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[18f]fluoromethyl group-introduced radiotracer for positron emission tomography for targeting brain neuroinflammation, synthesis thereof, and method for evaluating biological results using same

A technology of radioactive tracer and positron emission, applied in organic chemical methods, in vivo radioactive preparations, radioactive carriers, etc., can solve the problems of high possibility of radiation coverage, short half-life, usefulness evaluation of radioactive substances in neuroinflammation, etc.

Inactive Publication Date: 2016-04-27
BIO IMAGING KOREA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But due to[ 11 C] Peripheral benzodiazepine receptor 28 is also a compound labeled with carbon-11 with a short half-life, so it has the following disadvantages: it is a radioactive tracer that can be used for a short time after production, and the possibility of accompanying radiation coverage is high. And when produced once, it can only be applied to a maximum of two patients depending on the number of positron emission tomography machines owned
[0012] However, it is difficult to evaluate the usefulness of radioactive substances by the imaging method of neuroinflammation based on the prior art, and a method for evaluating the usefulness of radioactive substances is required.

Method used

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  • [18f]fluoromethyl group-introduced radiotracer for positron emission tomography for targeting brain neuroinflammation, synthesis thereof, and method for evaluating biological results using same
  • [18f]fluoromethyl group-introduced radiotracer for positron emission tomography for targeting brain neuroinflammation, synthesis thereof, and method for evaluating biological results using same
  • [18f]fluoromethyl group-introduced radiotracer for positron emission tomography for targeting brain neuroinflammation, synthesis thereof, and method for evaluating biological results using same

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Hereinafter, the method for preparing the final target compound by the two-step fluorine-18 labeling method will be described in detail.

[0057] Fluorine-18 produced by a cyclotron is adsorbed on ( S-HCO 3 ) cartridge, elution was performed with methanol / water containing a phase change catalyst of tetrabutylammonium bicarbonate. After the extracted solvent was dried by azeotropic distillation, diiodomethane (50 μL) was added to acetonitrile (0.4 mL). The reaction mixture was heated at 90° C. for 15 minutes and passed through a silica Sep-Pak cartridge trapped in dimethylformamide (DMF). After adding n-methyl-peripheral benzodiazepine receptor 28 (1 mg) and 5 M sodium hydroxide (6 μL) to the trapped solution, the mixture was reacted at 90° C. for 5 minutes. Adsorb the mixed solution on the tC18Sep-Pak cartridge, wash with 10 mL of water, and then use 1.5 mL of CH 3 CN was eluted. The eluted solution was separated in a high performance liquid chromatography system ...

Embodiment 2

[0059] Secondly, for the preparation of 1-(chloromethyl)-3-methyl-4-phenyl-1-(chloromethyl)-3-methyl-4-phenyl- The procedure of 1H-1,2,3-triazol-3-ium triflate as an intermediate substance for the synthesis of a fluorine-18 labeling precursor is illustrated.

[0060] The first step: Preparation of 1-(chloromethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium trifluoromethanesulfonate

[0061] After dissolving 1-(chloromethyl)-4-phenyl-1H-1,2,3-triazole (387 mg, 2.0 mmol) in 4 mL of acetonitrile, trifluoromethanesulfonate was added dropwise at room temperature Methyltriflate (0.33 mL, 3.0 mmol). The mixture was stirred for 1 hour at room temperature, and after removal of the reaction solvent, flash column chromatography (MeOH / CH 2 Cl 2 =5 / 95) to synthesize 710 mg (99%) of the target compound. 1 HNMR (500MHz, CDCl 3 )d8.94(s,1H),7.64-7.56(m,5H),6.29(s,2H),4.29(s,3H); 13CNMR (125MHz, CDCl 3 )d 144.2, 132.4, 130.0, 129.7, 129.5, 121.5, 120.6 (q, J=318Hz), 57.2, 39.2.HRMS(FAB)m / ...

Embodiment 3

[0063] Hereinafter, the steps for preparing the fluorine-18 labeling precursor and the reference substance will be described in detail.

[0064] The first step: 1-[2-(N-acetyl-N-4-phenoxypyridin-3-ylaminomethyl)phenoxymethyl]-3-methyl-4-phenyl-1H-1 ,2,3-Triazol-3-ium trifluoromethanesulfonate (1-[2-(N-Acetyl-N-4-phenoxypyridin-3-ylaminomethyl)phenoxymethyl]-3-methyl-4-phenyl-1H -1,2,3-triazol-3-iumtriflate) preparation

[0065] After dissolving positive peripheral benzodiazepine receptor 28 (peripheral benzodiazepine receptor 28-OH, 333 mg, 1.0 mmol) in 4 mL of dimethylformamide, t- BuOK (224 mg, 2.0 mmol) and 1-(chloromethyl)-4-phenyl-1H-1,2,3-triazole prepared in Example 1 (360 mg, 1.0 mmol). The reaction mixture was stirred for 5 hours at room temperature and then quenched with water. After extracting the reaction mixture with ethyl acetate (ethylacetate), flash column chromatography (5% MeOH / CH 2 Cl 2 ) were isolated and purified to prepare 230 mg (35%) of the labeled...

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Abstract

The present invention relates to an [18F]fluoromethyl group-introduced radiotracer for positron emission tomography for targeting brain neuroinflammation, a synthesis thereof, and a method for evaluating biological results using the same. In the present invention, a fluoromethyl group-introduced fluorine-18 labeled radiotracer was prepared by introducing [18F]fluoroiodomethane, in which a prosthetic group diiodomethane is labeled with fluorine-18, into PBR28-OH through two stages, or substituting fluorine-18 using a triazolium triflate precursor in one stage at high yield. It was confirmed that, as a result of comparison and evaluation with exiting known [11C]PBR28 in view of in vitro binding affinity, fat affinity, and pharmacodynamic characteristics in a brain neuroinflammation model, the fluoromethyl group-introduced fluorine-18 labeled radiotracer had similar binding affinity and fat affinity to [11C]PBR28. Further, it was confirmed from the PET image comparison and evaluation in the brain neuroinflammation model that the fluoromethyl group-introduced fluorine-18 labeled radiotracer exhibited excellent selective / specific absorption in the inflammatory region more quickly and had high stability at the brain neuroinflammation site. According to the present invention, with respect to the synthesis of the novel fluoromethyl group-introduced fluorine-18 labeled radiotracer for PET targeting brain neuroinflammation and the diagnosis of brain neuroinflammation diseases, fluorine-18 having a relatively longer half-life than [11C]PBR28 was capable of being excellently labeled through the minimum structural change, and its excellent selective and specific imaging and pharmacodynamic advantages were verified, and thus a useful radiotracer for PET targeting brain neuroinflammation can be expected.

Description

technical field [0001] The present invention relates to a brain neuroinflammation target positron emission tomography radiotracer introduced with [18F]fluoromethyl, its synthesis and a method for evaluating biological results using it, and more specifically relates to the use of selective peripheral nerve benzodiazepines The introduction of radiotracers for imaging of Zhuo receptors (peripheral benzodiazepine receptors (PBR, PBR, PBR)) can be evaluated by positron emission tomography (PET) for the imaging of cranial neuroinflammation [ 18 F] fluoromethyl N-(2-fluoromethoxyphenyl)-N-(4-phenoxypyridin-3-yl)acetamide (N-(2-fluoromethoxybenzyl)-N-(4-phenoxypyridin -3-yl)acetamide), its synthesis and its in vitro binding affinity, fat affinity and pharmacokinetic evaluation in the brain neuroinflammation model. Background technique [0002] Microglial cells in the central nervous system contribute to the activation and homeostasis of the nervous system, and secrete nervous syste...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/04A61K51/02A61P29/00
CPCA61B6/037A61B6/501A61B6/5217A61K51/0455A61P29/00C07B59/002C07D213/75G16H50/30A61K51/02A61K51/04C07B2200/05C07D401/04
Inventor 李炳喆文炳锡郑在皓
Owner BIO IMAGING KOREA
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