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Isatin derivatives for use as in vivo imaging agents

A compound and composition technology, applied in the field of new isatin 5-sulfonamide derivatives, can solve the problems of increased non-specific binding, poor image contrast, high lipophilicity, etc., and achieve high metabolic stability, accurate visualization and quantification Effect

Inactive Publication Date: 2011-08-31
IMPERIAL INNOVATIONS LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these known compounds suffer from various disadvantages, including low molecular stability, relatively low caspase-3 affinity and high lipophilicity
Low molecular stability leads to rapid metabolism resulting in low signal-to-noise ratio and poor contrast in images
Low caspase-3 affinity can also lead to poor image contrast
High lipophilicity results in poor systemic drainage and increases general nonspecific binding to macromolecules

Method used

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  • Isatin derivatives for use as in vivo imaging agents
  • Isatin derivatives for use as in vivo imaging agents
  • Isatin derivatives for use as in vivo imaging agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] Synthesis of Example 1-Compounds

[0176] A target compound library was created using ((S)-1-(4-fluorobenzyl)-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)isatin) as a lead compound. Modifications are made to the left side ether moiety and the N-1 position. A fluoro group was incorporated into the left-hand phenyl ether group, and heterocycle and alkyne tolerance at this position was investigated. The tolerance of the 1,2,3 triazole group at the N-1 position was also investigated. The target compound was synthesized by condensation of a functionalized pyrrolidine with 5-chlorosulfonyl isatin followed by alkylation of the isatin nitrogen using potassium carbonate / DMF, as figure 1 shown. All necessary starting materials are commercially available or as in Lee, D. et al. 8 , Chu, W. et al. and Kopka, K. et al. 13 prepared in.

[0177] Reaction of commercially available phenol as well as 4-hydroxytetrahydropyran with tosylate 17 provided pyrrolidines 19a-f in relativel...

Embodiment 2

[0225] Example 2 - Measurement of lipophilicity and affinity for caspases of target compounds

[0226] Affinity of target compounds for caspases New fluoroisatins 1-5 and 10-12, and existing isatin derivatives and intermediate compounds 22 and 23 for different activated caspases The affinities of 1, 3, 6, 7, and 8 were all measured by fluorescent in vitro caspase inhibition assays in collaboration with Kopka and his colleagues 13 Similar to what was stated. Inhibition of recombinant human caspases was assessed by measuring the accumulation of the fluorescent product 7-amino-4-methylcoumarin (7-AMC).

[0227] Recombinant human caspase-1, -3, -6, -7 and -8 and their peptide-specific substrates were purchased from Biomol International, UK. Inhibition of recombinant caspases by non-radioactive isatin was evaluated by fluorescence analysis measuring the accumulation of the fluorescent product 7-amino-4-methylcoumarin (7-AMC). All assays were performed in 96-well plates at a volu...

Embodiment 3-

[0240] Embodiment 3-[ 18 Synthesis of F]11

[0241] Preferably, the compound [ 18 F]11 is used [ 18 F] Fluoroethyl azide (compound 27) "click-label" (S)-1-(2-propynyl)-5-(2-(2,4-difluorophenoxymethyl)-pyrrolidine -1-sulfonyl) isatin (compound 25) produces 15，16 . Triazole (S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4- Difluorophenoxymethyl)-pyrrolidine-1-sulfonyl) isatin (compound 11) is obtained by 2-[ 18 F] fluoroethyl azide (compound 27) and alkyne precursor (S)-1-(2-propynyl)-5-(2-(2,4-difluorophenoxymethyl)-pyrrolidine- 1-sulfonyl)isatin (compound 25) was labeled by copper-catalyzed cycloaddition, as shown in Figure 2(i) and Figure 19 shown in . The same approach can be used to generate non-radiolabeled compound 11, using fluoroethyl azide instead of 2-[ 18 F] Fluoroethyl azide.

[0242] Under a nitrogen atmosphere, a buffer solution (sodium phosphate buffer, pH 6.0, 250 mM) of sodium ascorbate (50 μl, 8.7 mg, 43.2 μmol) was added to ...

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PUM

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Abstract

The present invention provides isatin 5-sulfonamide derivatives, pharmaceutical compositions comprising said derivatives, their use as molecular imaging agents, their use for the diagnosis or treatment of diseases or disorders associated with dysregulation of apoptosis, methods for synthesizing said derivatives, methods for the molecular imaging of caspase activity and apoptosis, and methods of assessing the therapeutic effect of a test substance on caspase activity.

Description

technical field [0001] The present invention relates to a novel derivative of isatin 5-sulfonamide and its use as a molecular imaging agent in the visualization and quantification of caspase activity and caspase-associated apoptosis, as well as in therapeutic applications use in . Background technique [0002] Apoptosis or programmed cell death (PCD) is the most prevalent pathway of cell death and proceeds through 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 this process is associated with a variety of diseases, including those associated with inhibition of apoptosis, such as cancer and autoimmune disorders, and those associated with overactive apoptosis, including neurodegenerative, hematological , AIDS, ischemia and allograft rejection. Therefore, visualization and quantification of apopt...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D403/14C07D405/14A61K31/404A61K51/00A61P25/28
CPCC07D405/14C07D403/14C07D403/12A61P1/16A61P7/00A61P9/10A61P19/02A61P25/28A61P37/06A61P43/00A61K31/404A61K51/04
Inventor E·O·阿博格G·史密斯Q-D·阮E·阿斯塔德M·E·格拉泽
Owner IMPERIAL INNOVATIONS LTD
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