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Apoptosis PET imaging agents

An imaging agent and covalent linking technology, which is applied in the direction of in vivo radioactive preparations, X-ray contrast agent preparation, pharmaceutical formulations, etc., to achieve the effect of easy image quantification

Inactive Publication Date: 2013-07-31
GE HEALTHCARE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Meszaros et al note that the nature of the co-ligand used with HYNIC can have a significant effect on the behavior of the system and state that no one co-ligand is ideal

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] Example 1: Synthesis of (Boc-aminooxy)acetyl-duramycin (precursor 1A).

[0190]

[0191]Duramycin (Sigma-Aldrich; 8.0 mg, 4.0 μmol), TFP (Boc-aminooxy)acetate (Invitrogen; 1.3 mg, 3.8 μmol) and DIPEA (2.1 μL, 12.5 μmol) were dissolved in NMP (1 mL )middle. The reaction mixture was shaken for 30 minutes. The mixture was then diluted with water / 0.1% TFA (6 mL), and the product was purified using preparative HPLC.

[0192] By preparative HPLC (Beckman System Gold chromatography system, using the following conditions: solvent A = H 2 O / 0.1% TFA with solvent B = ACN / 0.1% TFA, Gradient: 20-50% B in 40 minutes; Flow rate: 10 mL / min; Column: Phenomenex Luna 5 μm C18 (2) 250 x 21.2 mm; Detection: UV 214 nm) purification afforded 3.8 mg of pure precursor 1A (yield 44%). Purified material was analyzed by analytical LC-MS (gradient: 20-70% B in 5 minutes, t R : 1.93 minutes, measured value m / z : 1093.7, expected MH 2 2+ : 1093.5) analysis.

[0193] Separation of...

Embodiment 2

[0195] Example 2: Synthesis of (Eei-aminooxy)acetyl-duramycin (precursor 1B).

[0196]

[0197] Duramycin (Sigma-Aldrich; 50 mg, 25 μmol), NHS (Eei-aminooxy)acetate (Iris Biotech., 5.1 mg, 20 μmol) and DIPEA (17 μL, 100 μmol) were dissolved in NMP ( 1 mL). The reaction mixture was shaken for 45 minutes. The mixture was then diluted with water / 0.1% acetic acid (8 mL), and the product was purified using preparative HPLC.

[0198] Purification by preparative HPLC (as for Example 1 with a gradient of 14-45% B over 40 minutes, where A=water / 0.1% acetic acid and B=ACN) afforded 14 mg of pure precursor 1B (yield 26% ). The purified material was analyzed by LC-MS (gradient: 20-50% B in 5 minutes, t R : 2.5 and 2.7 minutes, measured values m / z : 1078.8, expected MH 2 2+ : 1078.5) analysis.

[0199] Chromatographic resolution of (Eei-aminooxy)acetyl-duramycin regioisomers was achieved on analytical HPLC using 0.1% TFA. However, the Eei protecting group is unstable in...

Embodiment 3

[0200] Example 3: Synthesis of Aminooxyacetyl-Duramycin (Precursor 2).

[0201]

[0202] Precursor 1B (14 mg) was treated with 2.5% TFA / water (2.8 mL) under argon for 40 min. The reaction mixture was diluted with water (31 mL) and the product was lyophilized (using isopropanol / dry ice under argon) to yield 18 mg of precursor 2. The lyophilized product was analyzed by LC-MS (gradient: 20-50% B in 5 minutes, t R : 2.5 and 2.1 minutes, measured values m / z : 1043.8, expected MH 2 2+ : 1043.5) analysis.

[0203] Chromatographic resolution of precursor 2 regioisomers can be achieved on analytical HPLC using 0.1% TFA. However, separation of the regioisomers was not attempted at this stage due to the high reactivity of free aminooxy groups towards traces of ketones and aldehydes in solvent and atmosphere.

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Abstract

The present invention relates to radiopharmaceutical imaging in vivo of apoptosis and other forms of cell death. The invention provides PET imaging agents which target apoptotic cells via selective binding to the aminophospholipid phosphatidylethanolamine (PE), which is exposed on the surface of apoptotic cells. Also provided are pharmaceutical compositions, kits and methods of in vivo imaging.

Description

field of invention [0001] The present invention relates to radiopharmaceutical in vivo imaging of apoptosis and other forms of cell death. The present invention provides PET imaging agents that target apoptotic cells via selective binding to the aminophospholipid phosphatidylethanolamine (PE) exposed on the surface of apoptotic cells. Also provided are pharmaceutical compositions, kits, and methods of in vivo imaging. [0002] Background of the invention [0003] Apoptosis or programmed cell death (PCD) is the most prevalent cell death pathway and proceeds via a highly regulated, energy-conserving mechanism. In a healthy state, apoptosis plays a key role in controlling cell growth, regulating cell number, promoting morphogenesis and removing harmful or abnormal cells. Dysregulation of the PCD process has been implicated in a variety of disease states, including those associated with inhibition of apoptosis, such as cancer and autoimmune disorders, and those associated with...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/08A61K51/04
CPCA61K51/088A61K51/0474A61K51/04A61K51/08A61K49/04
Inventor D.希斯科克B.E.阿尔博G.W.麦克罗比B.因德雷福尔R.布哈拉
Owner GE HEALTHCARE LTD