Diaryl sulfide derivatives, methods for their preparation and use as targeting imaging agents for serotonin transporters

A kind of technology of diaryl sulfide and serotonin, applied in the field of serotonin transporter targeting imaging agent

Active Publication Date: 2019-05-07
BEIJING NORMAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

but for 18 As far as F-labeled PET imaging agents are concerned, there is no imaging agent widely used in clinical practice. 18 F imaging agent

Method used

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  • Diaryl sulfide derivatives, methods for their preparation and use as targeting imaging agents for serotonin transporters
  • Diaryl sulfide derivatives, methods for their preparation and use as targeting imaging agents for serotonin transporters
  • Diaryl sulfide derivatives, methods for their preparation and use as targeting imaging agents for serotonin transporters

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Synthesis of Diaryl Sulfide Derivatives

[0027] Synthesis of 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(2-(2-fluoroethoxy)-ethoxy)-phenyl)sulfide (Compound A1)

[0028] Synthetic reaction equation:

[0029]

[0030] resolve resolution:

[0031] 0.15-0.2mmol 2-aminobenzene-(2-(N,N-dimethyl)methylamino-4-hydroxyl)-phenyl)sulfide (synthetic reference: (Shunichi Oya et al, Nuclear Medicine and Biology, 34(2007), 129–139) were dissolved in 4ml DMF (HPLC pure), and 2 times the molar amount of potassium carbonate and 1-p-toluenesulfonyl-2-fluoroethoxyethane (1.2 times the molar amount) were added, After passing nitrogen gas for 3-5min, the reaction solution was heated overnight in an oil bath at 80-90°C. After the reaction was completed, 30ml of water was added to terminate the reaction, and the product was extracted with ethyl acetate, and the organic phases were combined and dried using anhydrous sodium sulfate. Then it was purified by a silica gel column, and the...

Embodiment 2

[0036] Synthesis of Diaryl Sulfide Derivatives

[0037] 2-Aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(2-(2-(2-fluoroethoxy)-ethoxy)-ethoxy)-benzene) Synthesis of Thioether (Compound A2)

[0038] Synthetic reaction equation:

[0039]

[0040] Dissolve 0.15-0.2mmol 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-hydroxy)-benzene)sulfide in 4ml DMF (HPLC pure), add 2 times molar amount Potassium carbonate and 1-p-toluenesulfonyl-(2-(2-fluoroethoxy)-ethoxy)ethane (1.2 times the molar weight), then pass into nitrogen for 3-5min, and react the solution at 80- Heat in an oil bath at 90°C overnight. After the reaction, 30ml of water was added to terminate the reaction, and the product was extracted with ethyl acetate, the combined organic phases were mixed and dried using anhydrous sodium sulfate, then purified by a silica gel column, and the eluent used was methanol: dichloromethane: diethylamine =4:100:1 (volume ratio), the target product compound A2 was obtained, yield: 22.6%...

Embodiment 3

[0045] Synthesis of Diaryl Sulfide Derivatives

[0046] Synthesis of 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(cis-4-fluoro-2-enebutoxy)-benzene)sulfide (compound A3)

[0047] Synthetic reaction equation:

[0048]

[0049] resolve resolution:

[0050] ① Preparation of 1,4-di-p-toluenesulfonyl-2-butene

[0051] Dissolve 0.3ml of cis-2-butene-1,4-diol (3.16mmol) in 15ml of freshly distilled tetrahydrofuran (THF). After stirring in the bath for 10 min, 1 g of sodium tert-butoxide was added to obtain a white milky product, and the stirring was continued overnight. After the reaction, remove the solvent with a rotary evaporator, add 20ml of water, and extract three times with dichloromethane, combine the organic phases, and purify by column chromatography after drying over anhydrous sodium sulfate, the eluent is ethyl acetate:petroleum ether= 1:4 (volume ratio) to obtain 1,4-di-p-toluenesulfonyl-2-butene. Yield: 12.2%.

[0052] ② Preparation of 1-fluoro-4-p-toluenesul...

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PUM

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Abstract

Disclosed are a class of diarylsulfide derivatives, a preparation method therefor, and the use thereof as a serotonin transporter-targeted imaging agent, belonging to the field of radiopharmaceutical chemistry. The diarylsulfide derivative has the structural formula (1) below, this class of compounds exhibits a high affinity for central SERT, and at the same time exhibits a high selectivity for SERT relative to DAT (a dopamine transporter) and to NET (a norepinephrine transporter). Therefore, [18F]-diarylsulfide derivatives can be used as an SERT / PET imaging agent.

Description

technical field [0001] The invention belongs to the field of radiopharmaceutical chemistry, and relates to a class of diaryl sulfide derivatives, a preparation method thereof and an application as a five-serotonin transporter targeting imaging agent. Background technique [0002] The serotonin transporter (SERT) is a selective serotonin (5-HT) transmembrane transporter. SERT can reuptake 5-HT in the synaptic cleft, thereby regulating the transmission of nerve signals. In the central nervous system, SERT, which exists in the presynaptic membrane of neurons, can selectively transfer the neurotransmitter 5-HT from the synaptic cleft to the intracellular cytosol, thereby terminating the neurotransmitter’s pairing of the post-extrusion membrane. 5-HT receptors, and thus play an extremely important role in the reuptake process of 5-HT after release. Studies have shown that changes in SERT concentrations are associated with many neuropsychiatric disorders such as depression, depr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C323/37C07C319/20A61K51/04
CPCC07B59/00C07C319/20C07C323/37
Inventor 朱霖孔繁渊李根熏
Owner BEIJING NORMAL UNIVERSITY
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