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16α-[ 18 f] The automatic synthesis method of fluoro-17β-estradiol

An automatic synthesis, estradiol technology, applied in the direction of organic chemistry methods, chemical instruments and methods, steroids, etc., can solve the problems that hinder the clinical promotion and use of F-FES, complex and time-consuming steps, unfavorable automation, etc., to achieve Effects of short total synthesis time, high radiochemical yield, and few by-products

Active Publication Date: 2020-12-29
广州市原子高科同位素医药有限公司
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Problems solved by technology

[0004] current 18 In the F-FES synthesis method, the final product is usually separated and purified by preparative liquid phase or multiple solid phase extractions. The steps are complicated and time-consuming, which is not conducive to automation and hinders 18 Clinical promotion and application of F-FES

Method used

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  • 16α-[ <sup>18</sup> f] The automatic synthesis method of fluoro-17β-estradiol
  • 16α-[ <sup>18</sup> f] The automatic synthesis method of fluoro-17β-estradiol
  • 16α-[ <sup>18</sup> f] The automatic synthesis method of fluoro-17β-estradiol

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Experimental program
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Effect test

Embodiment 1

[0045] 16α-[ 18 Automated synthesis of F]fluoro-17β-estradiol

[0046] In order to simplify the description, the following 16α-[ 18 F] Fluorine-17β-estradiol is referred to as 18 F-FES.

[0047] 1.1 Reagents and materials

[0048] Reagent:

[0049] Amino polyether Kryptofix 2.2.2 (referred to as K 2.2.2 ),

[0050] Precursor 3-O-(methoxymethyl)-16,17-O-sulfonyl-16-epiestradiol (MMSE for short)

[0051] Standard 16α-fluoro-17β-estradiol,

[0052] The above three reagents were purchased from ABX Company in Germany;

[0053] Anhydrous acetonitrile (MeCN), potassium carbonate (K 2 CO 3 ), trifluoroacetic acid (TEA)

[0054] The above three reagents were purchased from Sigma-Aldrich, USA;

[0055] The rest of the reagents were of analytical grade and were not further purified unless otherwise specified.

[0056] instrument:

[0057] IBA CYCLONE 10 / 5 cyclotron, Belgium IBA company;

[0058] Sunvic [ 18 F] FDG automatic synthesis module, Beijing Shanweizhengzi Pharmac...

Embodiment 2

[0075] 18 Quality Control of F-FES Injection

[0076] 1.1 Chromatographic detection

[0077] Using HPLC for 18 The chemical purity and radiochemical purity of F-FES injection were tested and identified by co-injection of the final product and the standard 18 F-FES.

[0078] Instrument: Agilent 1200 Analytical High Performance Liquid Chromatograph equipped with Agilent interface 35900E UV detector and Bioscan radioactivity detector respectively;

[0079] Chromatographic column: Agilent ZORBAX SB C18;

[0080] Detection wavelength: 280nm;

[0081] Gradient mobile phase conditions:

[0082] 0-8 min, acetonitrile / water (2 / 98, v / v, 0.1% TFA);

[0083] 8-20 min, acetonitrile / water (10 / 90, v / v, 0.1% TFA);

[0084] 20-28 min, acetonitrile / water (20 / 80, v / v, 0.1% TFA);

[0085] Flow rate: 1 mL·min −1

[0086]1.2 Physical and chemical tests

[0087] Visually inspect the clarity and color of the product solution; and use precision pH test paper to determine 18 pH value of F-...

Embodiment 3

[0100] Several major 18 Research comparison of F-FES radiosynthesis methods

[0101] After research and comparison, it is found that the 18 In the F-FES method, by adopting a fast and efficient "one pot two steps" automatic synthesis 18 The F-FES method shortens the total radiosynthesis time to 45 minutes, improves the production efficiency, and the decay-corrected radiochemical yield is 45±4% (n=10), and the radiochemical purity is greater than 98%. For specific comparison results, see Table 2 for several major 18 Comparison of F-FES radiosynthesis methods.

[0102] The data of synthetic method 1~synthetic method 3 come from the following literatures:

[0103] Synthesis method 1: Mori T, Kasamatsu S, Mosdzianowski C, Welch MJ, Yonekura Y, and Fujibayashi Y. Automatic synthesis of 16α-[ 18 F]fluoro-17β-estradiol using a cassette-type [ 18 F]fluoro-deoxyglucose synthesizer[J]. Nuclear Medicine and Biology 2006;33:281-6.

[0104] Synthesis method 2: Oh S J, Chi D Y, Mosdz...

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Abstract

The invention provides an automatic synthesis method of 16 alpha-[18F]fluoro-17 beta-estradiol (18F-FES). The automatic synthesis method comprises the following steps: performing [18F] nucleophilic fluorination reaction of precursor 3-O-(methoxymethyl)-16,17-O-sulfonyl-16-estradiol (MMSE), hydrolysis reaction of a non-separated [18F] fluorinated intermediate and an alcohol-containing acidic solution as well as liquid-phase separation and purification through a substituted solid-phase column in the same reaction flask of an automatic synthesis module, thereby obtaining the product 18F-FES. Theautomatic synthesis method can realize automatic production of 16 alpha-[18F]fluoro-17 beta-estradiol by adopting a conventional FDG synthesis module and is short in total synthesis time and high in radiochemical yield.

Description

technical field [0001] The present invention relates to the technical field of preparing estrogen receptor PET imaging agent, especially relates to 16α-[ 18 F] Automated synthesis of fluoro-17β-estradiol. Background technique [0002] Breast cancer is the most common invasive cancer in women and worldwide, it is now the second leading cause of cancer death in women after lung cancer. In clinical practice, in vitro detection of estrogen receptor (Estrogen Receptor, ER) is usually used to predict tumor response to hormone therapy and patient prognosis, and positron emission tomography (PET), as a noninvasive detection method, can provide Region-related functional imaging information. [0003] As a kind of ER receptor PET imaging agent, 16α-[ 18 F] fluoro-17β-estradiol (referred to as 18 F-FES) can selectively bind to ER with high affinity, so 18 F-FES PET can reflect physiological function information such as ER expression level, distribution, density change and activity ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J1/00C07B59/00
CPCC07B59/007C07B2200/05C07J1/007
Inventor 唐刚华刘少玉汤睿昆
Owner 广州市原子高科同位素医药有限公司
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