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Methods and compositions for radiohalogen protein labeling

A radioactive and protein technology, applied in the field of protein intermediates and reagents, can solve the problems of reduction, poor membrane diffusion, etc.

Active Publication Date: 2015-10-21
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For lysine residues to 111 For In-DOTA-labeled antibodies, steps (1) and (2) also occur, but step (3) due to radiolabeled catabolites 111 Poor membrane diffusion of In-DOTA-lysine is greatly reduced

Method used

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  • Methods and compositions for radiohalogen protein labeling
  • Methods and compositions for radiohalogen protein labeling
  • Methods and compositions for radiohalogen protein labeling

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] Example 1 Synthesis of 2,2',2"-(10-(6-(2-(4-hydroxyphenyl)acetyl)-2,8,11-trioxo-12-oxa-3,6,9- Triazatetradecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tri-tert-butyl triacetate 2

[0162] To a 50-mL round bottom flask was added the following: 2,2',2"-(10-(2-((2-aminoethyl)amino)-2-oxoethyl)-1,4,7, 10-Tetraazacyclododecane-1,4,7-triyl)tri-tert-butyl triacetate 1 (0.5025g, 0.724mmol), paraformaldehyde (0.022g, 0.724mmol, 1 equivalent), 4 -Hydroxyphenylacetic acid (0.110 g, 0.724 mmol, 1 equiv) and ethyl isocyanoacetate (0.081 g, 0.724 mmol, 1 equiv). The mixture was refluxed in 10 mL of MeOH at 70° C. under argon for 5 hours. After removing the solvent in vacuo, purification was achieved by preparative reverse phase HPLC (100% 0.1% formic acid in water to 50% 0.1% formic acid in water / 50% CH 3 Gradient in CN) afforded 2 in 58.3% yield. 1 H NMR (300MHz, CDCl 3 )δ8.87(m,1H),8.48(m,1H),7.03(m,2H),6.81(m,2H),6.34(br s,1H),4.20-2.80(m,36H),1.45( s,27H),1.25(t,3H); ...

Embodiment 2

[0163] Example 2 Synthesis of 2-(2-(2-(4-hydroxyphenyl)-N-(2-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)) -1,4,7,10-Tetraazacyclododec-1-yl)acetamido)ethyl)acetamido)acetamido)acetic acid 3

[0164] 2,2',2"-(10-(6-(2-(4-hydroxyphenyl)acetyl)-2,8,11-trioxo-12-oxa-3,6, 9-Triazatetradecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tri-tert-butyl triacetate 2 (0.260g, 0.291mmol ) into a 50-mL round bottom flask with LiOH·H 2 O (0.018g, 0.437mmol, 1.5eq), 6mL of EtOH and 2mL of H 2 O. The reaction was stirred at room temperature for 12 hours. After removing the solvent in vacuo, purification was achieved by preparative reverse phase HPLC (from 100% 0.1% formic acid in water to 50% 0.1% formic acid in water / 50% CH 3 CN gradient) yielded 3.65.5% 1 H-NMR (300MHz, CDCl 3 )δ8.66(m,1H),8.07(m,1H),7.02(m,2H),6.29(m,2H),6.34(br s,1H),4.20-2.80(m,34H),1.44( s,27H); 13 C-NMR (75MHz, CDCl 3)δ174.51,174.14,173.70,173.45,172.43,169.80,167.18,156.59,156.45,130.43,130.02,125.93,116.0...

Embodiment 3

[0165] Example 3 Synthesis of 2,2',2"-(10-(14-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-6-(2-(4-hydroxybenzene Base) acetyl) -2,8,11-trioxo-3,6,9,12-tetraazatetradecyl)-1,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)tri-tert-butyl triacetate 4

[0166] 2-(2-(2-(4-hydroxyphenyl)-N-(2-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl) base)-1,4,7,10-tetraazacyclododec-1-yl)acetamido)ethyl)acetamido)acetamido)acetic acid 3 (0.113g, 0.131mmol) in a 50-mL round bottom The flask was charged with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.038g, 0.198mmol, 1.5eq) and 2-maleimidoethylamine·HCl (0.035g, 0.198 mmol, 1.5 equiv). The mixture was dissolved in 10 mL of CH 3 CN and stirred at room temperature for 12 hours. After removing the solvent in vacuo, purification was achieved by preparative reverse phase HPLC (from 100% 0.1% formic acid in water to 50% 0.1% formic acid in water / 50% CH 3 Gradient of CN) yielded 4. 1 H-NMR (300MHz, CDCl 3 )δ9.02(m,1H),8.07(m,1H),7.01(m,2H),6.79(m,2H...

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Abstract

Methods and compositions are provided for labeling proteins with radiohalogen-label reagents. Radiohalogen-labeled proteins may be used for imaging studies, as therapeutics and in diagnostic tests. The [125I] HIP-DOTA label reagent 6 is prepared by an efficient and convenient process.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application Serial No. 61 / 739,249, filed December 19, 2012, which is incorporated by reference in its entirety. technical field [0003] The present invention generally relates to methods of conjugating or labeling groups to proteins. The invention also relates to labeled proteins, as well as intermediates and reagents useful in the preparation of radiolabeled proteins for research and clinical development of new therapeutics and diagnostic tests. Background technique [0004] A known limitation of iodine radionuclides for labeling and biotracers of receptor targeting proteins is the propensity of iodotyrosine for rapid dissemination from cells followed by endocytosis and lysosomal degradation. In contrast, radiometal-chelate complexes such as indium-111-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ( 111 In-DOTA) accumulates in target cells due to the ...

Claims

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Application Information

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IPC IPC(8): A61K51/04A61K51/08A61K51/10
CPCA61K49/16A61K51/0482A61K51/088A61K51/103A61K51/1093C07K5/02C07K16/28A61K51/08A61K51/1051C07K1/13C07D207/404C07D207/452C07B59/002
Inventor C·A·鲍斯威尔L·卡里J·马里克S·威廉斯
Owner GENENTECH INC
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