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Complex of bifunctional connecting agent realizing core coordination with carbonyl metal and preparation method thereof

A technology of bifunctional linker and metal carbonyl, which can be applied to the 7/17 group organic compounds without C-metal bonds, preparations for in vivo tests, isotope-introduced organic compounds, etc. fit and other issues

Active Publication Date: 2019-03-08
北京久杰净化工程技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] So far, many researchers have conducted many explorations on HBED-CC labeling metal technetium, but most of them have focused on the TcO core to label HBED-CC, but have not been successful; and, due to the complex structure of HBED-CC, the technology Generally considered unsuitable for technetium carbonyl core labeling

Method used

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  • Complex of bifunctional connecting agent realizing core coordination with carbonyl metal and preparation method thereof
  • Complex of bifunctional connecting agent realizing core coordination with carbonyl metal and preparation method thereof
  • Complex of bifunctional connecting agent realizing core coordination with carbonyl metal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] 99m Tc(CO) 3 -L 2 Preparation of complexes:

[0075] (1) Ligand L 2 Synthesis

[0076] Synthesis of compound 3 (methyl 3-(4-hydroxyphenyl)propionate): p-hydroxyphenylpropionic acid (3g, 18.1mmol) and 50mL methanol were added to the round-bottomed flask, followed by the dropwise addition of trifluoro Boronium diethyl ether (0.3mL) was stirred at room temperature for 6 hours, and the organic phase in the filtrate was removed under reduced pressure using a rotary evaporator, and separated by a silica gel column with n-hexane / ethyl acetate (v / v, 2 / 8). Collect target component, remove solvent under reduced pressure, obtain 2.72g white solid (yield: 84%);

[0077] 1 HNMR (400MHz, CDCl 3 )δ: 7.07(d, 2H, J=8.4Hz), 6.76(d, 2H, J=8.4Hz), 4.72(s, 1H), 3.68(s, 3H), 2.89(t, 2H, J=7.6 Hz), 2.60 (t, 2H, J=7.6Hz); HRMS (ESI) theoretical molecular weight C 10 h 13 o 3 (M+H) + , 181.0865; measured molecular weight, 181.0815;

[0078] Synthesis of compound 4 (methyl 3-(3-form...

Embodiment 2

[0098] 99m Tc(CO) 3 -L 3 Preparation of complexes:

[0099](1) Ligand L 3 preparation of

[0100] 1) Double activated (HBED-CC) TFP 2 Synthesis:

[0101] From compound 1 (N, N'-bis[2-hydroxyl-5-(carboxyethyl) benzyl]ethylenediamine-N, N'-diacetic acid) as the reaction starting material, compound 1 and ferric chloride Mix and stir at room temperature for 20 minutes according to the equivalent of 1:1.1, and the product is purified by flash chromatography to obtain [Fe(HBEDCC)] – ; to 1000 μL concentration of 0.01M [Fe(HBED-CC)] – Add 10 equivalents of TFP (trifluopyrazine) and 4 equivalents of N, N'-diisopropylcarbodiimide to the DMF solution of DMF, react at room temperature for 3 days, and purify the product by preparative HPLC to obtain [ Fe(HBED-CC)]TFP 2 , after diluting with water, the diluted [Fe(HBED-CC)]TFP 2 The solution was injected onto the RP18 column, and the RP18 filter column was washed with 3mL, 1M hydrochloric acid and washed with 4mL of H 2 O washin...

Embodiment 3

[0115] Re(CO) 3 -L 2 Preparation of complexes

[0116] An aqueous solution of 10ml rhenium pentacarbonyl bromide (80mg, 0.2mmol) was refluxed at 105°C for 24 hours, and then the L 2 (30mg, 0.038mmol) added to containing Re (CO) 3 (H 2 O) 3 In the above reaction solution (2 mL) of the Br intermediate, the mixture was acidified with 0.1 N HCl to pH = 5 and heated at 95 °C for 3 h to give Re(CO) 3 -L 2 complex; its possible structure is as follows, such as image 3 Shown, is the Re(CO) prepared by Example 3 of the present invention 3 -L 2 UV-LC analysis chart. The analysis results show that the product has only one structure, and the existence of split peaks indicates that there are chiral isomers in the structure of the complex.

[0117]

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Abstract

The invention relates to a complex of a bifunctional connecting agent realizing core coordination with carbonyl metal and a preparation method thereof, and belongs to the technical field of radiopharmaceutical chemistry. The bifunctional connecting agent is N,N'-bi[2-hydroxyl-5-( propyloic) benzyl] ethylenediamine-N,N'-oxalic acid, and has a structure shown in the description, wherein at least onein R1 and R2 is a targeted small molecule or polypeptide or protein big molecule; the metal is Tc or Re. The carbonyl Tc / Re core marked HBED-CC complex is successfully obtained for the first time, different nuclide (68Ga, 99mTc / Re) marks of the same marking precursors can be realized; by aiming at the mutual supplementation of two development modes (PET / SPECT) in the same target point, the 188 / 186Re complex can be used for radioactive therapy medicine study. A novel idea is provided for the development of a Tc-99m single photon radioactive tracer agents and Re-188 / 186 radioactive treatment medicine; meanwhile, the application range of the HBED-CC derivatives as radiopharmaceutical marker precursors is also expanded.

Description

technical field [0001] The invention relates to a complex of a bifunctional linker coordinated with a metal carbonyl core and a preparation method thereof, in particular to a complex of a bifunctional linker labeled with a technetium carbonyl / rhenium core and a preparation method thereof, belonging to radiopharmaceuticals field of chemical technology. Background technique [0002] Molecular nuclear medicine is the use of radionuclide tracer technology to understand diseases at the molecular level, and to clarify changes in blood flow, metabolism, receptor density and function, abnormal expression of genes, changes in biochemical metabolism, and cell information transmission in target organs or tissues. It is a frontier and hot topic in the field of medical research in the world today, and it is the pursuit goal of modern molecular medicine. Therefore, it is an important part of molecular imaging and an important symbol of the development of modern medical imaging. The core...

Claims

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Application Information

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IPC IPC(8): C07F13/00A61K51/04A61K51/08C07K5/09C07K5/093C07K7/06C07K14/515C07B59/00A61K103/10
CPCA61K51/0406A61K51/0453A61K51/082C07B59/004C07B59/008C07B2200/05C07F13/005C07K5/0817C07K5/0819C07K7/06C07K14/515C07K19/00
Inventor 朱霖时圣寓查智豪孔繁渊郎红梅
Owner 北京久杰净化工程技术有限公司
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