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Development of novel positron drug [<18>F] TPO1 targeting translocation protein TSPO

A drug and pharmacy technology, applied in the direction of drug combination, antipyretics, pharmaceutical formulations, etc., can solve the problems of large individual differences in PET imaging

Active Publication Date: 2022-02-22
THE FIRST AFFILIATED HOSPITAL OF JINAN UNIV
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  • Summary
  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

At present, almost all TSPO-targeted positron drugs are sensitive to this polymorphism (such as [ 11 C] K of PBR28 i(LAB / HAB) As high as 55), resulting in large individual differences in PET imaging, the limitations of quantitative research and data comparison of brain PET in normal and diseased populations, severely limiting clinical and multi-center applications

Method used

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  • Development of novel positron drug [&lt;18&gt;F] TPO1 targeting translocation protein TSPO
  • Development of novel positron drug [&lt;18&gt;F] TPO1 targeting translocation protein TSPO
  • Development of novel positron drug [&lt;18&gt;F] TPO1 targeting translocation protein TSPO

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Experimental program
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Effect test

Embodiment 1

[0033] The synthesis of embodiment 1 TPO1:

[0034]

[0035] 4-fluoro-N-methyl-aniline (2.00g, 16.0mmol), 2-bromopropanoyl bromide (3.62g, 16.8mmol) were added to anhydrous dichloromethane (30mL), and triethylamine ( 3.5mL, 25mmol), the dropwise reaction was completed for half an hour and then moved to room temperature for reaction. Point plate analysis, the raw materials were completely reacted, poured into 25mL cold water, extracted with DCM (30mL×3), the organic phase was backwashed once with saturated brine, then dried with anhydrous sodium sulfate, spin-dried, column chromatography (PE / DCM=2 / 1) to obtain pale yellow oil 1 with a mass of 4.0 g. 1 H NMR (400MHz, CDCl 3)δ7.38-7.28 (m, 2H), 7.16 (t, J = 8.5Hz, 2H), 4.24 (q, J = 6.6Hz, 1H), 3.29 (s, 3H), 1.75 (d, J = 6.7 Hz,3H).HRMS(ESI): calcd for C 10 h 12 BrFNO[M+H] + 260.0086, found 260.0093.

[0036]

[0037] 2 (1.0g, 7.1mmol) was added to thionyl chloride (10mL, 137.8mmol), and then DMF (0.05mL) was added a...

Embodiment 2

[0041] The synthesis of embodiment 2Pre1:

[0042] (1) Utilize the same synthetic route of embodiment 1 to synthesize TPO1 (with Substitution of compound 1) affords aryl iodide 6. 1 H NMR (300MHz, CDCl 3 ): δ8.89(d, J=4.5Hz, 1H), 8.42(d, J=7.8Hz, 1H), 8.25(d, J=8.1Hz, 1H), 8.13(d, J=8.4Hz, 1H ),7.93-7.84(m,2H),7.72(d,J=8.7Hz,2H),7.63-7.57(m,1H),7.45(q,J=3.6Hz,3H),5.93-5.88(m, 1H),3.29(s,3H),1.59(d,J=6.6Hz,3H).HRMS(ESI):calcd for C 23 h 20 IN 4 o 2 [M+H] + 511.0631, found 511.0645.

[0043]

[0044] (2) Dissolve monovalent aryl iodide 6 (50 mg, 0.11 mmol) in a mixed solution of trifluoroacetic acid (0.39 ml) and chloroform (0.13 ml), and add potassium persulfate Oxone ( 100 mg, 0.165 mmol), after stirring at room temperature for 50 minutes, all solvents were evaporated under pressure, and the crude product was dried on a vacuum pump for about 30 minutes, and then ethanol (0.8 ml) was added. Dissolve the naked ring prosthetic group SPIAd (25.3 mg, 0.11 mmol) in 10%...

Embodiment 318F

[0046] Example 3 [ 18 F] Synthesis of TPO1

[0047] Radiochemical Labeling: Production of Fluoride-18 Anion by 18 O(p,n) 18 F, apply small volume [ 18 O]H 2 The O target was continuously bombarded with a proton beam of 18 MeV for 15 min. Using Waters Sep-Pak plus QMA solid phase extraction column, from [ 18 O]H 2 O captures and separates high-purity fluorine-18 negative ions. Dissolve 4.5 mg of tetraethylammonium bicarbonate (TEAB) in a mixed solution of 0.7 ml of acetonitrile and 0.3 ml of water, and use this solution to elute the fluorine-18 negative ions on the QMA and collect them in a V-shaped reaction flask. The reaction bottle was heated at 110 degrees Celsius, and simultaneously accompanied by dry nitrogen blowing at a flow rate of 10 milliliters per minute. After 5 minutes, the solvent in the reaction bottle was completely dried, and then 1 milliliter of anhydrous acetonitrile was added thereto, and continued at 110 Nitrogen blowing was carried out under the c...

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Abstract

The invention relates to development of a novel positron drug [<18>F] TPO1 targeting translocation protein TSPO. According to the invention, a novel TSPO ligand TPO1 is designed and developed, labeling is realized by using <18>F and a spiro hypervalent iodine ylide precursor Pre1, and the novel TSPO targeted positron drug [<18>F] TPO1 is synthesized; in-vitro radiation self-development is carried out on a human brain slice subjected to gene sequencing, and a result shows that the medicine is relatively high in specificity and relatively weak in sensitivity to rs6971; and a PET dynamic scanning result of a rat living body shows that the probe can pass through a blood brain barrier.

Description

technical field [0001] The invention belongs to the fields of research and development of radiopharmaceuticals and molecular imaging, and relates to a novel positron drug targeting translocation protein TSPO[ 18 F] The development of TPO1, specifically related to a positron drug containing an aromatic fluorine ring system structure and targeting the translocation protein TSPO with weak polymorphism sensitivity[ 18 F] Synthesis, labeling, and positron image analysis of TPO1. Background technique [0002] Neuroinflammation is a complex immune response in the central nervous system. Whether it is an inducement of nerve injury or a secondary response to disease, neuroinflammation plays an important role in the occurrence and development of a series of nervous system diseases. Therefore, an in-depth understanding of the dynamic changes of neuroinflammation can provide a theoretical basis for the diagnosis and therapeutic intervention of many neurological diseases, and is an impo...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D405/14A61K51/04A61P25/00A61P29/00A61K101/02
CPCC07D401/04C07D405/14A61K51/0459A61P25/00A61P29/00C07B2200/05
Inventor 王景浩王璐张玲玲叶伟健
Owner THE FIRST AFFILIATED HOSPITAL OF JINAN UNIV
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