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Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor

a translocator protein and radiotracer technology, applied in the field of fluorine-18labeled positron emission tomography radiotracer, can solve the problems of low tspo-specific signal, limited signal-to-noise ratio, and limited use of [sup>11/sup>c] pk11195, and achieve the effect of increasing the fluorine-18 labeling reactivity

Pending Publication Date: 2020-11-05
SEOUL NAT UNIV R&DB FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for producing a reaction solution containing fluorine-18, which can be used for labeling various molecules. The method involves adding a specific catalyst to increase the reactivity of the fluorine-18 labeling. The technical effect of this patent is to provide a more efficient and effective method for producing fluorine-18 reaction solutions.

Problems solved by technology

However, the widespread use of [11C] PK11195 has been limited due to problems with the carbon-11 used, such as a short-half life, non-specific binding in the body's brain, and a low signal-to-noise ratio.
However, [11C]DAA1106 has also been reported to have the problem of showing low TSPO-specific signals in TSPO.
However, since [11C] PBR28 is also a compound labeled with carbon-11 having a short half-life, it is a radiotracer that can be used only for a short time after production, and has disadvantages in that it involves a high possibility of radiation exposure and can be applied only to a maximum of two patients depending on the number of PET systems after produced once.

Method used

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  • Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor
  • Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor
  • Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor

Examples

Experimental program
Comparison scheme
Effect test

preparation examples

Preparation of Starting Material for Producing Iodonium Salt or Boron Ester Precursor

preparation example 1

-dichloro-2-(4-(trimethylstannyl)phenyl)-imidazo[1,2-a]pyridin-3-yl)-N,Nr-dipropylacetamide

[0082]

(Step 1): Preparation of 4-(4-bromophenyl)-4-oxo-B;N-dipropylbutanamide

[0083]3-(4-bromobenzoyl)propionic acid (2.0 g, 7.8 mmol) and 1,1′-carbonyldiimidazole (1.4 g, 8.6 mmol) were dissolved in tetrahydrofuran (THF, 50 ml) and stirred for 30 minutes. After 30 minutes, N,N′-dipropylamine (1.2 mL, 8.6 mmol) and triethylamine (1.3 ml, 9.4 mmol) were added thereto, followed by stirring for 3 hours. After the solvent was removed under reduced pressure, a 0.1 N aqueous solution of hydrogen chloride was added thereto, followed by extraction with ethyl acetate. The extracted organic layer was dried over sodium sulfate and filtered, and the remaining organic solvent was evaporated under reduced pressure. The residue was purified by column chromatography to afford the desired compound.

[0084]1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=7.4 Hz, 3H, CH3), 0.95 (t, J=7.4 Hz, 3H, CH3), 1.53 (q, J=7.4 Hz, 2H, CH...

example 3

n of 2-(6,8-dichloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide

[0102]

[0103]To a solution of 18-crown-6 (25.0 μmol) in acetonitrile (0.3 mL), a solution of cesium fluoride (25.0 μmol) in water (10 μL) was added. The solvent was completely evaporated by azeotropic distillation while the solution was heated at 90° C. under nitrogen. To the remaining material, a solution of (4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl) (p-tolyl)iodonium tosylate in acetonitrile (0.3 ml) was added, followed by heating at 80 to 140° C. for 1 hour with stirring. After cooling to room temperature, the reaction mixture was purified using an HPLC system (Waters, Xterra Semi-preparative C18 column, 10×250 mm, 10 μm; 50% acetonitrile-water, 254 nm, flow rate: 5.0 mL / min) equipped with a 254 nm UV detector and a radioisotope gamma-ray detector, and 2-(6,8-dichloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (BS224) was isolate...

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Abstract

Disclosed is a method for producing a fluorine-18-labeled, translocator protein overexpression-targeting PET radiotracer including: preparing a fluorine-18 reaction solution; producing a ((4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl) (aryl)iodonium) anion precursor as an iodonium salt precursor; producing a 2-(6,8-dichloro-2-(4-(4,4,5,6-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imidazo[1,2-a]pyridin-3-yl-N,N-dipropylacetamide precursor as a boron ester precursor; producing an iodonium salt precursor reaction solution; preparing a boron ester precursor reaction solution; and producing a radiotracer composition containing a fluorine-18-labeled radiotracer by reacting the iodonium salt or boron ester precursor reaction solution with the fluorine-18-labeled reaction solution. The use of the fluorine-18-labeled PET radiotracer makes it possible to diagnose patients with various brain diseases and tumors by obtaining new images of neuroinflammation, stroke and tumors associated with translocator protein overexpression through PET. In addition, by virtue of the long half-life of fluorine 18, the PET radiotracer can provide brain neuroinflammation and tumor imaging diagnostics to a larger number of patients compared to conventional carbon-11 tracers.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation of PCT / KR2018 / 015117 filed on Nov. 30, 2018, which claims priority to Korean Application No. 10-2018-0007226 filed on Jan. 19, 2018, which applications are incorporated herein by reference.TECHNICAL FIELD[0002]The present invention relates to a fluorine-18-labeled positron emission tomography radiotracer for targeting translocator protein overexpression, a fluorescent ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor, and more particularly to: a fluorine-18-labeled positron emission tomography (PET) radiotracer which is produced using an iodonium salt or boron ester precursor and has an excellent ability to be selectively and specifically taken up into inflammatory regions in neuroinflammation and tumor models; a translocator protein overexpression-targeting fluorescent ligand for fluorescence imaging-guided surgery and photodynamic therapy, which is...

Claims

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Application Information

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IPC IPC(8): A61K51/04C07B59/00
CPCA61K51/0455C07B59/002A61P25/00A61P35/00C07B59/00A61K49/0052A61K51/0453A61K41/0038A61K41/0057
Inventor KIM, SANG EUNLEE, BYUNG CHULLEE, SANG HEEDENORA, NUNZIOLAQUINTANA, VALENTINOLOPEDOTA, ANGELA ASSUNTACUTRIGNELLI, ANNALISAFRANCO, MASSIMO
Owner SEOUL NAT UNIV R&DB FOUND
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