Labeled evans blue dye derivative for in vivo serum albumin labeling

Inactive Publication Date: 2016-10-06
US DEPT OF HEALTH & HUMAN SERVICES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a new compound, called a linker group, that can be used to attach a chelating group to a molecule for use in imaging techniques such as PET and SPECT. The linker group can be attached to a variety of molecules, including proteins, and can have various functions such as alkyl, halo, hydroxy, and alkyloxy groups. The invention also provides a method for preparing the new compound and a method for imaging a mammal using the new compound. The technical effects of the invention include improved accuracy and sensitivity in imaging techniques and the ability to target specific molecules or cells in the body.

Problems solved by technology

However, to date, only very few blood-pool tracers have been introduced for PET.
However, due to their short half-lives (20.4 min for 11C and 2.05 min for 15O), these tracers can only be used in centers with an in-house cyclotron.
However, high liver uptake was observed on the 18F-SiFA-RSA blood pool scan, indicating that the albumin structure may have been disrupted to some extent during labeling.
Although many typical lesions can be detected by traditional imaging tests such as ultrasound, CT, and MRI, there remains a challenge to diagnose atypical lesions.
However, this method requires separate administration of two agents because of different rates of local migration of the colloidal particles and blue dye molecules.
However, most of these probes are composed of heavy metals making their clinical translation difficult due to the acute and chronic toxicity.
In addition, scattering and tissue attenuation cause poor results for pre-surgical evaluation of SLNs using optical imaging.

Method used

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  • Labeled evans blue dye derivative for in vivo serum albumin labeling
  • Labeled evans blue dye derivative for in vivo serum albumin labeling
  • Labeled evans blue dye derivative for in vivo serum albumin labeling

Examples

Experimental program
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Effect test

example 1

[0162]This example demonstrates a synthesis of the compound:

in accordance with an embodiment of the invention.

[0163]To a 4 mL glass vial containing 20.0 mg of o-tolidine (94 μmol) and 20.0 mg of 1, 4, 7-triazacyclononane-N,N′,N″-triacetic acid-3HCl (“NOTA”) (48 mop in 1 mL of DMSO was added 3.6 μL of diethyl cyanophosphonate (24 μmol) and 25 μL of diisopropylethylamine (DIPEA). The mixture was stirred at room temperature for 40 min and another 3.6 μL of diethyl cyanophosphonate was added and stirred at room temperature overnight. The mixture was then purified with semi-preparative HPLC. The peak containing the desired product was collected (Rt=10.0 min) and the solution was frozen over dry ice and lyophilized overnight to give 12.2 mg pure product in 26.4% yield. LC-MS (C26H35N5O5): [MH]+=498.2467 (m / z), calc: 497.2638.

example 2

[0164]This example demonstrates a synthesis of the compound:

in accordance with an embodiment of the invention.

[0165]To a 20 mL glass vial containing 2.5 mg of NOTA-tolidine (5.0 μmol) in 0.3 mL of water was added 18 μmol of HCl in 0.1 mL of water. The mixture was cooled in ice bath and 0.5 mg of sodium nitrite (7.2 μmol) in 0.1 mL of water was added to the vial. The mixture was stirred in ice bath for 20 min and the yellow diazonium salt solution was added dropwise to another vial in ice bath containing 4.0 mg of 1-amino-8-naphthol-2,4-disulfonic acid (10.0 μmol) and 2.4 mg of sodium bicarbonate (28.5 μmol) in 0.2 mL of water. The mixture was stirred in ice bath for 2 h and purified with semi-preparative HPLC. The product (denoted as NEB) was collected (Rt=19.0 min) and lyophilized overnight to give 1.4 mg pure product in 46.6% yield. LC-MS (C36H41N7O12S2): [M-H]−=826.2415 (m / z), calc: 827.2255.

example 3

[0166]This example demonstrates a synthesis of the compound:

in accordance with an embodiment of the invention.

[0167]To a 1 mL plastic tube containing 3 μL of 2 mM aluminum chloride in 0.5 M pH 4.0 sodium acetate buffer and 6 μL of 3 mM NEB in 0.5 M pH 4.0 sodium acetate buffer was added 0.13 mL acetonitrile and 0.05 mL of aqueous 18F-fluoride (0.3-0.9 GBq). The mixture was vortexed and heated in a 105° C. heating block for 10 min. The vial was cooled, and the solution was diluted with 10 mL of water and trapped on a Varian Bond Elut C18 column (100 mg). The radioactivity trapped on the C18 column was eluted with 0.3 mL of 80% ethanol / water containing 1 mM HCl. The ethanol solution was evaporated with argon flow, and the final product was dissolved in PBS and analyzed by HPLC.

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Abstract

Disclosed is a compound of formula (I):wherein L, R1-R5, A, B, M, and n are as defined in the specification, as well as a method of preparing the compound. Also disclosed are a method of blood-pool imaging in a mammal and a method of imaging a lymph node in a mammal, comprising use of the compound.

Description

BACKGROUND OF THE INVENTION[0001]As the most abundant plasma protein, serum albumin has emerged as a versatile carrier for therapeutic agents, primarily for treating diabetes, cancer, rheumatoid arthritis and infectious diseases (Elsadek B et al., Kratz F. J Control Release 2012; 157(1): 4-28). Serum albumin was also used directly as an imaging probe after labeling with fluorescent dyes for optical imaging (Klohs J. et al., J Neurosci Methods. 2009; 180(1): 126-132), radioisotopes for scintillation scanning or positron emission tomography (PET) (McAfee J G et al., J Nucl Med 1964; 5:936-946; Hoffend J. et al., Nucl Med Biol 2005; 32(3): 287-292), or Gd3+ for magnetic resonance imaging (MRI) (Lauffer R B et al., Radiology. 1998; 207(2): 529-538). The major applications of labeled serum albumin mentioned above include blood pool imaging and angiography.[0002]In clinical nuclear medicine, kit preparations for indirect and direct 99mTc-radiolabeling of red blood cells (RBCs) are still t...

Claims

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Application Information

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IPC IPC(8): A61K51/04C09B45/00
CPCC09B45/00A61K51/0482C07B59/004C09B29/30
Inventor CHEN, XIAOYUANLANG, LIXINNIU, GANG
Owner US DEPT OF HEALTH & HUMAN SERVICES
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