Conjugates of angiotensin ii and an imaging moiety

An imaging and drug technology, which is applied in the fields of new drugs for effective monitoring and treatment, and new pharmaceutical compositions and precursors for monitoring treatment, preparation of diagnostic agents, and can solve problems such as arrhythmia

Inactive Publication Date: 2007-01-24
GE HEALTHCARE AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Antiarrhythmic drugs have limited overall success and c

Method used

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  • Conjugates of angiotensin ii and an imaging moiety
  • Conjugates of angiotensin ii and an imaging moiety
  • Conjugates of angiotensin ii and an imaging moiety

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0190] Example 1 Ang II analogs with optical imaging dyes

[0191] Fluorescein-NH-(CH 2 ) 2 -Gly-Arg-Val-Tyr-Ile-His-Pro-Ile-OH

[0192] Peptide analogs of Ang II were synthesized starting from 0.1 mmol Fmoc-Ile-Wang resin on an Applied Biosystems 433A peptide synthesizer. An excess of 1 mmol of preactivated amino acid (O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate ( HBTU)). The N-terminus was bromoacetylated with 0.5 mmol bromoacetic anhydride in DMF for 30 minutes. The bromoacetylated resin was then treated with a solution of 0.5 mmol N-Boc-ethylenediamine dissolved in N-methylpyrrolidone (NMP) for 30 minutes. Peptides were cleaved from the resin with simultaneous removal of side chain protecting groups in 5 mL of TFA containing 2.5% triisopropylsilane (TIS) and 2.5% water for two hours. TFA was removed in vacuo, ether was added to the residue and the precipitated peptide was washed with ether and air dried.

[0193] 23 mg of crude peptide, 16 m...

Embodiment 2

[0195] Example 2 Tape for PET Imaging 18 Ang II analogue of F

[0196] 18 F-(CH 2 ) 3 -S-CH 2 CO-NH-(CH 2 ) 2 -Gly-Arg-Val-Tyr-Ile-His-Pro-Ile-OH

[0197]ATII peptide analogs were synthesized starting from 0.1 mmol Fmoc-Ile-Wang resin on an Applied Biosystems 433A peptide synthesizer. An excess of 1 mmol of preactivated amino acid (using HBTU) was used in the coupling step ending at arginine. The N-terminus was bromoacetylated with 0.5 mmol bromoacetic anhydride in DMF for 30 minutes. The bromoacetylated resin was then treated with a solution of 0.5 mmol N-Boc-ethylenediamine dissolved in NMP for 30 minutes.

[0198] Peptides were cleaved from the resin with simultaneous removal of side chain protecting groups in 10 mL of TFA containing 2.5% TIS and 2.5% water for two hours. TFA was removed in vacuo, ether was added to the residue and the precipitated peptide was washed with ether and air dried.

[0199] The resulting crude peptide was treated with one equivalent of...

Embodiment 3

[0200] Example 3 99m Tc-labeled Ang II analog

[0201] cPn216-Gly-Arg-Val-Tyr-Ile-His-Pro-Ile-OH

[0202]

[0203] Ang II peptide analogs were synthesized starting from 0.1 mmol Fmoc-Ile-Wang resin on an Applied Biosystems 433A peptide synthesizer. An excess of 1 mmol of preactivated amino acid (using HBTU) was used in the coupling step ending at arginine. The N-terminus was bromoacetylated with 0.5 mmol bromoacetic anhydride in DMF for 30 minutes. The resulting bromoacetyl resin was then treated with a solution of 0.2 mmol cPn216 and 0.4 NMM dissolved in DMF for 16 hours.

[0204] Peptides were cleaved from the resin with simultaneous removal of side chain protecting groups in 5 mL of TFA containing 5% TIS, 5% water and 2.5% phenol for two hours. TFA was removed in vacuo, ether was added to the residue and the precipitated product was washed with ether and air dried.

[0205] With preparative RP-HPLC (0-30% B within 40 minutes, wherein A=H 2 O / 0.1% TFA and B=CH 3 CN...

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PUM

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Abstract

The invention comprises pharmaceuticals of formula (I) Z-(L)n-V, wherein V denotes a peptide, L denotes an optional linker, Z denotes a group that optionally can carry an imaging moiety M, n denotes 0 or 1. The pharmaceuticals are active as therapeutic agents for the treatment of heart failure, cardiac arrhythmias and diseases of fibrosis prominent such as COPD, liver fibrosis and atherosclerosis. The novel pharmaceutical comprises targeting moieties bonded to the receptor which receives up regulation and/or excess expression in or not in siclen region. The imaging moieties contained in the targeting moieties carries imaging moieties which can form image for diagnosis, optional linkers and peptides. The novel pharmaceutical compound has high affinity to angiotensin receptor, in particular to angiotensin II(AngII)I type(AT1)receptor.

Description

field of invention [0001] The present invention provides novel drugs for effective treatment of heart failure, arrhythmia and other fibrosis-prominent diseases, as well as for diagnosis of fibrosis-prominent diseases and symptoms. The invention also provides novel pharmaceutical compositions and precursors for preparing diagnostic agents. In addition, the present invention also provides novel drugs for effective monitoring of therapy and methods of monitoring therapy. Still further objects of the invention are apparent from the claims. [0002] The novel drugs comprise targeting moieties that bind to receptors that may or may not be upregulated and / or overexpressed in the disease area. The targeting moiety comprises an imaging agent moiety with a diagnostically imageable moiety, an optional linker group and a peptide moiety. [0003] The novel pharmaceutical compound is effective for angiotensin receptors (Angiotensin Receptors), especially for angiotensin II (Ang II) type ...

Claims

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Application Information

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IPC IPC(8): A61K51/08A61P11/00A61K49/00A61P1/16A61P9/00A61P9/10A61P9/06C07K
Inventor A·库思伯特森B·因德雷沃尔M·埃里克森
Owner GE HEALTHCARE AS
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