL of anhydrous THF at room temperature for 10 minutes. Acetic acid (217 μL, 3.8 mmol) was then added dropwise, followed by sodium borohydride cyanohydride (357 mg, 5.68 mmol). The reaction mixture was stirred at room temperature under nitrogen protection for 22 hours. Water was added to quench the reaction, and the resulting mixture was extracted with butyl and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. Flash column chromatography using butyl yielded the title compound as a white powder (523 mg, 59%). 1 H NMR(400 MHz,chloroform-d)δ 7.65(d,J=8.9 Hz,2H),7.47(s,1H),7.36(d,J=8.9 Hz,2H),7.01(d,J=3.3 Hz,1H),6.47(dd,J=3.3,1.7 Hz,1H),3.91-3.72(m,6H),3.24(p,J=7.8 Hz,1H),2.81-2.68(m,1H),2.67-2.50(m,5H).C 19 H 21 IN3O3 + [M+H] + The calculated HRMS (ESI) value for this was 466.0622 m / z, while the measured value was 466.0628 m / z.

[0056] Example 2 - Synthesis of (R)-4-(4-(furan-2-carbonyl)piperazin-1-yl)-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one (compound (I))

[0057] (3-methoxyphenyl)boronic acid (43.0 mg, 0.28 mmol), compound 4 (120 mg, 0.26 mmol), cesium carbonate (210 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium(0) (23.6 mg, 0.03 mmol), and Sphos (21.2 mg, 0.05 mmol) were added to a two-necked flask. The system was then closed and filled with nitrogen. 5 mL of pre-purged nitrogen-free DMF was added to the flask, and the resulting mixture was heated overnight at 85°C under reflux. Once compound 4 was consumed, the reaction mixture was cooled to room temperature, filtered, and concentrated. The crude product was purified by preparative HPLC to obtain the desired product as a colorless solid (87 mg, 76%). The title compound was isolated by chiral separation using supercritical fluid chromatography (SFC). 1 H NMR(400 MHz,chloroform-d)δ 7.62(s,4H),7.51(dd,J=1.8,0.8 Hz,1H),7.39-7.32(m,1H),7.18-7.13(m,2H),7.11-7.08(m,1H),6.93-6.88(m,1H),6.53(dd,J=3.5,1.8 Hz,1H),4.30(dd,J=11.1,5.1 Hz,1H),4.26-4.05(m,5H),3.98-3.89(m,1H),3.87(s,3H),3.19-3.05(m,4H),2.98(d,J=7.3 Hz,2H).C 26 H 27 N3NaO4 + [M+Na] + The calculated HRMS (ESI) value for this period is 468.1894 m / z, while the measured value is 468.1894 m / z.

[0058] Example 3 - Synthesis of (R)-1-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-(4-(furan-2-carbonyl)piperazine-1-yl)pyrrolidine-2-one (compound (III)).

[0059] The procedure described for the synthesis of compound (I) was applied to 3-fluorobenzeneboronic acid (57.9 mg, 0.41 mmol), compound 4 (175 mg, 0.38 mmol), cesium carbonate (307 mg, 0.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (34.5 mg, 0.04 mmol), and Sphos (31 mg, 0.08 mmol). After chiral separation, the title compound was obtained as a white powder. 1 H NMR(400 MHz,chloroform-d)δ 7.66-7.62(m,2H),7.61-7.58(m,2H),7.52-7.50(m,1H),7.44-7.32(m,2H),7.28-7.23(m Overlapping with loloform-d,1H),7.16(dd,J=3.6,0.9 Hz,1H),7.08-7.01(m,1H),6.54(dd,J=3.5,1.8 Hz,1H),4.36(dd,J=11.2,5.0 Hz,1H),4.25-4.13(m,5H),4.08-3.97(m,1H),3.31-3.10(m,4H),3.06-3.00(m,2H).C 25 H 24 FN3NaO3 + [M+Na] + The calculated HRMS (ESI) value for this was 456.1694 m / z, while the measured value was 456.1699 m / z.

[0060] Example 4 - Synthesis of (R)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-(4-(furan-2-carbonyl)piperazin-1-yl)pyrrolidine-2-one (compound (II)).

[0061] The procedure described for the synthesis of compound (I) was applied to 4-fluorobenzeneboronic acid (33.1 mg, 0.24 mmol), compound 4 (100 mg, 0.22 mmol), cesium carbonate (175 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (19.7 mg, 0.02 mmol), and Sphos (17.7 mg, 0.04 mmol). After chiral separation, the title compound was obtained as a white powder. 1H NMR(400 MHz,chloroform-d)δ 7.64(d,J=8.7 Hz,2H),7.58(d,J=8.7 Hz,2H),7.55-7.51(m,3H),7.17-7.12(m,3H),6.55(dd,J=3.5,1.8 Hz,1H),4.32(dd,J=11.0,5.1 Hz,1H),4.26-4.02(m,5H),3.96(p,J=7.3 Hz,1H),3.14(br,4H),3.05-2.97(m,2H).C 25 H 25 FN3O3 + [M+H] + The calculated HRMS (ESI) value for this was 434.1874 m / z, while the measured value was 434.1875 m / z.

[0062] Example 5 - [ 11 Synthesis of C]-I [ka]

[0063] Scheme 2. Precursor 5 and [ 11 C]-Ia) BBr3, anhydrous DCM, 0°C, overnight synthesis; b) [ 11 C]CH3I,Cs2CO3, 5 min, anhydrous DMF, 90°C.

[0064] Step a- Synthesis of (R)-4-(4-(furan-2-carbonyl)piperazin-1-yl)-1-(3'-hydroxy-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one (5))

[0065] To a solution of compound (I) (107 mg, 0.241 mmol) in 5 mL of anhydrous dichloromethane, 1.90 mL, 1.93 mmol of 1 M boron tribromide in dichloromethane was added dropwise at 0°C. The reaction mixture was then stirred at room temperature until the reagents were consumed. The reaction was quenched by adding saturated NaHCO3 solution, and the resulting mixture was extracted with ethyl acetate. The combined organic phase was dried over MgSO4, filtered, concentrated, and purified by flash column chromatography (silica gel, EtOH / CHCl3 = 1 / 35~1 / 20). The title compound was obtained as a white solid (54 mg, 75%). Chiral separation was performed using supercritical fluid chromatography (SFC) to isolate compound 5 as the R-isoform. 1 H NMR(400 MHz,Acetone-d6)δ 7.83(d,J=8.8 Hz,2H),7.71-7.68(m,1H),7.63(d,J=8.8 Hz,2H),7.28(t,J=8.1 Hz,1H),7.15-7.10(m,2H),6.97(dd,J=3.4,0.7 Hz,1H),6.83(ddd,J=8.1,2.2,1.0 Hz,1H),6.58(dd,J=3.4,1.8 Hz,1H),4.11(dd,J=9.7,7.4 Hz,1H),3.89(dd,J=9.7,6.6 Hz,1H),3.80(br,4H),3.41-3.30(m,1H),2.76(dd,J=16.6,8.1 Hz,1H),2.70-2.55(m,5H).C 25 H 26 N3O4 + [M+H] + The calculated HRMS (ESI) value for this was 432.1918 m / z, while the measured value was 432.1920 m / z.

[0066] Process b- (R)-4-(4-(furan-2-carbonyl)piperazine-1-yl)-1-(3'-(methoxy- 11 C)-[1,1'-biphenyl]-4-yl)pyrroridine-2-one([ 11 Synthesis of C]-(I)

[0067] Using the Cyclone 18 / 9 cyclotron (18 MeV; IBA, Belgium), by impacting a nitrogen gas target enhanced with 0.5% oxygen, 14 N(p,α) 11 [ 11 [C]CO2 was produced. Subsequently, via a nickel catalyst [ 11 By the reduction of C]CO2, [ 11 We obtained [C]CH4 and used gas-phase iodination [ 11 [C]CH3I was produced. The obtained [ 11 [C]CH3I was bubbling into a reaction vial containing 5 mg of Cs2CO3 and 0.5 mg of phenol precursor (1 mg / mL in anhydrous DMF, 0.5 mL). The mixture was then heated at 90°C for 3 minutes. After dilution with 1.6 mL of water, the reaction mixture was loaded onto a semi-preparative HPLC for purification. The collected fraction was diluted with 8 mL of Milli-Q water, passed through a pre-conditioned C18 light cartridge (Waters, WAT023501), and subsequently washed with 5 mL of Milli-Q water. After elution with 0.5 mL of EtOH, the final radioactive ligand was combined with phosphate-buffered saline (9.5 mL, Gibco) to obtain a neutralized solution. The identity of the radioactive tracer was confirmed by co-injection with compound (I) in analytical HPLC, and the radiochemical purity was over 99%.

[0068] Example 6- [ 18 F]-II and [ 18 Synthesis of F]-III [ka]

[0069] Figure 3. Synthesis of precursors 6 and 7, and [ 18 F]-II and [ 18Radioactive synthesis of F]-III. a) 1,4-phenyl diboronic acid, potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, anhydrous DMF, 80°C, 4 hours, for case 6, 1,3-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene; for case 7, 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene; b) chiral supercritical fluid chromatography separation; c) 6 or 7, 18 F]F - Kryptofix(registered trademark) 222, K2C2O4, K2CO3 and Cu(OTf)2Py4, DMA / n-BuOH=2 / 1, 110℃, 10 minutes.

[0070] Steps a and b: Synthesis of (R)-4-(4-(furan-2-carbonyl)piperazin-1-yl)-1-(3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one (6).

[0071] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (7.9 mg, 0.011 mmol), potassium acetate (63.3 mg, 0.84 mmol), and 1,3-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (142 mg, 0.43 mmol) were added to a two-necked flask under nitrogen protection. Compound 4 (100 mg, 0.22 mmol) dissolved in 5 mL of anhydrous DMF was added to this flask all at once, and the resulting mixture was later heated at 85°C. Once compound 4 was consumed, water was added to quench the reaction. The mixture was extracted with phenylethylamine, and the combined organic layer was dissolved in MgSO4. 4、 The mixture was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate) to obtain the title compound as a brown powder (47 mg, 41%). Chiral separation was performed using supercritical fluid chromatography (SFC) to isolate R-isomer 6: 1H NMR(400 MHz,chloroform-d)δ 8.02(s,1H),7.78(d,J=7.4 Hz,1H),7.70-7.60(m,5FH),7.50-7.41(m,2H),7.07-6.99(m,1H),6.54-6.43(m,1H),4.13-3.65(m,6H),3.29(p,J=7.6 Hz,1H),2.79(dd,J=16.7,8.0 Hz,1H),2.72-2.40(m,5H),1.36(s,12H).C 31 H 37 BN3O5 + [M+H] + The calculated HRMS (ESI) value for this was 542.2826 m / z, while the measured value was 542.2828 m / z.

[0072] Steps a and b: Synthesis of (R)-4-(4-(furan-2-carbonyl)piperazin-1-yl)-1-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one (7).

[0073] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (10 mg, 0.014 mmol), potassium acetate (82 mg, 0.84 mmol), and 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (185 mg, 0.56 mmol) were added to a two-necked flask under nitrogen protection. Compound 4 (130 mg, 0.28 mmol) dissolved in 5 mL of anhydrous DMF was added to this flask all at once, and the resulting mixture was later heated at 85°C. Once compound 4 was consumed, water was added to quench the reaction. The mixture was extracted with toluene, and the combined organic layer was dissolved in MgSO4. 4、 The mixture was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, RINKAN) to obtain the title compound as a brown powder (148 mg, 49%). Chiral separation was performed using supercritical fluid chromatography (SFC) to isolate R-isomer 7: 1H NMR(400 MHz,chloroform-d)δ 7.87(d,J=7.8 Hz,2H),7.73-7.61(m,4H),7.59(d,J=8.0 Hz,2H),7.48(s,1H),7.03(d,J=3.3 Hz,1H),6.49(dd,J=3.3,1.7 C 31 H 37 BN3O5 + [M+H] + The calculated HRMS (ESI) value for this was 542.2826 m / z, while the measured value was 542.2828 m / z.

[0074] Process c- (R)-1-(3'-(fluoro- 18 F)-[1,1'-biphenyl]-4-yl)-4-(4-(furan-2-carbonyl)piperazine-1-yl)pyrrolidine-2-one([ 18 Synthesis of F]-III)

[0075] [ 18 [F] Fluoride ions are, 18 O(p,n) 18 98% enrichment via fluorine reaction 18Generated by the impact of water. The aqueous solution was transferred from the cyclotron to the hot cell and captured on a QMA cartridge (Waters SepPak Accell QMA cartridge carbonate). A mixture of Kryptofix 2.2.2 (6.3 mg / mL), K2C2O4 (1 mg / mL), and K2CO2 (0.1 mg / mL) in MeCN / H2O (4:1) was applied to elute the radioactivity into the reaction vial. After azeotropic drying with MeCN (0.8 mL × 3), 2 - 3 mg of precursor 6 containing 14 mg of Cu(OTf)2(py)4 dissolved in DMA / n - BuOH (0.3 mL, v / v = 2 / 1) was added to the residue, and the reaction mixture was heated at 110 °C for 10 minutes using an air - venting needle. After dilution with 2.7 mL of water, the mixture was subjected to semi - preparative HPLC purification. The title compound was recovered, concentrated, eluted, and neutralized using the same procedure as above.

[0076] Step c - (R)-1-(4’-(fluoro - 18 F)-[1,1’ - biphenyl]-4 - yl)-4-(4-(furan - 2 - carbonyl)piperazin - 1 - yl)pyrrolidin - 2 - one( 18 F]-II) synthesis

[0077] Using 2 - 3 mg of precursor 7, the title compound was synthesized by a procedure similar to that of ( 18 F]-III). Their identity was confirmed by co - injection of the corresponding compounds in analytical HPLC with a radiochemical purity exceeding 99%.

[0078] Example 7 - MAGL inhibitory activity The MAGL inhibitory activity of the compounds can be profiled by detecting the enzyme activity following the hydrolysis of 2 - arachidonoyl glycerol, a natural substrate that yields arachidonic acid, and subsequently performing mass spectrometry. This assay will be abbreviated as the "2 - AG assay" below.

[0079] The 2-AG assay was performed in a 384-well assay plate (PP, Greiner, catalog no. 784201) at a total volume of 20 μL. Compound dilutions were prepared in a polypropylene plate using a 3-fold dilution step in 100% DMSO (VWR Chemicals 23500.297) to achieve a final concentration range of 12.5 μM to 0.8 pM in the assay. 0.25 μL of the compound dilution (100% DMSO) was added to 9 μL of MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 ml), 0.01% (volt / volt) Tween). After shaking, the plate was incubated at room temperature for 15 minutes. To initiate the reaction, 10 μL of 2-arachidonoylglycerol was added to the assay buffer. The final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglyerol. After shaking, the reaction was incubated at room temperature for 30 minutes, and then quenched by adding 40 μL of acetonitrile containing 4 μM d8-arachidonic acid. The amount of arachidonic acid was tracked using an online SPE system (Agilent Rapidfire) in combination with a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE cartridge (G9205A) was used in an acetonitrile / water liquid setup. The mass spectrometer was operated in negative electrospray mode according to the mass transitions of 303.1 → 259.1 for arachidonic acid and 311.1 → 267.0 for d8-arachidonic acid. The activity of the compounds was calculated based on the intensity ratio [arachidonic acid / d8-arachidonic acid].

[0080] [Table 1]

[0081] Example 8 - In vitro autoradiography Frozen brain tissue from Wistar rats or mice was sliced ​​to a thickness of 10 μm using a cryostat (Cryo-Star HM 560 MV; Microm, Thermo Scientific, Wilmington, Delaware) and stored at -20°C before use. Before the experiment, the slices were thawed on ice for 10 minutes and then immersed in aqueous 50 mM Tris buffer (pH 7.4, 30 mM HEPES, 1.2 mM MgCl2, 110 mM NaCl, 5 mM KCl, 2.5 mM CaCl2) containing 3% fatty acid-free bovine serum albumin (BSA) at 0°C for 10 minutes for preconditioning. After drying, the slices were incubated with radioactive tracers in a humidified chamber at room temperature for 30 minutes. For shielding studies, 10 μM SAR127303 or 10 μM PF-06809247 was used. After incubation, the sections were decanted and washed. After drying, the slices were mounted on a phosphor imager plate (Fuji, Dielsdorf, Switzerland) and exposed for 60 minutes. The films were then scanned with a BAS5000 reader (Fuji), and data analysis was performed using AIDA 4.50.010 software (Raytest Isotopenmessgeraete GmbH, Straubenhardt, Germany).

[0082] result [ 11 Incubation of mouse or rat brain sections with [C]-I (approximately 1 nM) resulted in a heterogeneous distribution of radioactive signal accumulation consistent with the MAGL expression pattern in rodents (Figure 1). More precisely, [ 11The highest accumulation of 11 C]-I was observed in the cortex, hippocampus, and striatum where high levels of MAGL expression have been reported (Dinh TP, Carpenter D, Leslie FM, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci. 2002;99:10819-10824). Two irreversible and potent MAGL inhibitors, SAR127303 and PF-06809247, were applied at a concentration of 10 μM to block and compete with the specific binding of 11 C]-I on rat brain slices. A substantial decrease and uniform distribution of radioactivity were observed in both cases when the probe was simply incubated on MAGL KO brain slices. These results support the high specificity and selectivity of

[0083] Example 9 - In vivo PET scan Animals were anesthetized using isoflurane and placed in a PET / CT scanner (Super Argus, Sedecal, Madrid, Spain). The radioactive tracer was injected intravenously, and data were acquired 1 minute after injection. Dynamic PET scans were continued for 11 60 minutes for 18 C]-I, but extended to 90 minutes for 18 F]-II and 3 F]-III. The data obtained were reconstructed with a user-defined time frame having a voxel size of 0.3875×0.3875×0.775 mm. Regions of interest (ROIs) were defined on an MRI T2 (W (W. Schiffer) template provided by PMOD v4.002 (PMOD Technologies, Zurich, Switzerland) to generate the corresponding time-activity curves (TACs). The radioactivity accumulation in the whole brain and different regions was expressed as standardized uptake values (SUVs), which are the decay-corrected regional radioactivity normalized to the injected radioactivity and body weight.

[0084] result All three radioactive tracers were able to cross the blood-brain barrier and reached their highest accumulation levels in mouse brains within 5 minutes. [In the brains of MAGL KO mice and WT mice] 18 F]-II and [ 18 A representative whole-brain TAC from F]-III is shown in Figure 3. In MAGL KO mice, significantly faster clearance from the brain was observed compared to WT mice, indicating specific and selective binding in vivo. 18 F]T-401 (SUV max Approximately 0.7(Hattori Y, Aoyama K, Maeda J, et al. Design, Synthesis, and Evaluation of (4R)-1-{3-[2-( 18 F)Fluoro-4-methylpyridin-3-yl]phenyl}-4-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]pyrrolidin-2-one([ 18 Compared to F]T-401) reported as a Novel Positron-Emission Tomography Imaging Agent for Monoacylglycerol Lipase. J Med Chem. 2019;62:2362-2375), [ 11 C]-I(SUV at 1 minute pi) max approx. 1.32), [ 18 F]-II (SUV at 1 minute pi) max Approximately 1.56) and [ 18 F]-III (SUV at 1 minute pi) max Significantly increased brain uptake was achieved by approximately 1.63). The heterogeneous distribution of the probe in vivo closely matched the MAGL expression levels in the mouse brain. It closely resembled its in vitro autoradiogram. 11 A typical PET image of C-I is shown in Figure 2.

[0085] Example 10 - Drug Occupancy Test [ 18To investigate the efficacy of F]-II, drug occupancy tests were performed after verifying in vitro / vivo specificity. PF-06795071, a potent and selective covalent MAGL inhibitor initially developed for anti-inflammatory treatment, was applied to this study (McAllister LA, Butler CR, Mente S, et al. Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation. J Med Chem. 2018;61:3008-3026). PF-06795071 was prepared as a clear solution in a vehicle of DMSO / Cremophor / physiological saline (v / v / v=5 / 5 / 90). Animals were then subjected to [ 18 One hour before administration of F]-II (4.15-11.13 MBq, 6.84-13.19 nmol / kg), the subjects were treated with escalating doses of PF-06795071 (0.002, 0.01, 0.05, 0.2, and 2 mg / kg). In vivo PET scans and data reconstruction were performed as described in Example 9. SUV in receptor occupancy studies was performed as previously detailed by Kramer et al. 0-90分 To obtain this, SUV from whole-brain TAC was averaged for 0-90 minutes (Kramer SD, Betzel T, Mu L, et al. Evaluation of 11 C-Me-NB1 as a Potential PET Radioligand for Measuring GluN2B-Containing NMDA Receptors, Drug Occupancy, and Receptor Cross Talk.J Nucl Med.2018;59:698-703). D 50 The values ​​were fitted to a nonlinear curve using GraphPad Prism Software (version 8.3.4, GraphPad Software Inc.).

[0086] result In the mouse brain [ 18 A dose-dependent decrease in [F]-II accumulation was observed in PF-06795071 at doses ranging from 0.002 to 2 mg / kg. Subsequently, the mean SUV from the entire cerebral TAC was observed. 0-90分 The target occupancy was converted to a saturation equation to determine drug-target engagement (Figure 4). The dose required for PF-06795071 to occupy 50% of MAGL in the mouse brain was 0.034 mg / kg. This study visualizes drug-target engagement in vivo and uses a reversible MAGL PET tracer to non-invasively quantify drug occupancy. 18 The usefulness of F]-II was demonstrated. Target occupancy rates using reversible MAGL PET tracers in rodents are unprecedented. These findings are [ 18 This study demonstrates that [F]-II is a very promising PET probe for non-invasive visualization of MAGL in vivo and holds great potential for clinical translation.

[0087] Example 11 - X-ray structure of compound-II bound to MAGL Human MAGL protein containing mutant Lys36Ala, Leu169Ser, and Leu176Ser was concentrated to 10.8 mg / ml. Crystallization tests were performed using a sitting drop vapor diffusion setting at 21°C. Crystals appeared within 2 days from 0.1 M MES pH 6.5, 6-13% PEG MME 5K, and 12% isopropanol. The crystals were immersed for 16 hours in a crystallization solution supplemented with 10 mM compound II. For data acquisition, the crystals were flash-cooled at 100 K, and 20% ethylene glycol was added to the immersion solution as a cryoprotectant. X-ray diffraction data were collected at a wavelength of 0.9999 Å using an Eiger 2X 16M detector at beamline X10SA of Swiss Light Source (Villigen, Switzerland). The data were processed using XDS (Kabsch W, XDS.Acta Cryst.D66,125-132(2010)) and scaled using SADABS (BRUKER). The crystal belongs to space group C2221 with cell axes a=89.96Å, b=127.45Å, and c=63.03Å, and is diffracted at a resolution of 1.65Å.The structure was explored using the coordinates of PDB entry 3PE6 as a search model (Schalk-Hihi C, Schubert C, Alexander R, Bayoumy S, Clemente JC, Deckman I, DesJarlais RL, Dzordzorme KC, Flores CM, Grasberger B, Kranz JK, Lewandowski F, Liu L, Ma H, Maguire D, Macielag MJ, McDonnell ME, Mezzasalma Haarlander T, Miller R, Milligan C, Reynolds C, Kuo LC. Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution. Protein Sci. 20(4), 670-83 (2011)), followed by molecular substitution by PHASER (McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn This was determined by MD,Storoni LC,&Read,RJPhaser crystallographic software.J Appl Cryst.40,658-674(2007).

[0088] result The complex structure of human MAGL and compound-II confirmed the reversible binding mechanism between compound-II and the enzyme (Figure 5). The pyrrolidinone oxygen is located close to catalyst Ser122 and points to the oxyanion hole that forms hydrogen bonds with the main chain skeleton amide from Met123 and Ala51.

Claims

【Request Item 1】 【Chemistry 1】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, wherein the compound optionally contains a radioactive label.

2. The aforementioned radioactive label is １１ C and １８ A compound according to claim 1, selected from F. 【Request Item 3】 【Chemistry 2】 A compound according to claim 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following. 【Request Item 4】 【Chemistry 3】 The compound according to claim 2 or a pharmaceutically acceptable salt thereof. 【Request Item 5】 【Chemistry 4】 The compound according to claim 2 or a pharmaceutically acceptable salt thereof. 【Request Item 6】 【Chemistry 5】 The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

8. The compound according to claim 1 for use as a therapeutically active substance.

9. A pharmaceutical composition for imaging diagnostics of monoacylglycerol lipase (MAGL) in the mammalian brain, A pharmaceutical composition comprising a detectable amount of a radiolabeled compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a radiolabeled compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, for use in a monoacylglycerol lipase (MAGL) occupancy test.

11. (a) administering a detectable amount of a radiolabeled compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof to a mammal, and (b) detecting the radiolabeled compound if it is associated with MAGL. Imaging methods for monoacylglycerol lipase (MAGL) in the mammalian brain, including A pharmaceutical composition comprising a radiolabeled compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, for use in [a specific context].

12. Use of a radiolabeled compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical for imaging diagnostics of monoacylglycerol lipase (MAGL) in the brain of a mammal.

13. The compound according to claim 1 for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorders, migraines, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

14. A pharmaceutical composition comprising the compound described in Claim 1 for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorders, migraines, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

15. Use of the compound according to claim 1 in the preparation of a pharmaceutical for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorders, migraines, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

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