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Apoptosis imaging agents based on lantibiotic peptides

A technology of lantibiotics and imaging agents, applied in the directions of in vivo radioactive preparations, preparation of X-ray contrast agents, preparations for in vivo experiments, etc.

Inactive Publication Date: 2013-05-22
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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  • Apoptosis imaging agents based on lantibiotic peptides
  • Apoptosis imaging agents based on lantibiotic peptides
  • Apoptosis imaging agents based on lantibiotic peptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 15

[0154] Example 15 provides the determination of the conjugation site of the chelator, and Example 16 demonstrates that the conjugation site of the chelator has a significant effect on the binding affinity to phosphatidylethanolamine with an 18-fold difference (K d 5 nM vs. 90 nM). This provides a preference for linkage at the N-terminus (Cys of Formula II) than at Xaa of Formula II. a ) evidence of attachment of a radiometal complex. The EL4 lymphoma mouse xenograft tumor model of Example 17 was used as a model to mimic the apoptotic response following chemotherapy. Treatment-treated mice (etoposide / cyclophosphamide) showed a 4-fold increase in tumor apoptosis compared to vehicle control-treated animals. The biodistribution results of Example 17 showed higher uptake of each agent in chemotherapy-treated tumors, while correlation analysis indicated a trend towards higher uptake of the binders in tumors with higher levels of apoptosis. compared to 99m Tc-[conjugate 3A], 99...

Embodiment 1

[0194] Example 1: Synthesis of 1,1,1-tris(2-aminoethyl)methane.

[0195] Step 1(a): Dimethyl 3(methoxycarbonylmethylene)glutarate.

[0196] Carbomethoxymethylenetriphenylphosphine (167g, 0.5mol) in toluene (600ml) was treated with dimethyl 3-oxoglutarate (87g, 0.5mol) at 120°C under nitrogen atmosphere On an oil bath, the reaction was heated to 100°C for 36 hours. The reaction was then concentrated in vacuo and the oily residue was triturated with 40 / 60 petroleum ether / diethyl ether 1:1 (600ml). Triphenylphosphine oxide precipitated out and the supernatant liquid was decanted / filtered. The vacuum evaporated residue was Kugel distilled under high vacuum Bpt (oven temperature 180-200°C, 0.2 Torr) to give dimethyl 3-(methoxycarbonylmethylene)glutarate (89.08 g , 53%).

[0197] NMR 1 H(CDCl 3 ): δ 3.31 (2H, s, CH 2 ), 3.7 (9H, s, 3×OCH 3 ), 3.87 (2H, s, CH 2 ), 5.79 (1H, s, =CH) ppm.

[0198] NMR 13 C(CDCl 3 ), δ 36.56, CH 3 , 48.7, 2×CH 3 , 52.09 and 52.5 (2×CH 2 )...

Embodiment 2

[0223] Example 2: Preparation of 3-chloro-3-methyl-2-nitrosobutane.

[0224] A mixture of 2-methylbut-2-ene (147ml, 1.4mol) and isopentylonitrile (156ml, 1.16mol) was cooled to -30°C in a bath of cardice and methanol and stirred vigorously using a headspace air stirrer , was treated dropwise with concentrated hydrochloric acid (140ml, 1.68mol) at such a rate that the temperature was kept below -20°C. This takes about 1 hour due to the significant exotherm and care must be taken to prevent overheating. Ethanol (100 ml) was added to reduce the viscosity of the slurry formed at the end of the addition, and the reaction was stirred for an additional 2 hours at -20 to -10°C to complete the reaction. The precipitate was collected by filtration under vacuum, washed with 4 x 30 ml of cold (-20 °C) ethanol and 100 ml of ice-cold water, and dried in vacuo to give 3-chloro-3-methyl-2-nitroso as a white solid butane. The ethanol filtrate and washings were combined, diluted with water (...

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Abstract

The present invention relates to radiopharmaceutical imaging in vivo of apoptosis. The invention provides imaging agents which target apoptotic cells via selective binding to the aminophospholipid phosphatidylethanolamine (PE), which is exposed on the surface of apoptotic cells. The radiopharmaceuticals comprise radiometal complexes of chelator conjugates of PE-binding peptides. 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 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. Background of the invention [0002] 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 hyperactive ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/08A61K103/10
CPCA61K51/088A61K49/04A61K51/08
Inventor B.因德雷沃尔D.希斯科克B.E.阿尔博R.布哈拉M.E.格拉泽G.W.麦克罗比
Owner GE HEALTHCARE LTD
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