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Radioactive molecular probe taking TSPO as target point as well as preparation method and application thereof

A molecular probe and radioactive technology, applied in the field of radioactive probes, can solve the problems of low non-specific binding, high signal-to-noise ratio, poor brain penetration rate, etc., and achieve the effects of reducing radioactive radiation, stable yield, and regulating lipophilicity

Inactive Publication Date: 2020-05-08
THE FIRST AFFILIATED HOSPITAL OF FUJIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The first positron drug to image TSPO was [ 11 C](R)-PK11195, but due to its poor brain penetration rate and low signal-to-noise ratio, it cannot meet the clinical needs. More and more new positron drugs have been developed, and the representative ones include [ 11 C] PBR28, [ 11 C] PBR111, [ 11 C]DAA1106, [ 11 C] MBMP, [ 11 C]ER176, [ 18 F]AB5186, [ 18 F] FEDAA1106, [ 18 F] GE-180 and [ 18 F] DPA-714, etc., where [ 18 F] DPA-714, with its advantages of efficient and convenient radiolabeling method, low non-specific binding and high signal-to-noise ratio, has been extensively studied on PET imaging in various disease models, including brain trauma mouse models, Chronic hepatic encephalopathy mouse model, Huntington's disease baboon model, etc., are expected to be clinically used in the early diagnosis and therapeutic evaluation of neuroinflammatory diseases such as muscular atrophy, stroke sequelae, and Alzheimer's disease

Method used

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  • Radioactive molecular probe taking TSPO as target point as well as preparation method and application thereof
  • Radioactive molecular probe taking TSPO as target point as well as preparation method and application thereof
  • Radioactive molecular probe taking TSPO as target point as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] A kind of small molecule organic compound with specific targeting TSPO, as shown in general formula (I):

[0061]

[0062] Formula (I),

[0063] Wherein R is hydrogen, bromo, p-toluenesulfonyl, methanesulfonyl, p-nitrobenzenesulfonyl or hydroxyl; the number of structures of polyethylene glycol (PEG) connected by R can be 0-5, recorded as n= 0-5. Said compound is referred to as R-PEGn-DPA714 in the present invention. Its structure includes benzene ring, pyrazoloimidazole and diethylacetamide structures, which are formed by covalently connecting the three parent structures, and the nuclide labeling site is located on the para-side chain of the benzene ring , and connected to the benzene ring through the PEG chain, denoted as

[0064] Preferably, the above-mentioned small molecule organic compound with specific targeting TSPO has a structural formula of:

[0065]

[0066] R is hydrogen, bromo, p-toluenesulfonyl, methanesulfonyl, p-nitrobenzenesulfonyl or hydroxyl...

Embodiment 2

[0084] A radioactive molecular probe with TSPO as the target, the molecular probe contains benzene ring, pyrazoloimidazole and diethylacetamide structure and radionuclide 18 F, radionuclides 18 The reactive site of F is on the side chain of the benzene ring, and the radioactive molecular probe is [ 18 F] DPA714.

[0085] said [ 18 F] The preparation method steps of DPA714 radioactive molecular probe are as follows:

[0086] (1) 18 Production and activation of F

[0087] Using a GE cyclotron to pass 18 O(p,n) 18 Radioactivity produced by nuclear reactions 18 F negative ions, will contain 18 H of F negative ion 2 18 O passes through a Waters QMA anion solid-phase extraction column, the 18 F negative ions are concentrated on the QMA column; subsequent use of K 222 / K 2 CO 3 (13mg / 4.5mg) of acetonitrile / water (0.3mL / 0.3mL) mixed solution will adsorb on the QMA column 18 F negative ions are rinsed into the reaction bottle; heating and blowing nitrogen until the solut...

Embodiment 3

[0097] A radioactive molecular probe targeting TSPO[ 18 F] DPA714, by using GE TRACERlab FX2 N synthesizer (see figure 1 ), complete the automated preparation, comprising the following steps:

[0098] 18 Production and enrichment of F

[0099] Using a GE cyclotron to pass 18 O(p,n) 18 Radioactivity produced by nuclear reactions 18 F negative ions, will contain 18 H of F negative ion 2 18 O is transferred to the left conical transfer bottle, turn on the vacuum pump to 18 F negative ions pass through the Waters QMA anion solid-phase extraction column, and the 18 F negative ions are concentrated on the QMA column.

[0100] (1) 18 activation of F

[0101] The eluent (K 222 / K 2 CO 3 / Acetonitrile / Water 13mg / 4.5mg / 0.3mL / 0.3mL) prepacked in Vial 1, open V1 to adsorb on the QMA column 18 F Negative ions are rinsed into the reaction bottle REACTOR 1; heat REACTOR 1 to 95°C, pump negative pressure, blow nitrogen until the solution in the reaction bottle is evaporated to...

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Abstract

The invention discloses a small molecular organic compound with a specific targeting TSPO (Transfer Protein). The structure of the small molecular organic compound comprises a benzene ring, pyrazolo imidazole and a diethyl acetamide structure. The P-toluenesulfonyl on a side chain of a benzene ring is used as a marker site; carrier-free radioactive fluorine-18 is used as a radioactive source; andmild alkaline reaction conditions are designed and utilized. By using a functional GE TRACERlab FX2N synthesizer, a target compound [18F] DPA714 is obtained through a one-step reaction. The method hasthe advantages of mild reaction conditions, simple steps, and automatic labeling; the non-attenuation correction yield reaches 40% or above; the radiochemical purity of the product is higher than 99%, the specific activity is higher than 148GBq / [mu] mol (4Ci / [mu] mol). The invention solves the technical problems of low labeling yield, low specific activity, complex operation and the like in the prior art. A radioactivity molecular probe prepared from the small molecular compound is shown as an imaging evaluation result of a positron emission tomography (PET) in patients (including Alzheimer'sdisease and cerebral apoplexy) with neuroinflammation related diseases, and the radioactivity molecular probe has the characteristics of high sensitivity, high sensitivity, high sensitivity, high sensitivity, high sensitivity, high sensitivity and the like. It is proved that the molecular probe has good specificity, targeting, stability and non-target tissue clearance rate.

Description

technical field [0001] The present invention relates to the field of radioactive probes for disease diagnosis and treatment, in particular to an automatic preparation method for a DPA714 radioactive molecular probe containing a pyrazolopyrimidine ring structure and targeting translocation protein TSPO-positive diseases, and the compound as Clinical application of targeted radioactive molecular probes for disease diagnosis. Background technique [0002] The translocation protein TSPO is a hydrophobic protein (rich in tryptophan) encoded by the nucleus and contains 169 amino acids. It is highly conserved among various races and is mainly located in the outer mitochondrial membrane in tissues, especially when it is related to steroids. It is highly expressed in tissues related to hormone synthesis, such as salivary glands, gonads, adrenal glands, etc. It is also partially expressed in heart and kidney tissues, while the expression level is very low in brain and liver. TSPO is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K51/04A61K101/02
CPCA61K51/0459C07B2200/05C07D487/04
Inventor 要少波付莹缪蔚冰
Owner THE FIRST AFFILIATED HOSPITAL OF FUJIAN MEDICAL UNIV
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