Caspase-3 substrate comprising imaging agents

A technology of caspase and imaging agent, which can be used in tetrapeptide components, in vivo radioactive preparations, preparations for in vivo experiments, etc., and can solve problems such as abdominal cell death imaging

Inactive Publication Date: 2008-04-02
GE HEALTHCARE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This makes it impossible to image cell death in the abdomen (e.g. in kidney transplantation and tumor monitoring)

Method used

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  • Caspase-3 substrate comprising imaging agents
  • Caspase-3 substrate comprising imaging agents
  • Caspase-3 substrate comprising imaging agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] Example 1: Synthesis of compound 1-22

[0151] a) Peptide synthesis

[0152] On Rink Amide resin (obtained from NovaBiochem, a typical loading amount of 0.73 mmol / g), by standard solid-phase peptide chemistry [Barany et al., Int. J. Peptide Protein Research 30, 705-739 (1987)], the assembly corresponds to The peptidyl resin of the sequence of compound 1-22 in Figure 1. Applied Biosystems (Perkin Elmer) Model 433A peptide synthesizer was used. The residues (from the carboxyl end) were assembled on a 0.25 mmol scale using a single coupling (2.5 hour coupling cycle) with a 4-fold molar excess of Fmoc-amino acids (1 mmol cartridges), the Fmoc-amino acids using hexafluorophosphate 2-(1H-Benzotriazol-1-yl)-1,1,3,3-Tetramethylurea (HBTU) / 1-Hydroxybenzotriazole (HOBt) / Diisopropylethylamine ( DIEA) N-methylpyrrolidone (NMP) solution is preactivated. Use 20% piperidine in NMP solution to complete Fmoc deprotection under conductivity monitoring. The washing solvent is NMP. The amino...

Embodiment 2

[0164] Example 2: 123 Synthesis of I-labeled compound 2 (compound 2A)

[0165] Step (a): 127 I analog (compound 2)

[0166] Compound 2 was synthesized according to the following reaction scheme:

[0167] P33-7

[0168] Compound 1

[0169] 74μl(74μg, 1×10 -7 mol) Aqueous solution of compound 1

[0170] 200μl pH4, 0.2M ammonium acetate buffer

[0171] 100μl Na 127 0.01M NaOH solution of I, 1×10 -7 mol

[0172] 10μl 0.01M PAA solution, 1×10 -7 mol

[0173] Compound 2

[0174] Where PAA = peroxyacetic acid

[0175] 127 I. Mass spectrometry analysis of the prepared and purified material confirmed the identity.

[0176] Step (b): Preparation of compound 2A

[0177] To compound 1 dissolved in 74μl water (74μg, 1×10 -7 Mol) add 200μl pH 4, 0.2M ammonium acetate buffer, 10μl Na 127 0.01M NaOH of I (1×10 -8 Mol) solution, about 10-30μl (150-450MBq) Na 123 I 0.05M NaOH solution and 10μl 0.001MPAA solution (1×10 -8 Mole). will[ 123 I]-Compound 2 was purified by HPLC, diluted to 20 and 100 ...

Embodiment 3

[0178] Example 3: 123 Synthesis of I-labeled compound 6 (compound 6A)

[0179] Step (a): 127 I analog (compound 6)

[0180] Compound 6 was synthesized according to the following reaction scheme:

[0181] P34-8

[0182] Compound 5

[0183] 98μg of compound 5 in 98μl methanol solution, 9.96×10 -8 mol

[0184] 100μl pH4, 0.2M ammonium acetate

[0185] 100μl Na 127 0.01M NaOH solution of I, 1×10 -8 mol

[0186] 10μl 0.001M PAA solution, 1×10 -8 mol

[0187] Where PAA = peroxyacetic acid

[0188] 127 I. Mass spectrometry analysis of the prepared and purified material confirmed the characteristics.

[0189] Step (b): Preparation of compound 6A

[0190] After the formation of iodonium, compound 5 (98μg, 1×10 -7 Mol) was added to 100μl pH4, 0.2M ammonium acetate buffer, 10μl Na 127 0.01M NaOH of I (1×10 -8 Mol) solution, about 10-30μl (150-450MBq) Na 123 I 0.05M NaOH solution and 10μl 0.001M PAA solution (1×10 -8 Mol). Compound 6A was purified by HPLC, diluted to 20 and 100 MBq / ml in ...

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Abstract

The present invention relates to diagnostic imaging agents for in vivo imaging. The imaging agents comprise a synthetic caspase-3 substrate peptide labelled with an imaging moiety suitable for diagnostic imaging in vivo. The invention also provides radiopharmaceutical compositions comprising the imaging agents, together with kits for the preparation of the radiopharmaceuticals. Also described are non-radioactive precursors suitable for the preparation of the imaging agents. The imaging agents are useful for the diagnostic imaging and or therapy monitoring in vivo of various disease states where caspase-3 is involved.

Description

Invention field [0001] The present invention relates to a diagnostic imaging agent for in vivo imaging. The imaging agent contains a synthetic caspase-3 (caspase-3) substrate labeled with an imaging moiety suitable for in vivo diagnostic imaging. Background of the invention [0002] Programmed cell death caused by apoptosis is a complex process involving many cellular processes with multiple levels of regulation. It is triggered by one of two ways. The first is an exogenous pathway triggered by cell surface death receptors, and the second is an endogenous pathway via endogenous initiating factors (such as DNA damage caused by ultraviolet radiation). Both of these pathways end in coordinated death of cells. Co-ordinated death of cells requires energy, and unlike necrotic cell death, it does not involve inflammatory reactions. The cell that is about to apoptotic sends a "eat me" signal on its cell surface, enticing other cells to destroy them through phagocytosis. [0003] Apoptosi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/02A61K38/07A61K51/08
CPCA61K51/088A61K38/07
Inventor B·吉尔贝S·钱皮安A·M·吉布森S·-A·里克茨M·阿沃里B·E·阿博
Owner GE HEALTHCARE LTD
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