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[18F]trifluoromethyl sulfur-containing amino acid PET imaging agent, preparation method and application thereof

A technology of trifluoromethyl sulfur-containing amino acid and PET imaging agent, which is applied in the preparation of thioether, pharmaceutical formulations, radioactive preparations in vivo, etc., can solve the problem of affecting PET imaging quality, external stability or poor pharmacokinetic properties and other problems, to achieve the effect of good pharmacokinetic properties, good tumor uptake specificity, and simple molecular structure

Active Publication Date: 2018-12-28
GUANGDONG HUIXUAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

but currently some 18 F-labeled sulfur-containing amino acid imaging agent has the disadvantages of poor in vivo and in vitro stability or poor pharmacokinetic properties after a large change in the molecular space structure, which affects its PET imaging quality

Method used

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  • [18F]trifluoromethyl sulfur-containing amino acid PET imaging agent, preparation method and application thereof
  • [18F]trifluoromethyl sulfur-containing amino acid PET imaging agent, preparation method and application thereof
  • [18F]trifluoromethyl sulfur-containing amino acid PET imaging agent, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The synthesis of embodiment 1 S-trifluoromethyl-L-cysteine

[0045] synthetic route:

[0046]

[0047] Precursor compound (4S)-1,2,3-oxathiazolidine-2,2-dioxide-3,4-dicarboxylate tert-butyl ester References J.Med. Chem. 2010, 53, 876 –886 and Chemistry, 2018, https: / / doi.org / 10.1002 / chem.201801029 for synthesis, 1 H NMR (400 MHz, CDCl 3 ) δ 4.74 (t, 1H), 4.63 (d, 2H), 1.56 (s, 9H), 1.51 (s, 9H).

[0048] Synthetic steps:

[0049] (1) Add 194 mg of (4S)-1,2,3-oxathiazolidine-2,2-dioxide-3,4-dicarboxylic acid tert-butyl ester to a 20 mL reaction flask in sequence, (three Phenylphosphonium) inner salt of difluoroacetic acid (PDFA) 427.6 mg, sulfur (S 8 ) 115.2 mg, cesium fluoride (CsF) 455.7 mg and anhydrous N,N-dimethylformamide (DMF) 4.5 mL, heated to 70 ℃ under the protection of argon, and reacted for 20 minutes.

[0050] (2) After the reaction was cooled, the reaction solution was transferred to a 100 mL reaction flask, and 20 mL of ethyl acetate and 10% sodiu...

Embodiment 2

[0053] Example 2 [ 18 F] trifluoromethyl- L - Radiosynthesis of cysteine

[0054] synthetic route:

[0055]

[0056] Synthetic steps:

[0057] (1) In a cyclotron, by 18 O(p,n) 18 F nuclear reaction produces 18 f - ions, which are captured by the QMA column and delivered by the accelerator 18 f - ions, using K 2.2.2 / K 2 CO 3 The solution will 18 f - The ions are eluted to the reaction bottle; among them, K 2.2.2 / K 2 CO 3 The solution is 0.1 mL of 3.0 mg K 2 CO 3 aqueous solution, with 0.9 mL of 12mg K 2.2.2 Mixed solution of acetonitrile solution.

[0058] (2) Heat the reaction bottle to 95°C, remove the solvent under the condition of 80 mL / min nitrogen flow, and obtain the dry K 2.2.2 / K 18 F complex, then add anhydrous acetonitrile, get K after dissolving 2.2.2 / K 18 F complex acetonitrile solution, spare.

[0059] (3) 2 mg of tert-butyl (4S)-1,2,3-oxathiazolidine-2,2-dioxide-3,4-dicarboxylate was prepacked in the fluorination reaction bottle, (th...

Embodiment 3

[0062] The synthesis of embodiment 3 S-trifluoromethyl-D-cysteine

[0063] synthetic route:

[0064]

[0065] Precursor compound (4R)-1,2,3-oxathiazolidine-2,2-dioxide-3,4-dicarboxylate tert-butyl ester References J.Med. Chem. 2010, 53, 876 –886 and Chemistry, 2018, https: / / doi.org / 10.1002 / chem.201801029 for synthesis, 1 H NMR (400 MHz, CDCl3) δ 4.76 – 4.71 (m), 4.67 – 4.60 (m), 1.56 (s), 1.51 (s).

[0066] Synthetic steps:

[0067] The precursor compound of Example 1 was replaced by (4S)-1,2,3-oxathiazolidine-2,2-dioxide-3,4-dicarboxylate tert-butyl ester with (4R)-1 , 2,3-oxathiazolidine-2,2-dioxide-3,4-dicarboxylic acid tert-butyl ester, the rest of the synthesis steps are the same as in Example 1, and finally S-trifluoromethyl- D - Cysteine. 1 H NMR (600 MHz, D 2 O) δ 4.00(dd, 1H), 3.55 (dd, 1H), 3.39 (dd, 1H).

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Abstract

The invention provides an [18F]trifluoromethyl sulfur-containing amino acid PET imaging agent based on the principle of bioelectronic isosteric replacement without changing the spatial structure of original amino acid molecules. The PET imaging agent is [18F]trifluoromethyl-L-cysteine or [18F]trifluoromethyl-D-cysteine. The PET imaging agent can also be [18F]trifluoromethyl-L-methionine or [18F]trifluoromethyl-D-methionine. The PET imaging agent has higher uptake in tumor tissues and lower uptake in normal tissues and organs, and has good tumor specificity. The imaging agent has high stabilityin vitro and in vivo, showing good pharmacokinetic properties. A preparation method of the [18F]trifluoromethyl sulfur-containing amino acid PET imaging agent and an application thereof in tumor diagnosis and therapeutic effect detection are further provided.

Description

technical field [0001] The present invention relates to the technical field of preparing positron emission tomography imaging agent, especially relates to [ 18 F] trifluoromethyl sulfur-containing amino acid PET imaging agent and its preparation method and application. Background technique [0002] 2-[ 18 F] fluorodeoxyglucose ( 18 F-FDG) is currently the most common glucose metabolism imaging agent in clinical positron emission tomography (PET) imaging. It has been widely used in lesion detection and other aspects. but 18 F-FDG also has disadvantages such as poor specificity, low uptake in some tumors, and high uptake in inflammatory tissues, which may cause false positive or false negative results in tumor PET imaging. [0003] The increase in the proliferation rate of malignant tumor cells will not only increase the translocation of amino acids, but also increase the rate of incorporation of amino acids into proteins in tumor cells. Therefore, amino acid PET imaging...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/04C07C323/58C07C319/20
CPCA61K51/0406C07C323/58
Inventor 唐刚华刘少玉
Owner GUANGDONG HUIXUAN PHARMA TECH
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