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VIP analog and its radioactive marker and their preparation process

A vasoactive intestinal peptide and radioactive labeling technology, applied in the field of two 18F markers, can solve unsatisfactory problems and affect the stability in vivo

Inactive Publication Date: 2011-04-20
SHANGHAI INST OF APPLIED PHYSICS - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

18 F-VIP is a good choice as a peptide positron drug, however 18 F-[Arg 15 , Arg 21 ] VIP in vivo diagnosis of breast cancer results are not satisfactory, its target / non-target ratio relative to 2-fluoro( 18 F) 2-deoxyglucose ( 18 F-FDG) is two to three times lower; moreover, because the methionine at the 17th position of its amino acid sequence is easily oxidized, it affects its stability in vivo

Method used

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  • VIP analog and its radioactive marker and their preparation process
  • VIP analog and its radioactive marker and their preparation process
  • VIP analog and its radioactive marker and their preparation process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1 (R 8，15，21 , L 17 ) Synthesis of VIP

[0041] Manually synthesized by Fmoc / tBu solid-phase peptide synthesis method, the raw materials used are: Fmoc-LinkerAM Resin, Fmoc-Gly, Fmoc-Leu, Fmoc-Lys(Boc), Fmoc-Thr(tBu), Fmoc-Glu(OtBu), Fmoc-His(trt), Fmoc-Ser(tBu), Fmoc-Asp(OtBu), Fmoc-Ala, Fmoc-Val, Fmoc-Phe, Fmoc-Arg(pbf), Fmoc-Asn(trt), Fmoc-Tyr (tBu), Fmoc-Gln (trt), Fmoc-Ile, Fmoc-Asn (trt), all purchased from Bachem Company, [2-(1H-benzotriazol-1-yl)-1,1,3, 3-Tetramethyluronium hexafluorophosphate (HBTU) was purchased from Richelieu Biotechnoligies, 1-hydroxybenzotriazole (HOBT) was purchased from Sigma, and diisopropylethylamine (DIPEA) was purchased from Aldrich.

[0042] Fmoc-Linker AM Resin removes the Fmoc protecting group with DMF containing 20% ​​piperidine, washes with DMF 9 times, adds HBTU (1.2 equivalents) to the obtained resin, HOBt (3.6 equivalents) reacts at 0 C for 30 minutes, and then uses DIPEA (4.8 equivalents) coupled with 1 equival...

Embodiment 2

[0043] The synthesis of embodiment 2 compound 1

[0044] first step, 18 f - Activation, 100μL approximately 50mCi 18 f - Oxygen-enriched aqueous solution was added to the 222 and 1 mg of potassium carbonate in a conical reaction flask, heated in an oil bath at 90°C, fed nitrogen continuously, and dried the water. Then add 500 μL of acetonitrile, ventilate and blow dry; this process is repeated three times to ensure that the reaction system is completely anhydrous.

[0045] In the second step, 0.2 ml of anhydrous acetonitrile solution of 10 mg of formula II compound ethyl-4-trimethylamine benzoate-trifluorosulfonate was added to the dried 18 f - In the reaction bottle, carry out in 100 ℃ oil bath 18 f - Nucleophilic substitution reaction 10min obtains formula III compound 4-[ 18 F] ethyl fluorobenzoate. The product was characterized by radioactive thin-layer chromatography. The instrument used Bioscan system AR-2000 system (Bioscan Company, USA), the software was Wins...

Embodiment 3

[0050] The synthesis of embodiment 3 compound 2

[0051] first step: 18 f - The activation, with the first step of embodiment 2.

[0052] The second step: anhydrous acetonitrile (300 μL) solution containing 4 mg of formula VI compound N-succinimide 4-[(4-nitrobenzenesulfonyl)oxymethyl]benzoate was added to the reaction flask, Sealed and reacted in an oil bath at 80°C for 10 minutes to obtain the compound of formula VII N-succinimide-4-[ 18 F] Fluoromethylbenzoate. The product is characterized by the radioactive thin-layer chromatograph used in the second step of Example 2, and R f =0.94, the labeling rate was 81.6%.

[0053]The reaction mixture was separated and purified using a Sep-Pak silica gel column (Waters), rinsed with 2 ml of dichloromethane / n-hexane (1:1, V / V), and then eluted with 2 ml of dichloromethane to obtain about 15 mCi of the product. The radiochemical purity was greater than 98%, and the radiochemical yield was 30% (uncorrected for decay).

[0054] Th...

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Abstract

The present invention discloses a VIP analog with the amino acid sequence as shown in SEQ ID No. 1, that is, the VIP analog has the VIP amino acid sequence with the arginine residue substituting the aspartic acid residue in the position 8, the arginine residues lysine residues in the positions 15 and 21, and the leucine residue substituting the methionine residue in the position 17. The present invention also discloses a radioactive marker of the VIP analog, especially a (R<8, 15, 21>, L<17>) VIP analog marked by two kind of <18>F, and their preparation process. The (R<8, 15, 21>, L<17>) VIP analog of the present invention has high metabolic stability and excellent receptor associativity, and the radioactive markers is suitable for use in preparing radioactive developing reagent for detecting in vivo VIP acceptor.

Description

technical field [0001] The present invention relates to a VIP analogue and its radioactive marker, especially two 18 Labels of F, their preparation methods, and the application of the radioactive labels of the VIP analogues in the preparation of radioactive imaging reagents for detecting VIP receptors in vivo. Background technique [0002] Vasoactive intestinal peptide (VIP) is a 28 amino acid (His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala -Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn) was first extracted from porcine duodenum 25 years ago, and it belongs to glucagon-pancreatic secretion Su group peptides have a wide range of biological functions. The two receptors of VIP, VIPR1 and VIPR2, were found to be abundantly expressed on a variety of tumor cells, including: colon cancer cells, pancreatic cancer cells, prostate cancer cells, etc. The density of VIP receptors on these tumor cells is higher than that of somatostatin Receptor, VIP has quite high ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/47A61K51/08A61K101/02
Inventor 尹端沚程登峰汪勇先张岚
Owner SHANGHAI INST OF APPLIED PHYSICS - CHINESE ACAD OF SCI
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