Arylbenzyl ether compounds with affinity for monoamine oxidase B and their applications

Abstract

This invention relates to the fields of radiopharmaceutical chemistry and clinical nuclear medicine, specifically to an aryl benzyl ether compound with high affinity for monoamine oxidase B (MAO-B) and its applications. This aryl benzyl ether compound has the structure of general formula (I). After radiolabeling, this compound and its derivatives can be used to image MAO-B in the brain, serving as molecular probes for direct targeting of MAO-B and potential surrogate markers for reactive astrocytes.

Description

Technical Field

[0001] This invention relates to the fields of medicinal chemistry and clinical nuclear medicine, and more specifically, to an aryl benzyl ether compound with high affinity for monoamine oxidase B and its applications. Background Technology

[0002] Monoamine oxidases (MAOs) are flavin enzymes highly expressed in the outer mitochondrial membrane of neurons, astrocytes, and other cells. Based on substrate specificity and sensitivity to inhibitors, they can be classified into two subtypes: MAO-A and MAO-B. MAO-B is the dominant subtype in the central nervous system, distributed in the basal forebrain, brainstem, basal ganglia, and thalamus, and is responsible for 70% of global MAO activity. During normal aging, the activity and expression of MAO-B gradually increase with age.

[0003] Astrocytes are important glial cells that play a crucial role in the regulation and maintenance of the blood-brain barrier, synapse formation and ablation, and neurotransmitter circulation. Infections, injuries, and diseases of the central nervous system can activate astrocytes, a process known as astrocyte reactivity. Reactive astrocytes undergo structural and functional alterations, including cell hypertrophy, increased proliferation, and increases in glial fibrillary acidic proteins and vimentin. MAO-B overexpression is also observed in their mitochondrial outer membrane. Literature reports elevated MAO-B expression levels in the brains of patients with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple-system atrophy (MSA), reflecting neuroinflammation induced by glial cell activation in these diseases. The unique biological and pathological characteristics of MAO-B suggest it could serve as a potential target for imaging reactive glial cells during neuroinflammation.

[0004] Currently, several molecular probes targeting MAO-B have been reported. 11 C]-L-deprenyl-D2([ 11 [C]DED) is one of the most commonly used probes for MAO-B imaging in the brain, but its irreversible binding properties and the presence of radioactive metabolites that can penetrate the blood-brain barrier (BBB) ​​interfere with the accurate quantification of imaging results. 11 C]SL25.1188 can reversibly bind to MAO-B, but 11 C's short half-life (20.4 minutes) limits its use to PET centers with cyclotrons. 18F-labeled probes currently only have [ 18 F]SMBT-1 has been reported to be applicable to the imaging of activated astrocytes in the brains of AD patients, therefore, the development of novel [f]SMBT-1 is underway. 18 The F-labeled MAO-B probe, with its high affinity, high selectivity, and excellent pharmacokinetic properties, has high scientific research value and clinical guiding significance for the early diagnosis and targeted treatment of neurodegenerative diseases and neuroinflammatory-related diseases. Summary of the Invention

[0005] This invention proposes an aryl benzyl ether compound with high affinity for monoamine oxidase B (MAO-B) and its applications. This compound exhibits high affinity and selectivity for MAO-B, serving as an inhibitor of MAO-B. Furthermore, by labeling it with a suitable radioisotope, it can be used for nuclear medicine imaging, particularly for imaging activated astrocytes in the brain.

[0006] Firstly, the aryl benzyl ether compounds provided by this invention have the following general formula (I):

[0007]

[0008] in:

[0009] X1 represents N or CH; X2 and X3 each independently represent O or CH2;

[0010] R1, R2, and R3 each independently represent H, 123 / 124 / 125 / 127 I, 18 / 19 F or O(CH2) n 18 / 19 F, n represents 1-6;

[0011] Ar said

[0012] The compound of general formula (I) provided by this invention, which is mainly composed of aryl benzyl ether structures, has high affinity and selectivity for monoamine oxidase B, and has been radioisotoped. 18 Following F-labeling, the drug can serve as a molecular probe targeting MAO-B and a potential surrogate marker for reactive astrocytes in nuclear medicine imaging. It holds promise for diagnosis, drug dosage, and efficacy evaluation in patients with neurodegenerative diseases characterized by upregulated MAO-B expression, including Alzheimer's disease, progressive supranuclear palsy, primary age-related tau disease, Pick's disease, corticobasal degeneration, glial cell globular inclusion body tau disease, amyotrophic lateral sclerosis, and Parkinson's disease.

[0013] Preferably, the arylbenzyl ether compound is selected from the following compounds:

[0014]

[0015]

[0016] In compounds 1-19, F is... 18 F or 19 F.

[0017] The above-mentioned preferred compounds have higher activity, higher affinity for MAO-B, and higher selectivity.

[0018] Secondly, the present invention provides derivatives of the aryl benzyl ether compounds as pharmaceutically acceptable salts, esters, or amides or prodrugs of the aryl benzyl ether compounds.

[0019] Preferably, pharmaceutically acceptable salts of the aryl benzyl ether compounds include hydrochloride, phosphate, and sulfonate salts of the aryl benzyl ether compounds.

[0020] Thirdly, the present invention provides a monoamine oxidase B inhibitor, the active ingredient of which is an aryl benzyl ether compound as described in the first aspect above, or a derivative of an aryl benzyl ether compound as described in the second aspect above.

[0021] Fourth aspect: The present invention provides a diagnostic or detection reagent for central nervous system diseases characterized by upregulated monoamine oxidase B expression, wherein the active ingredient is an aryl benzyl ether compound as described in the first aspect above, or a derivative of an aryl benzyl ether compound as described in the second aspect above.

[0022] Preferably, the diseases include Alzheimer's disease, Parkinson's disease, frontotemporal degenerative disease, chronic traumatic encephalopathy, progressive supranuclear palsy, primary age-related tau proteinosis, Pick's disease, corticobasal degeneration, glial cell globular inclusion body tau proteinosis, amyotrophic lateral sclerosis, and Lewy body dementia.

[0023] Fifthly, the present invention provides the use of the aryl benzyl ether compounds described in the first aspect above, or derivatives of the aryl benzyl ether compounds described in the second aspect above, in the preparation of nuclear medicine imaging agents.

[0024] Specifically, the nuclear medicine imaging agent is a PET imaging agent. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 The following is a schematic diagram of the synthesis process of the compounds in Examples 1-30 of the Invention, wherein the reaction reagents and conditions involved are as follows: (a) potassium carbonate, acetonitrile or N,N-dimethylformamide, 90-120°C, 3 hours; (b) 1-bromo-2-fluoroethane, acetone, potassium carbonate, 80°C, 3 hours; (c) sodium borohydride, methanol, 0°C, 30 minutes; (d) phosphorus tribromide, dichloromethane, 0°C to room temperature, 2 hours; (e) m-chloroperoxybenzoic acid, dichloromethane, room temperature, 3 hours; (f) p-toluenesulfonic anhydride, trimethylamine (1M tetrahydrofuran solution), dichloromethane, room temperature, 10 hours; (g) [ 18 F]F - Kryptofix 2.2.2, potassium carbonate, anhydrous acetonitrile, 65°C, 5 min; (h) p-toluenesulfonic anhydride, chloroform, room temperature, 3 h; adamantyl substituted auxiliary acid, sodium carbonate (10% aqueous solution), ethanol, room temperature, 30 min; (i) [ 18 F]F - Kryptofix 2.2.2, potassium carbonate, anhydrous N,N-dimethylformamide, 120°C, 10 minutes.

[0027] Figure 2 The labeled compound in Example 35 of this invention [ 18 F]2 or [ 18 Figure 9 shows the results of the autoradiography inhibition experiment and immunofluorescence staining in rats.

[0028] Figure 3 The labeled compound in Example 37 of this invention [ 18 PET imaging results of F]2 in SD rats, among which Figure 3 A is [ 18 F]2 time-activity curves in the brains of control and inhibition group SD rats after injection; Figure 3 B shows the micro-PET / CT imaging results of SD rats in the transverse, coronal, and sagittal planes at different time points after injection of the tracer, as well as the whole-body MIP image at 60 minutes.

[0029] Figure 4 The labeled compound in Example 37 of this invention [ 18 PET imaging results of F]9 in SD rats, among which Figure 4 A is [ 18 F]9 time-activity curves in the brains of control and inhibition group SD rats after injection; Figure 4 B shows the micro-PET / CT imaging results of SD rats in the transverse, coronal, and sagittal planes at different time points after injection of the tracer, as well as the whole-body MIP image at 60 minutes.

[0030] Figure 5 The labeled compound in Example 38 of this invention [ 18 F]2 PET imaging results of APP / PS1 model mice and C57BL / 6 control mice. Detailed Implementation

[0031] To facilitate understanding of the present invention, the implementation process of the present invention will be further described below with reference to specific embodiments. These descriptions are only for further illustrating the features and advantages of the present invention, and are not intended to limit the scope of the claims.

[0032] Example 1: Synthesis of standard compound 1

[0033]

[0034] 2-Fluoro-5-hydroxypyridine (13.8 mg, 0.12 mmol) and 7-bromomethylcoumarin (29.2 mg, 0.12 mmol) were dissolved in 10 mL of DMF, and potassium carbonate (84.3 mg, 0.60 mmol) was added. The mixture was refluxed at 110 °C for 2 hours. After the reaction was complete, the DMF was removed under reduced pressure, 20 mL of dichloromethane was added, the mixture was sonicated, filtered, and the dichloromethane was removed under reduced pressure. Recrystallization gave 18.6 mg of a white solid, with a yield of 57.1%. 1 H NMR (600MHz, DMSO-d6) δ8.08(d,J=9.5Hz,1H),8.00(s,1H),7.75(d,J=7.9Hz,1H),7.70(t,J=6.1Hz,1H ),7.50(s,1H),7.44(d,J=7.8Hz,1H),7.15(dd,J=8.8,2.8Hz,1H),6.51(d,J=9.5Hz,1H),5.31(s,2H).

[0035] Example 2: Synthesis of standard compound 2

[0036]

[0037] Compound 2 was prepared using the same method as compound 1, with 5-bromomethyl-2-fluoropyridine and 7-hydroxycoumarin as raw materials. The product was a white solid, 220.5 mg, with a yield of 81.3%. 1H NMR (400MHz, CDCl3) δ8.31(s,1H),7.90(td,J=8.0,2.6Hz,1H),7.65(d,J=9.5Hz,1H),7.41(d,J=8 .5Hz,1H),7.00(dd,J=8.4,3.1Hz,1H),6.90(d,J=9.3Hz,2H),6.29(d,J=9.5Hz,1H),5.12(s,2H).

[0038] Example 3: Synthesis of standard compound 3

[0039]

[0040] Compound 3 was prepared using the same method as compound 1, with 5-bromomethyl-2-fluoropyridine and 2,4-dihydroxyacetophenone as raw materials. The product was a white solid, 212.9 mg, with a yield of 81.5%. 1 H NMR(400MHz, CDCl3) δ8.29(d,J=2.1Hz,1H),7.88(td,J=8.3,2.5Hz,1H),7.70–7.6 3(m,1H),6.99(dd,J=8.4,2.9Hz,1H),6.53–6.48(m,2H),5.08(s,2H),2.57(s,3H).

[0041] Example 4: Synthesis of standard compound 4

[0042]

[0043] Compound 4 was prepared using the same method as compound 1, with 5-bromomethyl-2-fluoropyridine and 4-hydroxyacetophenone as raw materials. The product was a white solid, 184.7 mg, with a yield of 75.3%. 1 H NMR (400MHz, CDCl3) δ8.30(s,1H),7.96(d,J=8.8Hz,2H),7.89(td,J=8.1,2.4Hz,1H),7.00(dd,J=8.5,4.1Hz,3H),5.12(s,2H),2.57(s,3H).

[0044] Example 5: Synthesis of standard compound 5

[0045]

[0046] Compound 5 was prepared using the same method as compound 1, with 5-bromomethyl-2-fluoropyridine and 3-hydroxy-4H-1-benzopyran-4-one as raw materials. The product was a white solid, 196.1 mg, with a yield of 72.3%. 1H NMR (400MHz, CDCl3) δ8.28(dd,J=8.0,1.6Hz,1H),8.25(d,J=2.0Hz,1H),7.98(td,J=8.0,2.5Hz,1H),7.82(s,1H),7.6 7(ddd,J=8.6,7.1,1.6Hz,1H),7.45(d,J=8.5Hz,1H),7.41(t,J=7.6Hz,1H),6.96(dd,J=8.4,2.9Hz,1H),5.17(s,2H).

[0047] Example 6: Synthesis of standard compound 6

[0048]

[0049] Compound 6 was prepared using the same method as compound 1, with 5-bromomethyl-2-fluoropyridine and 6-hydroxy-2H-benzofuran-3-one as raw materials. The product was a white solid, 187.4 mg, with a yield of 72.4%. 1 H NMR(400MHz, CDCl3)8.31(s,1H),7.89(td,J=8.0,2.5Hz,1H),7.61(d,J=8.6Hz,1H),7.01(dd,J =8.4,2.9Hz,1H),6.72(dd,J=8.6,2.1Hz,1H),6.63(d,J=2.1Hz,1H),5.12(s,2H),4.64(s,2H).

[0050] Example 7: Synthesis of standard compound 7

[0051]

[0052] Compound 7 was prepared using the same method as compound 1, with 2-fluorobenzyl bromide and 7-hydroxycoumarin as raw materials. The product was a white solid, 75.9 mg, with a yield of 81.9%. 1 H NMR(600MHz,DMSO-d6)δ8.00(d,J=9.5Hz,1H),7.65(d,J=8.6Hz,1H),7.59(td,J=7.6,1.6Hz,1H),7.49–7.39(m ,1H),7.30–7.23(m,2H),7.13(d,J=2.4Hz,1H),7.03(dd,J=8.6,2.4Hz,1H),6.31(d,J=9.5Hz,1H),5.25(s,2H).

[0053] Example 8: Synthesis of standard compound 8

[0054]

[0055] Compound 8 was prepared using the same method as compound 1, with 3-fluorobenzyl bromide and 7-hydroxycoumarin as raw materials. The product was a white solid, 65.4 mg, with a yield of 89.3%. 1 H NMR (400MHz, CDCl3) δ7.64(d,J=9.5Hz,1H),7.42–7.34(m,2H),7.20(d,J=7.7Hz,1H),7.15(d,J=9.5Hz,1H),7.0 4(td,J=8.4,2.3Hz,1H),6.92(dd,J=8.6,2.4Hz,1H),6.87(d,J=2.4Hz,1H),6.27(d,J=9.5Hz,1H),5.13(s,2H).

[0056] Example 9: Synthesis of standard compound 9

[0057]

[0058] Compound 9 was prepared using 4-fluorobenzyl bromide and 7-hydroxycoumarin as raw materials, following the preparation method of compound 1. The product was a white solid of 224.9 mg, with a yield of 83.2%. 1 H NMR (400MHz, CDCl3) δ7.64(d,J=9.5Hz,1H),7.44–7.37(m,3H),7.10(t,J=8.6Hz,2H),6.93–6.87(m,2H),6.26(d,J=9.5Hz,1H),5.09(s,2H).

[0059] Example 10: Synthesis of standard compound 10

[0060]

[0061] Compound 10 was prepared using the same method as compound 1, with 2-fluorophenol and 7-bromomethylcoumarin as raw materials. The product was a white solid, 35.8 mg, with a yield of 83.5%. 1 H NMR (600MHz, DMSO-d6) δ8.07(d,J=9.5Hz,1H),7.75(d,J=7.9Hz,1H),7.47(s,1H),7.44(d,J=7.9Hz, 1H),7.29–7.17(m,2H),7.12(t,J=7.8Hz,1H),7.02–6.89(m,1H),6.50(d,J=9.5Hz,1H),5.31(s,2H).

[0062] Example 11: Synthesis of standard compound 11

[0063]

[0064] Compound 11 was prepared using the same method as compound 1, with 3-fluorophenol and 7-bromomethylcoumarin as raw materials. The product was a white solid, 94.3 mg, with a yield of 82.5%. 1 H NMR (600MHz, DMSO-d6) δ8.07(d,J=9.5Hz,1H),7.74(d,J=7.9Hz,1H),7.47(s,29H),7.42(dd,J=7.9,1.3Hz,1H),7.36–7.30(m, 1H), 6.93 (dt, J=11.3, 2.4Hz, 1H), 6.89 (dd, J=8.2, 2.1Hz, 1H), 6.79 (td, J=8.3, 2.2Hz, 1H), 6.50 (d, J=9.5Hz, 1H), 5.25 (s, 2H).

[0065] Example 12: Synthesis of standard compound 12

[0066]

[0067] Compound 12 was prepared using the same method as compound 1, with 4-fluorophenol and 7-bromomethylcoumarin as raw materials. The product was a white solid, 95.7 mg, with a yield of 88.2%. 1 H NMR (600MHz, DMSO-d6) δ8.07(d,J=9.5Hz,1H),7.74(d,J=7.9Hz,1H),7.46(s,1H),7.42(d, J=7.9Hz,1H),7.14(t,J=8.8Hz,2H),7.10–6.99(m,2H),6.49(d,J=9.5Hz,1H),5.21(s,2H).

[0068] Example 13: Synthesis of standard compound 13

[0069]

[0070] Following the preparation method of compound 1, standard compound 13 was prepared from 2-fluorobenzyl bromide and 6-hydroxycoumarin, yielding a white solid of 65.3 mg and a yield of 79.8%. 1 H NMR (600MHz, DMSO-d6) δ8.01(d,J=9.6Hz,1H),7.58(t,J=7.4Hz,1H),7.43(dd,J=15.2,7 .1Hz,2H),7.36(d,J=9.0Hz,1H),7.33–7.23(m,3H),6.50(d,J=9.5Hz,1H),5.19(s,2H).

[0071] Example 14: Synthesis of standard compound 14

[0072]

[0073] Following the preparation method of compound 1, standard compound 14 was prepared from 3-fluorobenzyl bromide and 6-hydroxycoumarin, yielding 78.2 mg of a white solid with a yield of 83.9%. 1 H NMR (600MHz, DMSO-d6) δ8.01(d,J=9.6Hz,1H),7.52–7.42(m,1H),7.41–7.28(m,5H),7.23–7.12(m,1H),6.50(d,J=9.5Hz,1H),5.18(s,2H).

[0074] Example 15: Synthesis of standard compound 15

[0075]

[0076] Compound 15 was prepared from 4-fluorobenzyl bromide and 6-hydroxycoumarin using the same method as compound 1. The compound was a white solid, yielding 94.9 mg, with a yield of 91.6%. 1 H NMR(600MHz,DMSO-d6)δ8.01(d,J=9.6Hz,1H),7.52(s,2H),7.43–7.34(m,2H),7. 28(dd,J=9.0,3.0Hz,1H),7.27–7.20(m,2H),6.50(d,J=9.5Hz,1H),5.13(s,2H).

[0077] Example 16: Synthesis of standard compound 16

[0078]

[0079] Compound 16 was prepared using the same method as compound 1, with 2-fluorophenol and 6-bromomethylcoumarin as raw materials. The result was a white solid, 75.2 mg, with a yield of 87.9%. 1 H NMR (600MHz, DMSO-d6) δ8.15–8.07(m,1H),7.82(d,J=1.9Hz,1H),7.70(dd,J=8.5,2.0Hz,1H),7.44(d,J=8.5Hz,1H),7.27(td,J= 8.6, 1.3Hz, 1H), 7.23 (ddd, J=11.8, 8.1, 1.4Hz, 1H), 7.13 (t, J=7.9Hz, 1H), 7.00–6.89 (m, 1H), 6.52 (d, J=9.5Hz, 1H), 5.23 (s, 2H).

[0080] Example 17: Synthesis of standard compound 17

[0081]

[0082] Compound 17 was prepared using the same method as compound 1, with 3-fluorophenol and 6-bromomethylcoumarin as raw materials. The result was a white solid, 78.4 mg, with a yield of 81.2%. 1 H NMR (600MHz, DMSO-d6) δ8.10(d,J=9.6Hz,1H),7.82(d,J=1.9Hz,1H),7.69(dd,J=8.5,2.1Hz,1H),7.44(d,J=8.5Hz,1H),7.39–7.28 (m,1H),6.93(dt,J=11.3,2.4Hz,1H),6.88(dd,J=8.2,2.1Hz,1H),6.79(td,J=8.5,2.4Hz,1H),6.52(d,J=9.5Hz,1H),5.18(s,2H).

[0083] Example 18: Synthesis of standard compound 18

[0084]

[0085] Compound 18 was prepared using the same method as compound 1, with 4-fluorophenol and 6-bromomethylcoumarin as raw materials. The result was a white solid, yielding 87.3 mg, with a yield of 93.0%. 1 H NMR (600MHz, DMSO-d6) δ8.09(d,J=9.6Hz,1H),7.80(d,J=1.8Hz,1H),7.68(dd,J=8.5,2.0Hz,1H),7.43( d,J=8.5Hz,1H),7.13(t,J=8.8Hz,2H),7.04(dd,J=9.1,4.4Hz,2H),6.52(d,J=9.5Hz,1H),5.14(s,2H).

[0086] Example 19: Synthesis of intermediate compound 19

[0087]

[0088] 4-Hydroxybenzaldehyde (800 mg, 6.55 mmol) and 1-bromo-2-fluoroethane (4175.9 mg, 32.75 mmol) were dissolved in 30 mL of acetone, and potassium carbonate (1810.6 mg, 13.1 mmol) was added. The mixture was refluxed at 80 °C for 3 hours. After the reaction was complete, the mixture was filtered, and acetone was removed under reduced pressure. The product was a yellow oily liquid, 1057.5 mg, with a yield of 96.0%.1 H NMR(400MHz, CDCl3)δ9.88(s,1H),7.88–7.78(m,2H),7.06–6.99(m,2H),4 .85–4.82(m,1H),4.73–4.70(m,1H),4.34–4.31(m,1H),4.27–4.24(m,1H).

[0089] Example 20: Synthesis of intermediate compound 20

[0090]

[0091] 5-Bromomethyl-2-fluoropyridine 9 (350 mg, 2.08 mmol) was dissolved in 10 mL of methanol. Sodium borohydride (157.5 mg, 4.16 mmol) was slowly added under ice bath conditions. After reacting for 30 minutes, the reaction was quenched with water. Methanol was removed by vacuum distillation, and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and the solvent was removed by vacuum evaporation to obtain 319.6 mg of a colorless oily liquid, with a yield of 90.3%. 1 H NMR (600MHz, CDCl3) δ7.26 (dd, J = 8.7, 2.0Hz, 2H), 6.95–6.81 (m, 2H), 4.82–4.64 (m, 2H), 4.58 (s, 2H), 4.28–4.09 (m, 2H), 2.02 (s, 1H).

[0092] Example 21: Synthesis of intermediate compound 21

[0093]

[0094] Intermediate 20 (302.4 mg, 2.38 mmol) was dissolved in 10 mL of dichloromethane, and phosphorus tribromide (644.7 mg, 226 μL, 2.38 mmol) was slowly added dropwise at 0 °C. The mixture was then allowed to return to room temperature and the reaction was continued for 2 hours. After the reaction was complete, a saturated sodium bicarbonate solution was added, and the organic phase was dried over anhydrous MgSO4 after separation. The solvent was removed by evaporation under reduced pressure to obtain 510.4 mg of a yellow oil, with a yield of approximately 92.0%. Considering the potential for product deterioration, the product was not further purified and proceeded directly to the next step of the reaction.

[0095] Example 22: Synthesis of standard compound 22

[0096]

[0097] Compound 22 was prepared using intermediate 21 and 7-hydroxycoumarin as raw materials according to the preparation method of compound 1. It was a white solid of 239.5 mg with a yield of 76.2%.1 H NMR (400MHz, CDCl3) δ7.63(d,J=9.5Hz,1H),7.38(s,1H),7.36(s,1H),6.96(d,J=8.6Hz,2H),6.92–6.87(m,2H),6.26(d ,J=9.5Hz,1H),5.06(s,2H),4.83(t,J=4.0Hz,1H),4.71(t,J=4.0Hz,1H),4.27(t,J=4.0Hz,1H),4.20(t,J=4.0Hz,1H).

[0098] Example 23: Synthesis of intermediate compound 23

[0099]

[0100] Following the preparation method of compound 1, intermediate 23 was prepared from 3-bromomethylpyridine hydrobromide and 4-hydroxyacetophenone as raw materials. The intermediate was a white solid, 130 mg, with a yield of 57.2%. 1 H NMR (400MHz, CDCl3) δ8.70(s,1H),8.61(d,J=4.7Hz,1H),7.95(d,J=8.7Hz,2H),7.79(d,J =7.8Hz,1H),7.35(dd,J=8.0,4.8Hz,1H),7.01(d,J=9.0Hz,2H),5.15(s,2H),2.56(s,3H).

[0101] Example 24: Synthesis of intermediate compound 24

[0102]

[0103] Intermediate 23 (130.0 mg, 0.6 mmol) was dissolved in 15 mL of dichloromethane. Then, m-chloroperoxybenzoic acid (m-CPBA, 118.5 mg, 0.7 mmol) was added to the solution, and the reaction was carried out at room temperature for 3 hours. After the reaction was complete, the dichloromethane was removed under reduced pressure, and the product was separated by silica gel column chromatography to give 127.1 mg of a white solid, with a yield of 91.7%. 1 H NMR (400MHz, CDCl3) δ8.37(s,1H),8.20(d,J=5.2Hz,1H),7.96(d,J=9.0Hz,2H),7.34(d,J=5.1Hz,2H),6.99(d,J=9.0Hz,2H),5.11(s,2H),2.57(s,3H).

[0104] Example 25: Synthesis of precursor compound 25

[0105]

[0106] Intermediate compound 24 (200 mg, 0.82 mmol) was dissolved in 20 mL of dichloromethane. P-Toluenesulfonic anhydride (535.27 mg, 1.64 mmol) was added, and the mixture was stirred for 30 minutes. Then, a tetrahydrofuran solution of trimethylamine (1 M, 16.4 mL, 16.4 mmol) was slowly added, and the mixture was stirred for another 30 minutes. Next, p-Toluenesulfonic anhydride (267.64 mg, 0.82 mmol) was added, and the mixture was stirred for another 30 minutes. This process of adding p-Toluenesulfonic anhydride (267.64 mg, 0.82 mmol) was repeated twice. After reacting at room temperature for 10 hours, the organic phase was washed with saturated brine. The organic phase was concentrated under reduced pressure, and the resulting solid was dissolved in dichloromethane. The solid was then added dropwise to rapidly stirred diethyl ether, resulting in precipitation. The precipitate was transferred to a centrifuge tube, centrifuged, and the supernatant was discarded. The solid was then washed three more times with diethyl ether, centrifuged, and the supernatant was discarded. The solid was dried under vacuum to obtain a white solid. Further purification was performed using preparative HPLC with a C18 reverse-phase column, an aqueous acetonitrile solution (containing 0.1% TFA) as the mobile phase, a flow rate of 4 mL / min, and a product retention time of 22.3 min. After freeze-drying, a white solid was obtained, with an overall yield of 28.8%. 1 HNMR(400MHz,DMSO-d6)δ8.78(d,J=2.0Hz,1H),8.32(dd,J=8.6,2.2Hz,1H),8.12(d,J=8.7H z,1H),7.96(d,J=8.9Hz,2H),7.16(d,J=8.9Hz,2H),5.38(s,2H),3.59(s,9H),2.53(s,3H).

[0107] Example 26: Synthesis of intermediate compound 26

[0108]

[0109] Following the preparation method of compound 1, intermediate 26 was prepared from 3-bromomethylpyridine hydrobromide and 7-hydroxycoumarin as raw materials. It was a white solid, weighing 381.0 mg, with a yield of 75.5%. 1 H NMR (400MHz, CDCl3) δ8.69(d,J=37.5Hz,2H),7.85(d,J=7.9Hz,1H),7.65(d,J=9.5H z,1H),7.41(d,J=8.5Hz,2H),6.95–6.88(m,2H),6.29(d,J=9.5Hz,1H),5.17(s,2H).

[0110] Example 27: Synthesis of intermediate compound 27

[0111]

[0112] Intermediate 26 (381.0 mg, 1.5 mmol) was dissolved in 15 mL of dichloromethane. Then, m-chloroperoxybenzoic acid (m-CPBA) (310.0 mg, 1.8 mmol) was added to the solution, and the reaction was carried out at room temperature for 3 hours. After the reaction was complete, the dichloromethane was removed under reduced pressure, and the product was separated by silica chromatography to give 349.0 mg of a white solid, with a yield of 86.4%. 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),7.60(s,1H),7.49(d,J=6.5Hz,2H),7.46–7.33(m,4H),6.51(d,J=7.8Hz,1H),5.21(s,2H).

[0113] Example 28: Synthesis of precursor compound 28

[0114]

[0115] Intermediate 27 (180 mg, 0.66 mmol) was dissolved in 10 mL of dichloromethane. P-Toluenesulfonic anhydride (430.8 mg, 1.32 mmol) was added, and the mixture was stirred for 30 minutes. Then, a 1 M trimethylamine solution in tetrahydrofuran (13.2 mL, 13.2 mmol) was slowly added, and the mixture was stirred for another 30 minutes. Next, p-Toluenesulfonic anhydride (215.4 mg, 0.66 mmol) was added, and the mixture was stirred for another 30 minutes. This process of adding p-Toluenesulfonic anhydride (215.4 mg, 0.66 mmol) was repeated twice. After reacting at room temperature for 10 hours, the organic phase was washed with water. The aqueous phases were combined and concentrated under reduced pressure. The resulting solid was dissolved in dichloromethane and added dropwise to rapidly stirred diethyl ether. A precipitate formed; the solid was centrifuged, and the supernatant was discarded. The solid was then washed three more times with diethyl ether, centrifuged again, and the supernatant was discarded. The solid was dried under vacuum to obtain a white solid. Further purification was performed using preparative HPLC with a C18 reverse-phase column, a mobile phase of 20% acetonitrile aqueous solution (containing 0.1% TFA), a flow rate of 4 mL / min, and a product retention time of 25.4 min. After freeze-drying, a white solid was obtained, with an overall yield of 20.0%. 1 H NMR (400MHz, DMSO-d6) δ8.82–8.75(m,1H),8.34(dd,J=8.6,2.3Hz,1H),8.13(d,J=8.6Hz,1H),8.01(d,J=9.5Hz,1H),7. 68(d,J=8.7Hz,1H),7.15(d,J=2.5Hz,1H),7.07(dd,J=8.6,2.5Hz,1H),6.33(d,J=9.5Hz,1H),5.40(s,2H),3.59(s,9H).

[0116] Example 29: Synthesis of intermediate compound 29

[0117]

[0118] According to the preparation method of compound 1, intermediate 29 was prepared from 4-iodobenzyl bromide and 7-hydroxycoumarin, which was a white solid of 470 mg, with a yield of 33.5%. 1 H NMR (400MHz, CDCl3) δ7.73(d,J=8.4Hz,2H),7.63(dd,J=9.5,0.6Hz,1H),7.38(d,J=8.6Hz,1H),7.21 –7.15(m,2H),6.89(dd,J=8.6,2.5Hz,1H),6.86(d,J=2.4Hz,1H),6.26(d,J=9.5Hz,1H),5.07(s,2H).

[0119] Example 30: Synthesis of precursor compound 30

[0120]

[0121] Intermediate 29 (113.4 mg, 0.3 mmol) was dispersed in 10 mL of chloroform, and m-chloroperoxybenzoic acid (m-CPBA) (62.1 mg, 0.36 mmol) was added. After reacting at room temperature for 3 hours, the solvent was removed under reduced pressure. The resulting solid was dissolved in dichloromethane and washed with 100 mL of saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to obtain a white solid. The solid was dispersed in 15 mL of ethanol, and SPIAd (70.9 mg, 0.3 mmol, dissolved in 10% Na2CO3 solution) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, 30 mL of water was added to the reaction flask, and the mixture was extracted with DCM (4 × 20 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain a white solid. The solid was ultrasonically washed with dichloromethane and petroleum ether, centrifuged, and the supernatant was discarded. The washing was repeated twice, and the solid was dried to obtain 40.5 mg of white solid, with a yield of 23.4%. 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=9.5Hz,1H),7.80(d,J=8.3Hz,2H),7.64(d,J=8.6Hz,1H),7.54(d,J=8.4Hz,2H),7.07(d,J=2.4Hz,1H),7. 02(dd,J=8.6,2.4Hz,1H),6.30(d,J=9.5Hz,1H),5.27(s,2H),2.32(s,2H),1.94(s,2H),1.91(s,2H),1.79(s,2H),1.66(s,4H),1.62(s,2H).

[0122] Example 31: MAO-A / B Activity Assay

[0123] I. Experimental Procedure

[0124] 1. MAO-A activity assay

[0125] (1) Dilute the MAO suspension extracted from mouse liver homogenate with PBS, determine the standard working curve and select the appropriate amount of enzyme to use. In this experiment, the enzyme was diluted 2 times before use.

[0126] (2) Preparation of substrate solution: Weigh 7.97 mg tyramine and dissolve it in 10 mL PBS solution; Preparation of colorimetric solution: Weigh 2 mg horseradish peroxidase and add 2 mL distilled water to obtain horseradish peroxidase solution for later use. Accurately weigh 2.03 mg 4-aminoantipyrine and 3.36 mg vanillin, dissolve them in 19.6 mL PBS solution, and then add 400 μL of the prepared horseradish peroxidase solution; Preparation of inhibitor: 1000 nM selegiline aqueous solution.

[0127] (3) Add 30 μL of enzyme solution and 25 μL of inhibitor to a 96-well transparent plate and incubate at 37°C for 30 minutes; then add 50 μL of the test sample at a gradient concentration (10 μL / 200 μL / 300 μL). -4 -10 -10 M) Continue incubation for 30 minutes; then add the substrate and colorimetric reagent solution sequentially and continue incubation for 90 minutes.

[0128] (4) After completion, the UV absorbance at 490 nm was measured using an ELISA reader. The IC50 was calculated with the final concentration of the sample as the x-axis and the absorbance as the y-axis. 50 value.

[0129] 2. MAO-B activity assay

[0130] (1) The test compound was prepared into a series of gradient concentrations (10) -4 -10 -10 M) PBS solution containing 10% DMSO.

[0131] (2) Preparation of working solutions. First, prepare solution 1: dissolve 0.5 mg Amplex Red in 100 μL DMSO; solution 2: dissolve 2 mg horseradish peroxidase in 1.5 mL PBS solution; solution 3: dissolve 14 mg substrate (benzylamine hydrochloride) in 1 mL water. (Solutions 1-3 should be prepared fresh before use). Then, take 100 μL of solution 1, 50 μL of solution 2, and 250 μL of solution 3, and add PBS solution to bring the total volume to 5 mL.

[0132] (3) Prepare enzyme solution. Take 10 μL of pre-amplified MAO-B (25 mg / mL) and dilute it to 10 mL with PBS.

[0133] (4) Add 20 μL of the test compound solution and 98 μL of the enzyme solution to the black 96-well plate in sequence, incubate at 37°C for 30 minutes, add 82 μL of the pre-prepared working solution after incubation, incubate at 37°C for 10 minutes, and then measure the fluorescence intensity at an excitation wavelength of 535 nM and an emission wavelength of 587 nM using an ELISA reader.

[0134] (5) Calculate the IC50 value with the logarithm of the final concentration of the sample to be tested as the abscissa and the fluorescence intensity as the ordinate.

[0135] Table 1 Results of MAO-A / B activity assay for compound 1

[0136]

[0137]

[0138] 1 NA means "not applicable".

[0139] Example 32: Aβ Activity Assay

[0140] I. Experimental Procedure

[0141] (1) Add 100 μL of radioactive ligand ([ 125 I]IMPY, 100000 cpm / 100 μL), 100 μL of the compound in ethanol (10 -4 M to 10 -10 M), 700 μL BSA (0.1% PBS solution) and Aβ 1-42 The aggregate (100 μL, final concentration 0.7 μM) was added sequentially to borosilicate glass test tubes.

[0142] (2) Incubate at 37°C for 2 hours.

[0143] (3) The cells were separated by filtration using an MP-48T cell collector and washed three times with 10% ethanol.

[0144] (4) Collect contents containing Aβ 1-42 Aggregates 125 Glass fiber filter paper containing I-ligand was placed at the bottom of numbered counting tubes, and the radioactivity count in each tube was measured using a Perkinelmer Wizard 2 2480 γ-ray counter. The half-inhibition constant (IC) was used. 50 The suppression constant (K) was obtained through fitting calculation. i ) Calculate K according to the Cheng-Prusoff equation: i =IC 50 / (1+[L] / K d ).

[0145] II. Experimental Results

[0146] The experimental results are shown in Table 2. Most compounds showed good Aβ activity (K i The fact that the concentration was in the micro-mol range indicates that the series of compounds have a very poor binding ability with Aβ and a low degree of off-target binding.

[0147] Table 2: Compound Aβ 1-42 Activity test results

[0148]

[0149]

[0150] Example 33: 18 Preparation of F-labeled compounds

[0151] I. Experimental Procedure

[0152] 1. Compounds [ 18 F]2,[ 18 Preparation of F]4

[0153] [ 18 F]F - Ions were enriched on a QMA column and then elute with 1 mL of ACN / H2O (v / v = 4:1; 13 mg K) 2,2,2 ,1.1mg K2CO3) will [ 18 F]F - Elute the QMA column into a 10 mL penicillin vial, heat in a 120°C metal bath, continuously purge with N2 to dry, then add 1 mL of anhydrous acetonitrile for azeotropic evaporation and dryness. Repeat three times to ensure the reaction system is anhydrous. Dissolve 1 mg of the labeled precursor compound in 0.5 mL of anhydrous acetonitrile, and transfer the solution to a container containing […]. 18 F]F - The reaction mixture was placed in a glass reaction tube and heated to 65°C for 5 minutes. After cooling, 10 mL of deionized water was added to dilute the reaction mixture. The mixture was purified by passing it through a pre-treated Sep-Pak C18 solid-phase extraction column, and the column was washed with 10 mL of deionized water to remove unreacted [products]. 18 F]F - Inorganic salts. The column was eluted with 1 mL of anhydrous ethanol to remove the labeled compound and labeled precursor compound adsorbed on the column. The product was then separated and purified by high performance liquid chromatography using a Venusil MP C18 analytical column (5 μm, 10 mm × 250 mm) equipped with a gamma-ray scintillation detector. The eluent of the target product was collected, the solvent was dried by nitrogen, and the obtained product was dissolved in 10% ethanol and diluted with purified water to the required concentration.

[0154] 2. Compounds [ 18 Preparation of F]9

[0155] [ 18 F]F - Ions were enriched on a QMA column and then elute with 1 mL of ACN / H2O (v / v = 4:1; 13 mg K) 2,2,2 ,1.1mg K2CO3) will [ 18 F]F - Elute the QMA column into a 10 mL penicillin vial, heat in a 120°C metal bath, continuously purge with N2 to dry, then add 1 mL of anhydrous acetonitrile for azeotropic evaporation to dry. Repeat three times to ensure the reaction system is anhydrous. Dissolve 3 mg of the labeled precursor compound in 300 μL of anhydrous DMF, and transfer the solution to a container containing […]. 18 F]F - The product was placed in a glass reaction tube and heated to 120°C for 10 minutes. After cooling, the product was separated and purified by high-performance liquid chromatography (HPLC) using a Venusil MPC18 column (5 μm, 10 mm × 250 mm) equipped with a gamma-ray scintillation detector. The eluent of the target product was collected. The eluent was diluted with 20 mL of water, and the mixture was subjected to solid-phase extraction through a pretreated Sep-Pak C18 column. The Sep-Pak column was washed with 10 mL of deionized water, and the product was eluted with 1 mL of anhydrous ethanol to prepare a 10% ethanol saline solution for subsequent animal experiments.

[0156] II. Experimental Results

[0157] [ 18 F]2,[ 18 F]4,[ 18 The labeling rate of F]9 was greater than 50%, and after HPLC separation and purification, the radiochemical purity was greater than 95%. The chromatographic column was a Venusil MP C18 reverse-phase column (5μm, 10mm×250mm), and the mobile phase flow rate was 4mL / min.

[0158] Example 34: Determination of lipid-water partition coefficient

[0159] I. Experimental Procedure:

[0160] 1. Take 3 mL of n-octanol and 3 mL of PBS solution into a 15 mL centrifuge tube. Add 100 μCi of purified radioligand using a pipette. Vortex for 3 minutes and then centrifuge for 3 minutes. Take 100 μL of sample from each of the n-octanol and PBS solutions, determine the radioactivity count, and calculate the lipid-water partition coefficient according to the following formula.

[0161]

[0162] 2. Transfer 1 mL of n-octanol to another centrifuge tube, add 2 mL of n-octanol and 3 mL of PBS solution, vortex for 3 minutes, and then centrifuge for 3 minutes. Take 100 μL of sample from the n-octanol and 500 μL of sample from the PBS solution, repeat the measurement and calculation until a stable Log D value is obtained.

[0163] II. Experimental Results

[0164] The Log D values ​​for compounds 2, 4, and 9 were measured to be 2.17, 2.33, and 2.66, respectively.

[0165] Example 35: In vivo autoradiography inhibition experiment and immunohistochemical staining

[0166] I. Experimental Procedure:

[0167] (1) In vivo autoradiography inhibition experiment

[0168] Thirty minutes before injection of the radioactive tracer, rats in the inhibition group were pre-injected via tail vein with a saline solution of the inhibitor selegiline (dose calculated at 1 mg / kg), while the control group received no treatment. Subsequently, the rats were injected with the tracer via tail vein. 18 F]2 or [ 18 [F]9 (79.6-157.0 MBq, 0.1 mL, physiological saline solution containing approximately 10% ethanol), and after 15 minutes, the rat was dissected and the whole brain was removed. OCT embedding agent was evenly coated onto the sample holder. The rat's whole brain was fixed in the horizontal section position and placed in a cryostat at an ambient temperature of -20°C for freezing. After the sample was frozen, the sample holder was fixed to the cutting stage, and the angle between the slice and the sample was adjusted. The brain slice thickness was adjusted to 25 μm. After the slide containing the brain slice dried, it was exposed to a phosphor screen for 2 hours. After exposure, the phosphor screen was scanned in a darkroom using an autoradiography system.

[0169] (2) Immunohistochemical staining

[0170] Frozen sections of rat brains with identical stromal sections were immersed in pre-chilled PBS solution for 5 minutes, followed by immersion in pre-chilled acetone for 30 minutes to fix cell morphology. Subsequently, they were sequentially immersed in pre-chilled TE solution containing 0.3% Triton X-100 (pH=9) for 20 minutes, and then in methanol solution containing 3% H2O2 for 10 minutes to block endogenous catalase. After rinsing, the sections were incubated in 3% BSA solution at room temperature for 1 hour to block serum. After rinsing, primary antibody (monoamine oxidase, Proteintech, 12602-1-AP, dilution 1:100) was added, and the sections were incubated overnight at 4°C. After warming, the sections were washed with TBST, followed by incubation with secondary antibody (Goat anti-rabbit (HRP*) (RS0002), dilution 1:1000) for 1-2 hours. The sections were then mounted and scanned.

[0171] II. Experimental Results:

[0172] Experimental results are as follows Figure 2 As shown, the tracer is visible in the autoradiography results. 18 [F]2 showed significant uptake in the ependymium, habenula, and striatum of the lateral ventricle of rats. Rats in the group receiving prior injection of selegiline showed a significant decrease in radioactive signal intensity at the same locations in these areas. [Tracer] 18 F]9 has a higher affinity for MAO-B, and its specific uptake areas in the rat brain are also more extensive. In addition to the striatum, ependyma of the lateral ventricles, and habenula, radioactive signal accumulation was also observed in the hippocampus, cerebellum, and cerebral cortex. The radioactive signal of the tracer in these areas could be effectively inhibited by selegiline. The experimental results verified the tracer's […]. 18 F]2 and [ 18 F]9 can specifically bind to MAO-B.

[0173] The results of immunofluorescence staining were largely consistent with those of autoradiography. Fluorescent signals of astrocyte morphology could be observed in areas of concentrated radioactive signal (ependymium of the lateral ventricle, habenula, striatum, cerebellum, etc.), further confirming that the tracer accumulated in areas of high MAO-B expression in the brain and specifically bound to the target.

[0174] Example 36: Biodistribution experiment in normal mice

[0175] I. Experimental Procedure:

[0176] 5-10 μCi 18The F-labeled compound (100 μL of physiological saline solution containing 10% ethanol) was injected intravenously into normal mice (ICR, male, 3-4 weeks old, n=3). Mice were sacrificed at 2 and 60 minutes post-injection, and the relevant organs were dissected for wet weight and radioactivity count. Data are expressed as percentage of radioactivity per gram of organ (%ID / g).

[0177] II. Experimental Results:

[0178] The experimental results are shown in Table 3. Compound [ 18 F]2,[ 18 F]4 and [ 18 F]9 can cross the blood-brain barrier smoothly, with peak brain uptake at 2 minutes and rapid clearance in the brain of normal mice. Bone uptake is low within 0-60 minutes, suggesting good stability of the probe in vivo with no obvious metabolic defluorination.

[0179] Table 3: Compounds [ 18 F]2,[ 18 F]4 and [ 18 Distribution of F]9 in normal mice

[0180]

[0181] Example 37: Micro-PET / CT Imaging and Inhibition Experiment of SD Rats.

[0182] I. Experimental Methods:

[0183] Inhibition group SD rats (n=2, 350-500g) were injected via tail vein with selegiline solution (2.5mg / mL, dosage calculated as 1mg / kg) 30 minutes prior to treatment, while control group rats (n=1-2, 400-485g) received no treatment. The labeled compound was administered under isoflurane anesthesia. 18 F]2 or [ 18 F]9 (12.8-14.2 MBq, 0.5-0.8 mL, 10% ethanol saline solution) was injected into rats via the tail vein, followed immediately by a 0-60 minute dynamic PET scan of the head, framed at 15×1 min, 5×5 min, and 2×10 min. After the head scan, a 60-70 minute whole-body PET / CT scan was performed. Quantitative data correction and automatic reconstruction were performed after data acquisition. Using CT as the localization basis, regions of interest (ROIs) were drawn on PMOD software, and the standardized uptake values ​​(SUVs) of these regions were calculated to construct time-activity curves (TACs).

[0184] II. Experimental Results:

[0185] The results of micro-PET / CT dynamic scanning of SD rats showed that, 18 F]2 and [ 18 F]9 can rapidly cross the blood-brain barrier (BBB), and the accumulation of radioactive signals in the brain region is clearly visible. 18 F]2 Whole brain uptake value SUV 1 minute after injection max =2.18, the radioactive signals in the brain were basically completely cleared within 60 minutes, SUV 1min / 60min =12.0;[ 18 F]9 injection reaches peak brain uptake 2 minutes after injection, SUV max =2.13, then quickly cleared from the brain, SUV 2min / 60min =7.9. ​​The in vivo micro-PET / CT imaging results are basically consistent with the in vitro biological distribution.

[0186] Inhibition experiments showed that pre-injection of the inhibitor selegiline could reduce [ 18 F]2 and [ 18 F]9 uptake in the brain, and its effect on [ 18 The inhibition of F]9 was more significant, which also confirms that [ 18 The high affinity between F]9 and MAO-B.

[0187] Example 38: PET imaging of APP / PS1 model mice

[0188] I. Experimental Methods:

[0189] APP / PS1 model mice (n=3, 22 months old, 30-35 mg) or C57BL / 6 control mice (n=2, 22 months old, 32 mg) were administered the labeled compound intravenously under isoflurane anesthesia. 18 After F]2, data acquisition was immediately performed using the instrument. The acquisition procedure and data reconstruction processing method were the same as in Example 37.

[0190] II. Experimental Results:

[0191] micro-PET / CT imaging results showed that, 18 F2 exhibited favorable biological properties in APP / PS1 and C57BL / 6 mice, showing high initial uptake and rapid brain clearance rates in all brain regions. The initial brain uptake value (SUV) in APP / PS1 mice was particularly high. 1min =2.29, Clearance rate SUV 1min / 60min =12.3; C57BL / 6 mouse brain uptake value SUV 1min =2.51, Clearance rate SUV 1min / 60min=12.1. Compared with the control group C57BL / 6 mice, there was no significant difference in the initial brain entry volume and clearance rate of the APP / PS1 model mice.

Claims

1. An arylbenzyl ether compound, characterized in that, Selected from the following compounds: 1) 2), where F is 18 F or 19 F.

2. A diagnostic or detection reagent for central nervous system diseases characterized by upregulated monoamine oxidase B expression, characterized in that, Its active ingredient is the aryl benzyl ether compound as described in claim 1.

3. The diagnostic or testing reagent according to claim 2, characterized in that, The diseases mentioned are Alzheimer's disease, Parkinson's disease, frontotemporal degenerative disease, chronic traumatic encephalopathy, progressive supranuclear palsy, primary age-related tau disease, Pick's disease, corticobasal degeneration, glial cell globular inclusion body tau disease, amyotrophic lateral sclerosis, and Lewy body dementia.

4. The use of the aryl benzyl ether compound of claim 1 in the preparation of nuclear medicine imaging agents.

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