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 THEINVENTION The present invention relates to organic compounds useful for therapy or prevention in mammals, in particular monoacylglycerol lipase (MAGL) inhibitors for treating or preventing MAGL-associated diseases or conditions 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] 2. Background of the Invention Monoacylglycerol lipase (MAGL) is a serine hydrolase that is highly expressed in the central nervous system (CNS) as well as in 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 conditions (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, aids in drug discovery and development by providing valuable information on drug-target engagement, access to drug occupancy, and treatment 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). The early developed MAGL radioligands were mainly irreversible, e.g., 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), which have hardly been able to 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 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 has low brain uptake and CNS-penetrating radioactive metabolites. These characteristics hinder visualization of MAGL in the brain and complicate 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 suitable reversible MAGL PET tracers, MAGL occupancy by therapeutic intervention or MAGL changes under pathological conditions have not been reported so far in the preclinical stage. In summary, reversible PET tracers remain needed to validate target engagement of therapeutic MAGL inhibitors and to examine MAGL expression levels under healthy and disease 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). Summary of the Invention

[0005] In a first aspect, the present invention provides a method for producing a composition comprising the steps of: [ka] or a pharma- ceutically acceptable salt thereof, wherein said compound optionally comprises a radiolabel.

[0006] In a further aspect, the present invention provides a compound as described herein for use as a therapeutically active substance.

[0007] In a further aspect, the present invention provides a compound as described herein for use in the treatment or prevention of a disease or condition associated with MAGL.

[0008] In a further aspect, the present invention provides a radiolabeled compound as described herein for use in a monoacylglycerol lipase (MAGL) occupancy assay.

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

[0010] In a further aspect, the present invention provides a pharmaceutical composition comprising a radiolabeled compound described herein and a pharma- ceutically acceptable carrier. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows an in vitro autoradiogram of [11C]-I (Cx=cortex; Hp=hippocampus; Cb=cerebellum; St=striatum; Th=thalamus) and MAGL mRNA expression in mouse brain retrieved from mouse.brain-map.org (experiment: 69015242). [Diagram 2] FIG. 2 shows representative averaged PET images of [11C]-I from 9.0 to 52.5 min in the brains of MAGL knockout (KO) and wild-type (WT) mice. [Diagram 3] 1 shows time activity curves (TACs) of [18F]-II and [18F]-III in the whole brain of MAGL KO and WT mice. [Figure 4] Figure 4 shows the receptor occupancy by [18F]-II, which was calculated by the molar activity per injection and included in the saturation function. The SUV0-90 min was fitted to the saturation function and the data was transferred to receptor occupancy. ○ means [18F]-II with PF-06795071, ● means [18F]-II alone (baseline). [Diagram 5] 1 shows the X-ray co-crystal structure of Compound-II reversibly bound to human MAGL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description of the Invention definition It is to be understood that any feature, integer, characteristic, compound, chemical moiety or group described in connection with a particular aspect, embodiment or example of the invention is applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or any novel or any novel combination of steps of any method or process so disclosed.

[0013] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, 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 the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like.

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

[0015] The term "mammal" includes humans, non-human primates, such as chimpanzees and other ape and monkey species, farm animals, such as cows, 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 a particular embodiment, a mammal is a human. The term mammal does not denote a particular age or sex.

[0016] The terms "radiolabel" and "radioisotope" may 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 excipient" and "therapeutically inactive excipient" can be used interchangeably and refer to any pharma- ceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as, for example, a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant used in manufacturing a pharmaceutical product.

[0018] The term "treatment" as used herein includes: (1) inhibiting a condition, disorder or state (e.g., in the case of maintenance treatment, arresting, reducing or delaying the onset or recurrence of at least one clinical symptom or subclinical disease thereof), and / or (2) alleviating the state (i.e., causing regression of the condition, disorder or state, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the treated patient is either statistically significant or at least perceptible to the patient or the physician. However, it will be understood that when a patient is administered a medicine to treat a disease, the outcome may not necessarily be an effective treatment.

[0019] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited the clinical or asymptomatic symptoms of the condition, disorder or condition.

[0020] The term "neuroinflammation" as used herein refers to acute and chronic inflammation of nervous tissue, which is the main tissue component of two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branching 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" ("TBI", also known as "intracranial injury") relates to damage to the brain due to an external mechanical force, such as rapid acceleration or deceleration, impact, blast, or penetration by a projectile.

[0022] The term "neurodegenerative disease" refers to diseases associated with the progressive loss of neuronal structure or function, 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 mental disorder) refers to a behavior or mental pattern that can cause distress or impaired functioning in life. Such characteristics may occur as persistent, relapsing, and remitting, or as a single episode. Examples of mental disorders include, but are not limited to, anxiety 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 particular example of pain is neuropathic pain, which is caused by injury or disease affecting any part of the nervous system involved in bodily sensations (i.e., the somatosensory system). In one embodiment, the "pain" is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, the "pain" is chemotherapy-induced neuropathy.

[0025] The term "neurotoxicity" refers to toxicity in the nervous system. It occurs when exposure to natural or man-made toxic substances (neurotoxins) alters the normal activity of the nervous system, causing damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, exposure to substances used in chemotherapy, radiation treatment, 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 carcinoma, and ovarian cancer.

[0027] Compounds of the Invention In one aspect, the present invention provides a method for producing [ka] or a pharma- ceutically acceptable salt thereof, wherein said compound optionally comprises a radiolabel.

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

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

[0030] In a preferred embodiment, the present invention comprises: [ka] or a pharma- ceutically acceptable salt thereof.

[0031] In one embodiment, a radiolabeled compound according to the invention comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0032] In one embodiment, a radiolabeled compound according to the invention comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0033] In one embodiment, a radiolabeled compound according to the invention comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0034] Uses of the Compounds of the Invention The compounds of the present invention are potent reversible MAGL inhibitors that can be used to treat or prevent diseases or conditions associated with MAGL. Exemplary diseases or conditions that can 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, migraine, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

[0035] Thus, in one aspect, the invention provides a method of treating or preventing 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, migraine, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound of Formula I, II or III or a pharma- ceutically acceptable salt thereof.

[0036] In a further aspect, the present invention provides a compound of formula I, II or III, or a pharma- ceutically acceptable salt thereof, for use in the methods of treatment or prophylaxis described herein.

[0037] In a further aspect, the present invention provides the use of a compound of formula I, II or III, or a pharma- ceutically acceptable salt thereof, in a method of treatment or prophylaxis as described herein.

[0038] In a further aspect, the present invention provides the use of a compound of Formula I, II or III or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of 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, migraine, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

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

[0040] Thus, in one aspect, the present invention provides a method for imaging monoacylglycerol lipase (MAGL) in a mammalian brain, comprising: (a) administering to a mammal a detectable amount of a radiolabeled compound described herein or a pharmaceutical composition comprising a detectable amount of a radiolabeled compound described herein; (b) detecting the radiolabeled compound when associated with MAGL; The present invention provides a method comprising:

[0041] In a further aspect, the present invention provides a radiolabeled compound as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a radiolabeled compound as described herein, for use in a monoacylglycerol lipase (MAGL) occupancy assay.

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

[0043] In a further aspect, the present invention provides a radiolabeled compound as described herein or a pharma- ceutical composition comprising a radiolabeled compound as described herein, or a pharma- ceutical acceptable salt thereof, for use in a method for diagnostic imaging of monoacylglycerol lipase (MAGL) in a mammalian brain.

[0044] In a further aspect, the present invention provides the use of a radiolabeled compound as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a radiolabeled compound as described herein, in a method for diagnostic imaging of monoacylglycerol lipase (MAGL) in a mammalian brain.

[0045] In a further aspect, the present invention provides the use of a radiolabeled compound as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for diagnostic imaging of monoacylglycerol lipase (MAGL) in a mammalian brain.

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

[0047] In one embodiment, said imaging of monoacylglycerol lipase (MAGL) in the mammalian brain comprises contacting monoacylglycerol lipase (MAGL) with a radiolabeled compound disclosed herein or a pharma- ceutically 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 hydrochloric acid, CH3CN, 50 °C, 4-5 h, 85%; c) Sodium cyanoborohydride, furan-2-yl(piperazin-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-pyrrol-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 min, the reaction mixture was heated at 50° C. for 14 h. The reaction was cooled to room temperature and 1 M HCl was added to adjust the pH to 3. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were 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 h. The reaction was concentrated and the product was crystallized from methanol / diisopropyl ether (1:1). After washing with diisopropyl ether, the desired product was obtained as a white powder (1.46 g, 25%). 1 H 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). 11 H 11 INO2 + [M+H] + HRMS (ESI) calculated for 315.9829 m / z, observed 315.9828 m / z.

[0052] Step b - Synthesis of 4-hydroxy-1-(4-iodophenyl)-1,5-dihydro-2H-pyrrol-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. Once 2 was consumed as monitored by LC-MS, 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 directly applied to the next step without further purification.

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

[0055] Compound 3 (570 mg, 1.89 mmol) and furan-2-yl(piperazin-1-yl)methone (409 mg, 2.27 mmol) in 10 mL of anhydrous THF were stirred at room temperature for 10 min. Then, acetic acid (217 μL, 3.8 mmol) was added dropwise followed by sodium cyanoborohydride (357 mg, 5.68 mmol). The reaction mixture was stirred at room temperature under nitrogen protection for 22 h. Water was added to quench the reaction, and the resulting mixture was extracted with EtOAc and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. Flash column chromatography was performed with EtOAc to give 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] + HRMS (ESI) calculated for 466.0622 m / z, observed 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)pyrrolidin-2-one (Compound (I))

[0057] (3-Methoxylphenyl)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-neck flask. The system was then closed and filled with nitrogen. 5 mL of DMF, previously purged with nitrogen, was added to the flask and the resulting mixture was heated at 85° C. under reflux overnight. Once compound 4 was consumed, the reaction was cooled to room temperature, filtered and concentrated. The crude product was purified by preparative HPLC to give the desired product as a colorless solid (87 mg, 76%). Chiral separation was performed using supercritical fluid chromatography (SFC) to isolate the title compound. 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] + Calculated HRMS(ESI) m / z 468.1894, found 468.1894 m / z.

[0058] Example 3 - Synthesis of (R)-1-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-(4-(furan-2-carbonyl)piperazin-1-yl)pyrrolidin-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) to give the title compound as a white powder after chiral separation. 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] + HRMS (ESI) calculated for 456.1694 m / z, observed 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)pyrrolidin-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) to give the title compound as a white powder after chiral separation. 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 C 25 H 25 FN3O3 + [M+H] + HRMS (ESI) calculated for 434.1874 m / z, observed 434.1875 m / z.

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

[0063] Scheme 2. Precursor 5 and [ 11 C]-Ia) Synthesis of BBr3, anhydrous DCM, 0°C, overnight; 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)pyrrolidin-2-one (5)

[0065] To a solution of compound (I) (107 mg, 0.241 mmol) in 5 mL of anhydrous dichloromethane was added 1 M boron tribromide in dichloromethane (1.90 mL, 1.93 mmol) dropwise at 0 °C. The reaction mixture was then stirred at room temperature upon consumption of the reagent. The reaction was quenched by adding saturated NaHCO3 solution, and the resulting mixture was extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by flash column chromatography (silica gel, EtOH / CHCl3 = 1 / 35 to 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 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] + HRMS (ESI) calculated for 432.1918 m / z, observed 432.1920 m / z.

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

[0067] by bombarding a nitrogen gas target enriched with 0.5% oxygen using the Cyclone 18 / 9 cyclotron (18 MeV; IBA, Belgium). 14 N(p,α) 11 C nuclear reaction [ 11 C]CO2 was then produced by the nickel-catalyzed [ 11 C]CO2 reduction [ 11 C]CH4 and then gas-phase iodination was used to obtain [ 11 C]CH3I was produced. 11 [C]CH3I was bubbled into a reaction vial containing 5 mg of Cs2CO3 and 0.5 mg of the phenol precursor (1 mg / mL in anhydrous DMF, 0.5 mL). The mixture was then heated at 90 °C for 3 min. After dilution with 1.6 mL of water, the reaction mixture was loaded onto a semi-preparative HPLC for purification. The collected fractions were diluted with 8 mL of Milli-Q water and passed through a preconditioned C18 light cartridge (Waters, WAT023501), followed by washing with 5 mL of Milli-Q water. After elution with 0.5 mL of EtOH, the final radioligand was combined with phosphate buffered saline (9.5 mL, Gibco) to obtain a neutralized solution. The identity of the radiotracer was confirmed by co-injection with compound (I) in an analytical HPLC, and the radiochemical purity was greater than 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 [ 18Radiosynthesis of [F]-III. a) 1,4-phenyldiboronic acid, potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, anhydrous DMF, 80 °C, 4 h, for 6, 1,3-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene; for 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® 222, K2C2O4, K2CO3 and Cu(OTf)2Py4, DMA / n-BuOH=2 / 1, 110°C, 10 min.

[0070] Step a, 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)pyrrolidin-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-neck flask under nitrogen protection. Compound 4 (100 mg, 0.22 mmol) dissolved in 5 mL of anhydrous DMF was added to the flask in one portion 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 EtOAc and the combined organic layers were washed with MgSO 4、 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by flash column chromatography (silica gel, EtOAc) to give the title compound as a brown powder (47 mg, 41%). Chiral separation was performed using supercritical fluid chromatography (SFC) to isolate 6 as the R-isomer: 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] + HRMS (ESI) calculated for 542.2826 m / z, observed 542.2828 m / z.

[0072] Step a, 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)pyrrolidin-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-neck flask under nitrogen protection. Compound 4 (130 mg, 0.28 mmol) dissolved in 5 mL of anhydrous DMF was added to the flask in one portion 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 EtOAc and the combined organic layers were washed with MgSO 4、 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by flash column chromatography (silica gel, EtOAc) to give the title compound as a brown powder (148 mg, 49%). Chiral separation was performed using supercritical fluid chromatography (SFC) to isolate 7 as the R-isomer: 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 Hz,1H),4.04-3.94(m,1H),3.92-3.72(m,5H),3.30(p,J=7.5 Hz,1H),2.80(dd,J=16.7,8.1 Hz,1H),2.73-2.54(m,5H),1.36(s,12H).C 31 H 37 BN3O5 + [M+H] + HRMS (ESI) calculated for 542.2826 m / z, observed 542.2828 m / z.

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

[0075] [ 18 F] fluoride ion 18 O(p,n) 18 98% enrichment by F nuclear reaction 18O was produced by water bombardment. The aqueous solution was transferred from the cyclotron to a hot cell and trapped 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 a 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 min with a vent needle. After dilution with 2.7 mL of water, the mixture was carried forward to semi-preparative HPLC purification. The title compound was collected, 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 Synthesis of F]-II)

[0077] Using 2–3 mg of precursor 7, ([ 18 The title compounds were synthesized by a similar procedure to [F]-III), and their identities were confirmed by co-injection of the corresponding compounds in analytical HPLC with radiochemical purity of >99%.

[0078] Example 7 - MAGL Inhibitory Activity Compounds may be profiled for MAGL inhibitory activity by detecting enzymatic activity following hydrolysis of the natural substrate 2-arachidonoylglycerol to yield arachidonic acid, followed by mass spectrometry, hereinafter abbreviated as "2-AG assay."

[0079] The 2-AG assay was performed in a total volume of 20 μL in 384-well assay plates (PP, Greiner, Cat. No. 784201). Compound dilutions were made in 3-fold dilution steps in 100% DMSO (VWR Chemicals 23500.297) in polypropylene plates to give a final concentration range of 12.5 μM to 0.8 pM in the assay. 0.25 μL of compound dilution (100% DMSO) was added to 9 μL of MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100ml), 0.01% (vol / vol) Tween). After shaking, the plate was incubated at room temperature for 15 min. To start the reaction, 10 μL of 2-arachidonoylglycerol in assay buffer was added. The final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglyerol. After shaking and incubation at room temperature for 30 min, the reaction was quenched by adding 40 μL of acetonitrile containing 4 μM d8-arachidonic acid. The amount of arachidonic acid was followed 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, following the mass transitions 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 cut at a thickness of 10 μm on a cryostat (Cryo-Star HM 560 MV; Microm, Thermo Scientific, Wilmington, DE) and stored at −20°C before use. Before the experiment, slices were thawed on ice for 10 min 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) for 10 min at 0°C for preconditioning. Once dry, incubation was performed in a humidified chamber with the radiotracer for 30 min at room temperature. For blocking studies, 10 μM SAR127303 or 10 μM PF-06809247 were used. After incubation, the sections were decanted and a washing procedure was performed. The slices were dried and then mounted on a phosphor imager plate (Fuji, Dielsdorf, Switzerland) and exposure lasted for 60 min. The films were later scanned by 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 slices 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). 11The highest accumulation of [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 in a blocking manner at a concentration of 10 μM to measure the [C]-I accumulation on rat brain slices. 11 C-I competed for specific binding. Substantial reduction and homogenous distribution of radioactivity was observed in both cases, when the probe was simply incubated on MAGL KO brain sections. These results are consistent with the in vitro [ 11 These results confirm the high specificity and selectivity of [C]-I and suggest a reduced possibility of off-target binding in vivo.

[0083] Example 9 - In vivo PET scan Animals were anesthetized using isoflurane and placed in a PET / CT scanner (Super Argus, Sedecal, Madrid, Spain). Radioactive tracers were injected intravenously and data were acquired 1 min after injection. Dynamic PET scans were performed using 11 C]-I lasted for 60 minutes, but [ 18 F]-II and [ 18 The time was extended to 90 min for [F]-III. The data obtained are in a format of 0.3875 × 0.3875 × 0.775 mm 3 Brain images were reconstructed in user-defined time frames with a voxel size of 100 μm. Regions of interest (ROIs) were defined on the MRI T2 (W. Schiffer) template provided by PMOD v4.002 (PMOD Technologies, Zurich, Switzerland) to generate corresponding time-activity curves (TACs). Radioactivity accumulation in the whole brain and in different regions was expressed as standardized uptake values ​​(SUVs), which are decay-corrected regional radioactivity normalized to injected radioactivity and body weight.

[0084] result All three radioactive tracers were able to cross the blood-brain barrier and reached maximum accumulation levels in the mouse brain within 5 min. 18 F]-II and [ 18 Representative whole-brain TACs from [F]-III are shown in Figure 3. Significantly faster clearance from the brain was observed in MAGL KO mice 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 F]T-401) as a Novel Positron-Emission Tomography Imaging Agent for Monoacylglycerol Lipase. J Med Chem. 2019;62:2362-2375)) compared with 11 [C]-I (SUV at 1 min p.i. max approx. 1.32), [ 18 F]-II (SUV at 1 min p.i. max Approximately 1.56) and [ 18 F]-III (SUV at 1 min p.i. max A significantly increased brain uptake was achieved by 1.63% of the sera. The heterogeneous distribution of the probe in vivo was highly consistent with the MAGL expression levels in mouse brain. 11 Representative PET images of [C]-I are shown in Figure 2 .

[0085] Example 10 - Drug Occupancy Test [ 18To investigate the usefulness of [F]-II, drug occupancy studies were performed after verifying in vitro / vivo specificity. A potent and selective covalent MAGL inhibitor PF-06795071, originally developed for anti-inflammatory treatment, was applied in 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 / saline (v / v / v=5 / 5 / 90). Animals were then placed in a 50-mL 10 ... 18 Patients were treated with increasing doses of PF-06795071 (0.002, 0.01, 0.05, 0.2 and 2 mg / kg) 1 h prior to administration of [F]-II (4.15-11.13 MBq, 6.84-13.19 nmol / kg). In vivo PET scans and data reconstruction were performed as described in Example 9. SUV 0-90分 SUVs from whole brain TACs were averaged from 0 to 90 min to obtain (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 For the values, nonlinear curves were fitted with GraphPad Prism Software (version 8.3.4, GraphPad Software Inc).

[0086] result In mouse brain, 18 A dose-dependent decrease in [F]-II accumulation was observed at doses of PF-06795071 ranging from 0.002 to 2 mg / kg. The mean SUV 0-90分 was transferred to target occupancy and fitted to a saturation equation to determine drug-target engagement (Figure 4). The dose required for PF-06795071 to occupy 50% MAGL in mouse brain was 0.034 mg / kg. This study demonstrates the utility of PF-06795071 as a reversible MAGL PET tracer to visualize drug-target engagement in vivo and to noninvasively quantify drug occupancy. 18 We demonstrated the utility of [F]-II. Target occupancy with a reversible MAGL PET tracer in rodents is unprecedented. These findings support our understanding of the efficacy of [ 18 Our results indicate that [F]-II is a highly promising PET probe for noninvasively visualizing 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 with mutations Lys36Ala, Leu169Ser and Leu176Ser was concentrated to 10.8mg / ml. Crystallization trials were performed in a sitting drop vapor diffusion setup at 21°C. Crystals appeared within 2 days from 0.1M MES pH6.5, 6-13% PEG MME5K, 12% isopropanol. Crystals were soaked in crystallization solution supplemented with 10mM compound II for 16 hours. For data collection, crystals were flash cooled at 100K and 20% ethylene glycol was added to the soaking solution as cryoprotectant. X-ray diffraction data were collected at a wavelength of 0.9999Å using an Eiger2X 16M detector at beamline X10SA at the Swiss Light Source (Villigen, Switzerland). The data were processed with XDS (Kabsch W, XDS. Acta Cryst. D66, 125-132 (2010)) and scaled with SADABS (BRUKER). The crystal belongs to space group C2221 with cell axes a=89.96 Å, b=127.45 Å, c=63.03 Å and diffracts to 1.65 Å resolution.The structure was determined by molecular replacement with PHASER (McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn et al., J. Biol. 2013, 631-632 (2013)) using the coordinates from 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)). MD,Storoni LC,&Read,RJPhaser crystallographic software. J Appl Cryst. 40,658-674(2007)).

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

Claims

【Request 1】 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein said compound optionally comprises a radiolabel.

2. The radiolabel is １１ C and １８ 2. The compound of claim 1, wherein the compound is selected from: F. 【Request 3】 【Chemical 2】 3. The compound of claim 2, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 【Request 4】 【Chemical 3】 3. The compound according to claim 2, wherein: 【Request 5】 【Chemical 4】 3. The compound according to claim 2, wherein: 【Request 6】 【Chemical 5】 3. The compound according to claim 2, wherein:

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

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

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

10. A pharmaceutical composition comprising the 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 to a mammal a detectable amount of the radiolabeled compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof; and (b) detecting the radiolabeled compound when associated with MAGL. A method for imaging monoacylglycerol lipase (MAGL) in the mammalian brain, comprising: A pharmaceutical composition comprising the radiolabeled compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for use in

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

13. 10. The compound of claim 1 for use in the treatment or prevention of 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, migraine, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

14. A pharmaceutical composition comprising a compound of claim 1 for use in the treatment or prevention of 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, migraine, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

15. Use of a compound of claim 1 in the preparation of a medicament for use in the treatment or prevention of 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, migraine, depression, inflammatory bowel disease, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain.

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