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Polyamine micromolecular developer, production method and application thereof

A technology of small molecule compound and PET imaging agent, which is applied in the field of preparing PET imaging agent and cell apoptosis-coupled polyvalent polyamine small molecule compound, can solve the problem of poor early imaging effect and difficult to detect apoptotic cells , large molecular weight, etc.

Inactive Publication Date: 2012-05-09
THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the labeled Annexin V also has the following serious deficiencies: (1) The molecular weight is relatively large (3.6×10 4 ), slower blood clearance, lower target / non-target radioactivity ratio, poor early imaging [1，9] ; (2) The cost of labeling Annexin V is high and expensive; (3) It is immunogenic [5]
However, if the free Zn in early tumor apoptotic cells 2+ When the concentration is low, it is difficult for Dansylamidoethylcyclen to detect apoptotic cells, and there is no research report on radionuclide-labeled Dansylamidoethylcyclen

Method used

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  • Polyamine micromolecular developer, production method and application thereof
  • Polyamine micromolecular developer, production method and application thereof
  • Polyamine micromolecular developer, production method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] 【Example 1】 18 F-FEN-DPAZn2 and 18 Synthesis of F-FB-DPAZn2 precursor

[0123] 1. Synthesis of dimethyl 15-hydroxyisophthalate (1)

[0124] 5-Hydroxyisophthalic acid (10 g, 54.9 mmol) was dissolved in 100 mL of methanol, 5 mL of concentrated sulfuric acid was added, and heated under reflux for 12 hours. The system was cooled, and a white solid was precipitated, filtered, the filter cake was washed with methanol, and dried to obtain 10.93 g of a white solid, with a yield of 94%. Melting point: 102-104°C.

[0125] 1.23, Synthesis of 5-dimethylolphenol (2)

[0126] Dimethyl 5-hydroxyisophthalate (1) (5 g, 23.8 mmol) was added to 100 mL of dry tetrahydrofuran, and lithium aluminum hydride (2.7 g, 71.4 mmol) was added in batches, and heated to reflux for 3 hours. The system was cooled to room temperature, and distilled water was added dropwise until no bubbles were generated. Add dilute hydrochloric acid to adjust the pH to 3, extract with ethyl acetate (50 mL×3), comb...

Embodiment 2

[0137] [Example 2] 18 F-FEN-DPAZn2 and 18 Radiosynthesis of F-FB-DPAZn2

[0138] 2.1 18 Radiochemical synthesis of F-FEN-DPA2 [see the reaction formula of compound (7) into compound (8)]

[0139] Such as figure 1 As shown, with PET-MF-2V-IT-I type fluorine-18 multifunctional synthesis module (produced by Paite (Beijing) Technology Co., Ltd., Tang G*, Tang X, Wen F, Wang M, Li B.A facile and rapid automated synthesis of 3'-deoxy-3'-[ 18 F]fluorothymidine. Appl Radiat Isot, 2010, 68: 1734-1739.) carried out 18 F mark, the specific mark operation is as follows:

[0140] 2.1.1 18 f - Accelerator produced by Cyclone 10 / 5 type IBA, through 18 O(p,n) 18 F reaction production. Apply 2.0mL H 2 18 O target, produced by continuously bombarding the target with 10.5MeV, 25μA proton beam for 10-60min 18 f - , take a certain activity 18 f - The target water passes through the QMA column;

[0141] 2.1.2 18 F - After being captured by QMA, use 1.5 mL of K in bottle a 2 CO ...

Embodiment 3

[0172] [Example 3] organic synthesis of fluorescent imaging agent Dansy1-DPA2 and Dansy1-DPAZn2

[0173] Dansylation-N-(2-{2-[2-(3,5-di-N,N-bis(2-methylpyridine)aminomethyl-phenoxy)ethoxy]-ethoxy Base} ethyl) amino) (Dansy1-DPA2) [synthetic route see compound (7) into (10) part].

[0174] (2-{2-[2-(3,5-di-N,N-bis(2-picoline)aminomethyl-phenoxy)ethoxy]-ethoxy}ethyl)- Amino (7) (300mg, 0.46mmol) was dissolved in 15mL of acetonitrile, added triethylamine (56.7mg, 0.56mmol, 1.2eq.), added 20ml of dry dichloromethane, cooled to 0°C in an ice bath, dansyl chloride (149mg, 0.56mmol, 1.2eq.), under argon protection, stirred at room temperature for 3h. TLC monitoring, the reaction has been completed. First, the solvent was evaporated, 20ml of distilled water was added, extracted with ethyl acetate (20ml×4), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and then column chromatographed (ethyl acetate:methanol ammonia=15:1) to obtain Green oily f...

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Abstract

The invention relates to a polyamine micromolecular compound, comprising the following structures described in the specification, wherein M<x+> is 0, Zn<2+>, Ga<3+>, Gd<3+>, Ca<2+> or other divalent metal ions and trivalent metal ions; S is a reporter group (including a nuclide labeling prothetic group, a paramagnet, a fluorescein or a microvesicle), such as the nuclide labeling prothetic group: -<11>CH3, -CH2CH2<18>F, -CH2CH2(OCH2CH2)2NHCOC6H4<18>F-p or -CH2CH2(OCH2CH2)2NH-CH2CH2<18>F; R is -H, -OCH3, -OCH2CH3 or -Cl; and R1, R2, R3 and R4 are hydrogen, carboxyl, alkane, alkylene or heteroalkyl. The invention further relates to application of the compound in preparing cell death or apoptosis developers of target phosphatidyl serine (PS) and / or apoptotic cell early free Zn<2+>. The compound provided by the invention is a specific multiamine micromolecular developer for target phosphatidyl serine (PS) and / or apoptotic cell early free Zn<2+>, which can be used for monitoring curative effects of PS-related anti-tumor chemotherapy, radiotherapy, biological therapy and the like; the compound can be used for early differential diagnosis of neurodegenerative diseases (senile dementia and Parkinson's disease), cerebral apoplexy, AIDS (Acquired immune deficiency syndrome), thrombus, atheromatous plaque and myocardial infarction; and the compound can also be used for differential diagnosis and curative effect monitoring of other diseases related to PS expression in the cell death or apoptosis process, such as inflammation development and anti-inflammation therapeutic development.

Description

【Technical field】 [0001] The present invention relates to a positron emission tomography (PET) imaging agent (medicine), its production method and its application, especially relates to cell apoptosis coupled multivalent polyamine small molecule compound, its production method and its application in the preparation of PET imaging agent in the application. 【Background technique】 [0002] One of the tumor treatment mechanisms is to interfere with DNA synthesis and cell division, induce tumor cell apoptosis, and achieve the purpose of inhibiting or eliminating tumors. Malignant tumor cells will develop drug resistance to chemotherapy, radiotherapy or certain hormonal treatments, which is related to their ability to escape induction of apoptosis. The degree of initial tumor cell apoptosis after tumor treatment can also reflect the sensitivity of treatment. Therefore, the detection of apoptosis plays a very important role in the evaluation of malignant tumor therapy. The tradit...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D213/38A61K51/00A61K101/02A61K101/00
Inventor 唐刚华王红亮唐小兰
Owner THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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