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Radioactive < 18 > F labeled compound and application thereof

A radioactive and chemical compound technology, applied in the field of medical imaging probes, can solve the problems of low penetration depth of fluorescent probes, easy quenching of optical signals, and difficult clinical application, etc., and achieves commercial application and clinical promotion, high sensitivity , good repeatability

Pending Publication Date: 2021-12-28
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The probes disclosed in the above-mentioned prior art are almost all probes based on optical imaging. Optical probes have the characteristics of high sensitivity and good resolution, but due to the relatively low penetration depth of fluorescent probes, they can only be used for Imaging of cells or small animals, and the optical signal is easily quenched in vivo, so it is difficult to apply to clinical applications
No radionuclide-labeled probes have been reported in the prior art for the detection of nitroreductase or imaging studies of hypoxic tumors or bacterial infections based on nitroreductase responses

Method used

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  • Radioactive &lt; 18 &gt; F labeled compound and application thereof
  • Radioactive &lt; 18 &gt; F labeled compound and application thereof
  • Radioactive &lt; 18 &gt; F labeled compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Synthesis and Labeling of Compound 1

[0038] The structural formula of compound 1 is

[0039] The synthetic route of compound 1 is as follows:

[0040]

[0041] Specifically include the following steps:

[0042] (1) Accurately weigh 13.8g of 4-chloronitrobenzene, 25g of diethanolamine and 41.4g of potassium carbonate into a 250mL round bottom flask, and reflux at 120°C for 4h. After the reaction, it was cooled to room temperature, and slowly added dropwise into 500 mL of deionized water. The resulting aqueous solution was filtered and extracted three times with 1.5 L of ethyl acetate, and the solvent was removed from the extracted ethyl acetate solution by rotary evaporation to obtain a red crude product. The crude product was separated by column chromatography (ethyl acetate:petroleum ether=1:1) to obtain compound 5.

[0043] (2) Accurately weigh 2.26g of compound 5 and dissolve in 20mL of dichloromethane, and add 2.01g of triethylamine. The mixed...

Embodiment 2

[0047] Example 2: Synthesis and Labeling of Compound 2

[0048] The structural formula of compound 2 is

[0049] The synthetic route of compound 2 is as follows:

[0050]

[0051] Specifically include the following steps:

[0052] (1) Accurately weigh 10g of 3,4-dinitrochlorobenzene, 3.48g of potassium carbonate and 10g of diethanolamine in a 100mL round bottom flask, and react at 50°C for 10min. After the reaction, the reaction solution was diluted with 100 mL of methanol and the crude product was separated by column chromatography (ethyl acetate:petroleum ether=1:1) to obtain compound 8.

[0053] (2) Accurately weigh 3.14 g of compound 8, dissolve it in 20 mL of dichloromethane, add 3.03 g of triethylamine, and stir at room temperature for 30 min. The reaction solution was added dropwise to a solution of thionyl chloride in dichloromethane (2.61 g in 5 mL of dichloromethane) in an ice-water bath. After the dropwise addition was completed, it was heated to reflux for...

Embodiment 3

[0056] Example 3: Nitroreductase Reduction of Compound 1

[0057] 10 μg / mL nitroreductase solution (100 μL), 200 μM NADPH (100 μL) and 500 μCi compound 1 injection (20 mL) were added to 0.5 mL pH 7.4 Tris buffer solution. The mixed solution was incubated at 37° C. for 3 h under nitrogen protection. The reacted solution (100 μL) was loaded into HPLC for analysis. HPLC conditions: A phase: deionized water; B phase: acetonitrile; A: B = 50%: 50%; 1mL / min.

[0058] From the results of HPLC analysis, it can be seen that after compound 1 was incubated with nitroreductase for 3 hours, 88% of the original drug was converted into other substances, and 37% of it was reduced, that is, the nitro group on the molecule was reduced to an amino group, which was absorbed by the nitroreductase. Electron groups become electron donating groups. Illustrate that the probe compounds in the examples of the present invention can be reduced under the action of nitroreductase, and the specific result...

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Abstract

The invention discloses a radioactive < 18 > F labeled compound and application thereof. The structural formula of the radioactive < 18 > F labeled compound is shown in the specification, wherein R1 is H or < 18 > F, R2 is H or < 18 > F, R3 is H or < 18 > F, R4 is H or < 18 > F, R5 is CH2CH2OTs or CH2CH2Cl or CH2CH218F, R6 is CH2CH2OTs or CH2CH2Cl or CH2CH218F, and at least one of R1, R2, R3, R4, R5 and R6 is labeled by < 18 > F. Under the action of nitroreductase, the compound can be specifically reduced into molecules capable of being coupled with DNA, and is not interfered by other molecules in a body. The PET imaging technology is combined, so that biological processes related to nitroreductase activity, such as imaging diagnosis and treatment of related diseases such as bacterial infection and hypoxic tumors, can be realized. The probe provided by the invention effectively solves the problem of insufficient penetration depth of a fluorescent probe, has the advantages of simple preparation, high yield, good in-vivo imaging and treatment effects and the like, and has good clinical application.

Description

technical field [0001] The invention belongs to the technical field of medical imaging probes, in particular to a radioactive 18 F labeled compounds and their applications. Background technique [0002] Nitroreductase (NTR) is a class of cytoplasmic enzymes dependent on flavin mononucleotide or flavin adenine dinucleotide, which can gradually convert aromatic nitro or heterocyclic nitro groups with the assistance of NADH or NADPH reduced to amino. NTR is not only expressed in Gram-positive bacteria and Gram-negative bacteria, but also highly expressed in hypoxic solid tumors. Therefore, NTR can serve as a marker of bacterial infection and hypoxic tumors in vivo. In current research, fluorescent probes are designed to image related diseases by detecting the activity of nitroreductase in vivo. [0003] CN104592984A discloses a specific fluorescent probe for nitroreductase and its application. The substrate of the specific probe is 5-nitroacenaphthenequinone, which can be u...

Claims

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Application Information

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IPC IPC(8): C07C309/73C07C303/30A61K51/04A61K101/02
CPCC07C309/73A61K51/04C07B2200/05
Inventor 张现忠黄路梅方建阳刘欢欢
Owner XIAMEN UNIV
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