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Targeting multimeric imaging agents through multilocus binding

A contrast agent and multi-site technology, which is applied in the field of contrast enhancement, new multi-body compounds, and contrast agents for diagnostic imaging, can solve the problems of increasing contrast, reducing flexibility, and large background of rigid contrast agents, so as to improve imaging contrast and imaging Effect of Contrast Improvement

Inactive Publication Date: 2002-11-27
EPIX PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Second, these reagents are not directed
Increasing the number of IEMs has proven unsuccessful because the contrast agent is non-uniform in size and structure, making synthesis difficult, difficult to target, or failing to increase contrast proportionally with the number of IEMs
Reducing flexibility was also unsuccessful, as rigid contrast agents cause large background when unbound

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] Embodiment 1 measures the method for relaxation rate

[0153] The relaxivity of compounds of the invention was evaluated with a Bruker NMS-120 Minnispec NMR spectrophotometer operated at 0.47 Tesla (20 MHz H-1 Larmor frequency) and 37°C. The T of the water proton is determined by the inversion recovery pulse sequence using the software of the device 1 . Relaxation rates were determined in the presence of target (typically 4.5% HSA) by preparing 4 independent samples. The first contained only 4.5% HSA in phosphate buffered saline (PBS), the other three contained 20, 30 and 40 [mu]M Gd(III) in addition to 4.5% HSA in PBS, respectively. Incubate samples at 37 °C for at least 15 min to ensure T 1 Temperature equilibration before measurement. The content of Gd(III) in the samples was determined by inductively coupled plasma-mass spectrometry (ICP-MS). by s -1 The indicated relaxivity rate (1 / T1) was plotted against the Gd(III) concentration (mM) to determine the relaxi...

Embodiment 2

[0155] Example 2 Experimental model for testing fibrin binding contrast agent of the present invention

[0156] In these examples the contrast agent with high relaxivity and specificity for imaging blood clots (thrombosis) is able to distinguish blood clots from circulating fibrinogen. It can provide sensitive and effective detection of thrombus formation in various states of disease progression. It can be used to diagnose the presence of early and late thrombosis.

[0157] One animal model that can be used is the rabbit jugular vein thrombosis model (jugular vein clamped). The vein was clamped in two places, and the rabbit blood between the two clamps was removed. Human fibrinogen, rabbit red blood cells and thrombin were added between the two clamps to generate a thrombus containing human fibrin. Typically such thrombi are aged for 30 minutes.

[0158] In this rabbit jugular vein model, the conventional measuring instrument is 1.5 Tesla with spoiled gradient (spoiled gra...

Embodiment 3

[0159] Example 3 Example Compounds: Preparation

[0160] A preferred example of the present invention is a contrast agent for MRI imaging having the structure shown in FIG. 13 .

[0161] The contrast agent in Figure 13 contains 4 DTPA-Gd moieties used as IEMs. IEMs are attached to the ethylenediamine framework through a linker comprising a series of repeating amides. TBM are two peptides that exhibit high affinity for fibrin. These two peptides can be cyclized by forming a disulfide bond between two cysteine ​​residues. TBM is attached to the framework by oxime and amide linkages.

[0162] At 37°C, 10μM contrast medium, 2.5mg / ml fibrin, 50mM Tris, 150mM NaCl, 2mM Ca 2+ , At pH 7.4, the combination of the prototype thrombus agent with the amino acid fragment of DD(E) in fibrin was 51%. The relaxation rate of the bound compound at 20MHz and 37°C is 101.4mM -1 the s -1 , each Gd chelate is 25.4mM -1 the s -1 . The relaxation rate of free contrast agent is 67.7mM -1 t...

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PUM

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Abstract

The present invention relates to contrast agents for diagnostic imaging. In particular, the present invention relates to novel multimeric compounds that exhibit improved relaxation rates when binding endogenous proteins or other physiologically relevant sites. Such compounds include: a) two or more image-enhancing moieties (“IEMs”) (or signal-generating moieties) comprising multimeric subunits; b) two or more target-binding moieties (“TBMs”) that provide In vivo positioning and multibody rigidification; c) a framework ("backbone"); and d) an optional linker for attaching the IEMs to the framework. The invention also relates to pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions to enhance contrast in diagnostic imaging.

Description

field of invention [0001] The present invention relates to contrast agents for diagnostic imaging. In particular, the present invention relates to novel multimeric compounds which, upon binding, exhibit improved affinity to physiologically relevant targets, such as proteins, and surprisingly improved relaxivity properties. Such compounds include: [0002] a) two or more image-enhanced segments (“IEMs”); [0003] b) two or more target-binding moieties ("TBMs") that provide in vivo localization and multibody rigidification; [0004] c) the frame ("skeleton"); [0005] d) An optional linker ("linker") that attaches the IEMs to the framework. [0006] The invention also relates to pharmaceutical compositions comprising these compounds, and the use of these compounds and compositions for contrast enhancement in imaging processes. Background of the invention [0007] Diagnostic imaging methods, such as magnetic resonance imaging (MRI), X-rays, nuclear radiopharmaceutical imag...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/04A61K49/00A61K49/06A61K49/08A61K49/14
CPCA61K49/0021A61K49/0032A61K49/0052A61K49/085A61K49/10A61K49/124A61K49/128A61K49/14A61K49/06
Inventor R·B·劳弗T·J·麦克默瑞S·迪马A·科沃杰伊J·阿梅迪奥P·卡拉文张昭达S·奈尔
Owner EPIX PHARMA
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