Efficient preparation method of fluorine [< 18 > F] safinamide and application of PET imaging agent

A PET imaging agent, safinamide technology, applied in the field of nuclear medicine, can solve the problems of long cycle, high consumption, and difficulty in approving applications in other disease fields

Pending Publication Date: 2022-07-29
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Regrettably, it has been more than ten years since the application research of safinamide in the treatment of Parkinson's disease has gone from the first clinical trial to being widely used on the market. The main reason for limiting this progress is that the current research methods for safinamide Focus on anatomical plasma methods or traumatic in vivo experiments. These experiments have a long cycle, high consumption and it is difficult to know the real metabolism, distribution, and effects of safinamide in the body.
As a result, even though safinamide has shown wider application prospects and greater application potential, it is difficult to be approved for use in other disease areas in the short term

Method used

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  • Efficient preparation method of fluorine [&lt; 18 &gt; F] safinamide and application of PET imaging agent
  • Efficient preparation method of fluorine [&lt; 18 &gt; F] safinamide and application of PET imaging agent
  • Efficient preparation method of fluorine [&lt; 18 &gt; F] safinamide and application of PET imaging agent

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] 3A (615 mg, 1.5 mmol) was dissolved in dry tetrahydrofuran (10 mL), then sodium hydride (60% in mineral oil, 132 mg, 3.3 mmol) was added dropwise to the solution at 0 °C and stirred for 1 h. The reaction mixture was heated to 25°C, di-tert-butyl dicarbonate (1.63 g, 24 mmol) was added slowly, and the mixture was stirred for a further 2 hours. Finally, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic solution was then washed sequentially with water, 1M HCl and brine and the organic portion was collected, the final organic solution was dried over Na2SO4, filtered and concentrated. The product was finally purified by silica gel column chromatography (5-50% ethyl acetate / petroleum ether) to give a colorless solid (4A, 170 mg, 0.28 mmol, 68% yield). 1 H NMR (400MHz, Chloroform-d) δ 7.67 (d, J=1.8Hz, 1H), 7.54 (dt, J=7.8, 1.5Hz, 1H), 7.26 (dd, J=7.8, 1.5Hz, 1H) ,7.13–6.96(m,3H),6.80(dd,J=8.3,4.6Hz,2H),4.86(s,2H),4.69–3.70(m,3H),1.33...

Embodiment 2

[0061] Similarly, the production of 4B only needs to replace the equimolar amount of 3A in Example 1 with 3B, and the rest of the operations are the same, and finally a colorless oily substance 4B can be obtained. 1 H NMR (400MHz, Chloroform-d) δ 7.59 (t, J=1.8Hz, 1H), 7.46 (dt, J=7.9, 1.6Hz, 1H), 7.34 (dt, J=7.8, 1.3Hz, 1H) ,7.25(p,J=4.8Hz,3H),6.99-6.88(m,2H),5.01(s,2H),4.90-3.89(m,3H),1.71(d,J=2.8Hz,2H), 1.46(d,J=4.3Hz,18H),1.34(d,J=7.0Hz,3H),1.31–1.22(m,1H).

[0062] Wherein the preparation of 3A / 3B can be obtained based on the prior art, and a preparation method thereof is such as figure 2 The starting compounds are shown in 1A / 1B.

[0063] ②Synthesis of precursor Mel-SF, SPIAd-SF, SPI5-SF

[0064] Compound 4A (1 equiv.) and m-chloroperoxybenzoic acid (1 to 2 equiv.) were dissolved in an anhydrous organic solution (such as tetrahydrofuran, dichloromethane, N,N-dimethylformamide, etc.) with stirring, at 40 °C Stir at 80°C for 1 hour to 6 hours. The reaction mixture wa...

Embodiment 3

[0066]In a closed reaction vial, compound 4A (1 equiv) was stirred with 85% m-chloroperoxybenzoic acid (1.1 equiv) in dichloromethane (DCM) at 40°C for 80 minutes. After cooling to room temperature, KOH (7 equiv.) and Mylbauer's acid (1.3 equiv.) were added and stirred for a further 45 minutes. The reaction mixture was then diluted with DCM and filtered through filter paper. The solvent of the collected organic phase was removed under reduced pressure at 35°C until the first solid precipitated. Then, hexane was added slowly and the mixture was left to stand at -20°C for 12 hours to complete the precipitation. The solid was collected by filtration, washed with n-hexane, and dried in air and vacuum. Finally, the crude product was purified by silica gel column chromatography (SiO2, 40-100% ethyl acetate / petroleum ether) to obtain the Mel-SF precursor.

[0067] Mel-SF (41% yield, white solid): 1 H NMR (400MHz, Chloroform-d) δ7.86-7.76(m,1H), 7.69-7.57(m,1H), 7.47-7.36(m,1H), 7...

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Abstract

The invention discloses an efficient preparation method of fluorine [18F] safinamide and application of a PET (positron emission tomography) developer, and the method comprises the following steps: firstly, designing to prepare a precursor of the fluorine [18F] safinamide, and then realizing direct radioactive fluoro labeling on aromatic rings in the precursor through nucleophilic substitution reaction to obtain the fluorine [18F] safinamide. The precursor is Mel-SF, SPIAd-SF, SPI5-SF, Me3Sn-SF, or Bpin-SF, and the SF is SF or SF; the prepared fluorine [18F] safinamide can be used as a PET (Polyethylene Terephthalate) imaging agent for imaging a cell line capable of secreting monoamine oxidase B, can also be used for imaging living animals, can penetrate through a blood brain barrier and realize brain region imaging, can be reversibly combined with multiple target spots in vivo, can also be used for imaging animal in-vitro tissues, and can be applied to imaging of animal in-vitro tissues. The method has potential application prospects in the medical fields of medical early diagnosis, adjuvant therapy, pathogenesis research and the like.

Description

technical field [0001] The invention relates to the development of radiopharmaceuticals, belongs to the technical field of nuclear medicine, and in particular relates to an efficient preparation method of fluoro[18F]safinamide, and its application as a PET probe with the ability to target monoamine oxidase B, which is used in medical It has potential application prospects in medical fields such as early diagnosis, adjuvant therapy, and pathogenesis mechanism research. Background technique [0002] Safinamide is an adjunct drug currently approved as an adjunct to Parkinson's treatment, which can reduce the degradation of levodopa and exogenously injected levodopa in the body by inhibiting the activity of monoamine oxidase B (monoamine oxidase B), thereby maintaining levodopa in the body. Dopa is at a high level and can achieve the effect of treating Parkinson's disease. However, as the research progresses, safinamide also exhibits potassium-sodium ion channel inhibition, glu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C237/08C07D319/06C07D319/08C07F7/22C07F5/02C07B59/00A61K51/04A61K101/02
CPCC07C231/12C07D319/06C07D319/08C07F7/2208C07F5/025C07B59/001A61K51/0427A61K51/041A61K51/04C07B2200/05C07C237/08
Inventor 和庆钢徐洋洋张宏田梅余开武古望军傅珠荣
Owner ZHEJIANG UNIV
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