Radiosynthetic method of subglutamic acid pet imaging agent

A technology of radiosynthesis and glutamic acid, applied in the direction of organic chemical methods, chemical instruments and methods, and preparation of carboxylic acid amides, can solve the problems of long time for radiosynthesis, difficulty in automatic production, and low radiochemical yield, and achieve a solution Effects of Automated Production Difficulties

Active Publication Date: 2018-08-17
GUANGDONG HUIXUAN PHARMA TECH
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Problems solved by technology

[0006] The purpose of the present invention is exactly to solve subglutamic acid PET imaging agent (N-2- 18 F-fluoropropionyl)-L-α-glutamic acid ( 18 F-NFPGlu) currently has the problems of long radiosynthesis time, low radiochemical yield and unfavorable automatic synthesis. A new precursor was designed and synthesized and synthesized quickly and efficiently through a simple "two-step on-column hydrolysis method". 18 F-NFPGlu
Application of the law also solves the 18 F-DFPGlu and 18 Difficulties in automated production of F-NFPBGlu

Method used

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Experimental program
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Embodiment 1

[0029] The preparation of embodiment 1 precursor and standard

[0030] 1.1 Precursor (N-2-bromopropionyl)-L-α-diethyl glutamate and standard (N-2- 19 F-fluoropropionyl)-L-α-glutamic acid ( 19 Preparation of F-NFPGlu). Its synthetic routes are shown in Reaction Schemes 4 and 5, respectively.

[0031] 2-Bromopropionyl bromide (3.24g, 15.00mmol) was added to L-diethyl glutamate hydrochloride (3.17g, 15.00mmol) and N,N-diisopropyl Diethylamine (4.07 g, 31.50 mmol) in anhydrous dichloromethane (50 mL) was reacted overnight at room temperature. After the reaction, dilute with water (100mL), extract three times with dichloromethane, 50ml each time (3*50mL), combine organic phase, 10% citric acid aqueous solution (100mL), water (100mL) and saturated sodium chloride aqueous solution (100mL ) were washed once each, and then washed with anhydrous Na 2 SO 4 Drying, filtration, and concentration to remove the organic solvent gave white solid (N-2-bromopropionyl)-L-α-glutamic acid die...

Embodiment 2

[0041] Synthesis of embodiment 2 hypoglutamic acid PET imaging agent

[0042] 2.1 Synthesis method of subglutamic acid PET imaging agent. The synthetic routes are shown in Reaction Formulas 1, 2, and 3, respectively.

[0043] (N-2- 18 F-fluoropropionyl)-L-α-glutamic acid ( 18 F-NFPGlu), using (N-2-bromo-propionyl)-L-α-diethyl glutamate as the precursor raw material, through the two-step reaction of nucleophilic fluorination and "in-column hydrolysis", it can realize its radiosynthesis. 1) Fluorination reaction, (N-2-bromo-propionyl)-L-α-diethyl glutamate, in amino polyether Kryptofix2.2.2 (K 2.2.2 ) under the catalysis and [K / K2.2.2] +18 f - A nucleophilic substitution reaction occurs, producing 18 F labeled intermediate (N-2- 18 F-fluoropropionyl)-L-α-glutamic acid diethyl ester. After diluting with water, the mixed solution was passed through a Sep-Pak Al 2 o 3 A series column of N Plus column and two Sep-Pakplus C18 cartridges, radioactive intermediates are captu...

Embodiment 3

[0049] Example 3 Determination of product purity.

[0050] Determination by radioactive high performance liquid chromatography (HPLC) 18 F-NFPGlu, 18 F-DFPGlu or 18 Radiochemical purity of F-NFPBGlu injection. Standards with defined structure 19 F-NFPGlu, 19 F-DFPGlu or 19 F-NFPBGlu, respectively with the corresponding injection 18 F-NFPGlu, 18 F-DFPGlu or 18 The F-NFPBGlu injection is injected into the HPLC together to determine whether its retention time is consistent, so as to confirm the accuracy of the prepared injection. It has been determined that its radiochemical purity is greater than 90%, and the typical test results are shown in Figure 6 and Figure 7 . HPLC analysis conditions: analytical column is ZORBAX Eclipse XDB-C18 column, mobile phase is 0.1% TFA acetonitrile solution: 0.1% TFA aqueous solution, line gradient elution: at 0min, acetonitrile solution containing 0.1% TFA / 0.1% TFA Aqueous solution: 2 / 98; when gradually increasing to 8 minutes, 0.1%...

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Abstract

The invention discloses automatic synthesis methods of two enantiomorphous glutamic acid PET (Positron Emission Tomography) imaging agents, namely, (N-2-<18>F-)fluoropropionyl-L-alpha-glutamic acid(<18>F-NFPGlu) and (N-2-<18>F-)fluoropropionyl-D-alpha-glutamic acid(<18>F-DFPGlu), and preparation methods of corresponding precursors, namely, (N-2-bromo-propionyl)-L-alpha-glutamate diethyl ester and (N-2-bromo-propionyl)-D-alpha-glutamate diethyl ester. The invention relates to organic synthesis of a <18>F-NFPGlu precursor and a <18>F-DFPGlu precursor and realization of short-time, high-yield and automatic radio-synthesis of <18>F-NFPGlu and <18>F-DFPGlu by taking corresponding precursors as starting raw materials through a simple 'two-step on-column thermal decomposition method'. The radio-synthesis method can also be applied to synthesis of a <18>F-labeled beta-glutamic acid-NH2 group imino acid compound, namely, (N-2-<18>F-fluoropropionyl)-beta-glutamic acid (<18>F-NFPBGlue) and a precursor thereof. The formula is shown in the specification.

Description

【Technical field】 [0001] The present invention relates to two kinds of positron emission tomography (PET) imaging agents (N-2- 18 F-fluoropropionyl)-L-α-glutamic acid ( 18 F-NFPGlu) and (N-2- 18 F-fluoropropionyl)-D-α-glutamic acid ( 18 The radiosynthetic method of F-DFPGlu). The present invention also relates to (N-2- 18 F-fluoropropionyl)-β-glutamic acid ( 18 The radiosynthetic method of F-NFPBGlu). [0002] The present invention also relates to 18 F-NFPGlu precursor, 18 F-DFPGlu precursor and 18 Synthetic method of F-NFPBGlu precursor. 【Background technique】 [0003] PET uses nuclide labeling of positron emitters, such as some physiologically required compounds or metabolic substrates such as glucose, fatty acids, amino acids, receptor ligands, and water, etc. After being introduced into the body, a positron emission tomography (PET) scanner is used In vivo biochemical images obtained. It has received widespread clinical attention for its ability to display the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/12C07C233/47
CPCC07B2200/07C07C231/12C07C233/47
Inventor 唐刚华刘少玉聂大红
Owner GUANGDONG HUIXUAN PHARMA TECH
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