CN101780286A - Chemotactic factor receptor CXCR4 non-peptide antagonist medicaments for radiodiagnosis and treatment - Google Patents

Chemotactic factor receptor CXCR4 non-peptide antagonist medicaments for radiodiagnosis and treatment Download PDF

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CN101780286A
CN101780286A CN 200910000806 CN200910000806A CN101780286A CN 101780286 A CN101780286 A CN 101780286A CN 200910000806 CN200910000806 CN 200910000806 CN 200910000806 A CN200910000806 A CN 200910000806A CN 101780286 A CN101780286 A CN 101780286A
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medicine
radiodiagnosis
amd3100
cxcr4
peptide antagonist
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张锦明
田嘉禾
沈丽
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Chinese PLA General Hospital
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Chinese PLA General Hospital
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Abstract

The invention discloses chemotactic factor receptor CXCR4 non-peptide antagonist medicaments for radiodiagnosis and treatment, which are prepared by complexing AMD3100 serving as the parent with radioactive metal ions or labeling by using positron nuclides. The medicaments are used for diagnosing and treating CXCR4 related diseases, such as AIDS, malignant tumor, arthritis and stem cell therapy. The medicaments can be used for diagnosing and treating AIDS, malignant tumor, arthritis and stem cell therapy.

Description

The radiodiagnosis and the medicine of chemokine receptors CXCR4 non-peptide antagonist
Technical field
The present invention relates to a kind of medicine that is used to diagnose and treat the CXCR4 relevant disease, be specifically related to a kind of radiodiagnosis and medicine of chemokine receptors CXCR4 non-peptide antagonist.This radioactive compound is suitable for diagnosis and treatment and CXCR4 relevant disease, as the diagnosis (SPECT and PET) and the treatment of diseases such as AIDS, malignant tumor, arthritis and stem-cell therapy.
Background technology
The tumor receptor developer is divided at present: first kind nerve polypeptide class, comprise neurosecretion receptor, gastrin releasing peptide, vasoactive peptide etc., as: 111In/ 90Y-Octreotide, 131I-MIBG, 68Ga-VIP etc., these video pictures provide a kind of brand-new effective method for diagnosis/treatments frequently-occurring or the high mortality tumor such as the breast carcinoma of multiple histological type, neuroblastomies; Second class is the sex hormone receptor class, mainly contains 18The F-estradiol ( 18F-FES) and 18F-FDHT, wherein 18F-FES has been successfully applied to breast carcinoma tamoxifen therapeutic process and has monitored with curative effect and assess; The 3rd class is the sigma-receptor class, and sigma-receptor has overexpression in malignant tumor such as melanoma, carcinoma of prostate, breast carcinoma, colon cancer and nonsmall-cell lung cancer, research at present 123I-MBA is expected to be applied to the diagnosis of above tumor; The 4th class is epidermal growth factor (EGFR) receptor, EGFR has high expressed in many tumors, in growth of tumour cell and malignization, play an important role, and closely related with formation, tumor invasion and transfer, chemotherapy of tumors resistance and the prognosis of new vessels, the EGFR receptor developer of labelling has 11C/ 18F-PD153035 is applied to clinical research at present.In addition, also have and the closely-related integrin receptor α of tumor v beta 3 receptor, dopamine receptor, folacin receptor etc.More than all receptor and developer in the diagnosis of tumor and treatment, play a part importantly, but do not see that bibliographical information is used for the research of visual diagnosing tumor and treatment targeted drug based on chemokine receptors CXCR4 at present.
CXCR4 belongs to the specificity chemokine receptors, and the existing most of malignant tumor of bibliographical information are metastatic carcinoma high expressed CXCR4 particularly, under the chemotactic of metalloproteases MMP-2 or MMP-9 effect and SDF-1, neoplasm metastasis takes place.The biological axle of SDF-1/CXCR4 plays a crucial role to plantation, survival and the propagation of cancerous cell at metastasis site.Present known CXCR4 expression degree in tumor is relevant with the grade malignancy of tumor, and is closely related with cancer progress degree, particularly at the metastatic carcinoma high expressed, and the transfer ability of indication tumor cell.
The effect of the biological axle of regulation and control SDF-1/CXCR4 can influence lapsing to of the tumor course of disease, the CXCR4 antagonist aspect oncotherapy, still be in clinical before in the experimentation.Comprising AMD3100, ALX40-4C, T140 with and analog TN14003 etc.At present, with CXCR4 is new Biotherapeutics method the following aspects of target: non-peptide micromolecular compounds CXCR4 receptor antagonist such as AMD3100 and micromolecule polypeptide class CXCR4 receptor antagonist such as T22, anomalous signals pathway capable of blocking, monoclonal antibody can in and the CXCR4 of tumor cell surface, and the RNA perturbation technique suppresses CXCR4 gene expression.
The full name of AMD3100 is 1,1 '-[1,4-phenylene two (methylene)]-two-1,4,8, the 11-tetraazacyclododecane tetradecane, its structural formula is seen Fig. 1, be potent, the non-peptide class of selectivity chemotactic factor CXCR4 receptor antagonist, by suppressing sticking of the inductive cancerous cell of SDF-1 and biological characteristicses such as migration, propagation with the CXCR4 receptors bind.AMD3100 can combine CXCR4 with the SDF-1 competition as a kind of novel receptor blocking agent, has been proved and can have suppressed most of malignant tumor, and malignant tumor is played therapeutical effect.Further show certain toleration in the clinical medicine experiment, but the AMD3100 toxicity of clinical demonstration therapeutic dose mainly acts on heart.This toxic effect AMD3100 as the clinical application that is used for oncotherapy of common drug.
Summary of the invention
The purpose of this invention is to provide and a kind ofly be used to diagnose and the radiopharmaceutical of treatment and CXCR4 relevant disease, (1) based on AMD3100, exploitation is fit to AMD3100 (M*) radiopharmaceutical of diagnosing tumor.(2) based on AMD3100, exploitation is fit to AMD3100 (M*) radiopharmaceutical of oncotherapy.(3) based on AMD3100, and to its modification, use the positron radionuclide labelling, exploitation is suitable for the radiopharmaceutical of PET video picture.
Realize the technical scheme of the object of the invention: a kind of radiodiagnosis and medicine of chemokine receptors CXCR4 non-peptide antagonist, this medicine is to be parent and radioactive metal ion complexation with AMD3100 or to form with the positron radionuclide labelling, be used for diagnosis and treatment with the CXCR4 relevant disease, as the diagnosis and the treatment in AIDS, malignant tumor, arthritis and stem-cell therapy field.
Above-mentioned AMD3100 can with the radioactive metal nucleic 64Cu, 68Ga, 99mTc, 111In or 186The Re complexation, as the medicine of radiodiagnosis (SPECT), its structure is as follows:
Wherein: M is the radioactive metal nucleic, 64Cu, 68Ga, 99mTc, 111In or 186Re.
Above-mentioned AMD3100 and radioactive metal nucleic 64Cu, 90Y, 99mTc or 188The Re complexation, as follows as its structure of medicine of radiation treatment:
Wherein: M is the radioactive metal nucleic, 64Cu, 90Y, 99mTc or 188Re.
The positron radionuclide that connects on the ring of the above-mentioned intermediary benzene of AMD3100 can be fluoro-18, bromo-76 or carbon-11, and its position can be on four commutable optional positions on the middle phenyl ring, and as the medicine of radiodiagnosis PET, its structure is as follows:
Figure G200910000806XD0000033
Wherein: X is for can be fluoro-18, bromo-76 or carbon-11.
Nitrogen-atoms on the above-mentioned AMD3100 both sides macro ring can join aliphatic chain, and the end of aliphatic chain is taken positron radionuclide fluoro-18 or bromo-76, as radiodiagnosis PET medicine.
Beneficial effect of the present invention: utilize the targeting of AMD3100, AMD3100 is as micromolecular compound and Cu simultaneously 2+, Zn 2+Or Ni 2+Deng metal ion stronger affinity is arranged, the chemical dose that the AMD3100 of bind metal ion and CXCR4 adhesion have improved tens times of diagnosis that utilize nuclear medicine again and medicine when using clinically is only in microgram or nanogram level, based on the series diagnosis of AMD3100 research and the negligible characteristics of chemical toxicity of radiotherapy medicine, carry out and send out the radiopharmaceutical that series is suitable for diagnosing tumor and treatment.
Description of drawings
Fig. 1 is the structural formula of AMD3100.
The specific embodiment
Below in conjunction with specific embodiment the present invention is described.
Example 1, medicine AMD3100 ( 99mTc), its structural formula is as follows:
Figure G200910000806XD0000041
Its preparation method: take by weighing the AMD3100 hydrobromate of 100 μ g, add the SnCl of 50 μ g 2, add again an amount of fresh drip washing high technetium ( 99mTc) hydrochlorate, 80 ℃ of heating one minute, separation and purification can be used as radiodiagnosis (SPECT) and medicine.
Example 2, medicine AMD3100 ( 111In)
Preparation method: take by weighing the AMD3100 hydrobromate of 100 μ g, the adding prepared fresh 111InCl 3, regulate acidity, 80 ℃ of heating can be used as the medicine of radiodiagnosis SPECT after one minute.
Example 3, radiopharmaceutical AMD3100 ( 64Cu)
Figure G200910000806XD0000051
Preparation method: take by weighing the AMD3100 hydrobromate of 100 μ g, the adding prepared fresh 64Cu Cl 2, regulate acidity, 80 ℃ of heating can be used as radiodiagnosis (SPECT) and medicine after one minute.
Example 4, radiopharmaceutical AMD3100 ( 68Ga)
Figure G200910000806XD0000052
Preparation method: take by weighing the AMD3100 hydrobromate of 100 μ g, the adding prepared fresh 68Ga Cl 4, regulate acidity, 80 ℃ of heating can be used as radiodiagnosis SPECT medicine after one minute.
Example 5, radiopharmaceutical AMD3100 ( 186Re)
Figure G200910000806XD0000053
Preparation method: take by weighing the AMD3100 hydrobromate of 100 μ g, the adding prepared fresh 186Re Cl 4, regulate acidity, 80 ℃ of heating can be used as radiodiagnosis SPECT and medicine after one minute.
Example 6, radiopharmaceutical AMD3100 ( 188Re)
Figure G200910000806XD0000061
Preparation method: take by weighing the AMD3100 hydrobromate of 100 μ g, the adding prepared fresh 188Re Cl 4, regulate acidity, 80 ℃ of heating can be used as the radiation treatment medicine after one minute.
Example 7, radiopharmaceutical AMD3100 ( 90Y), its structural formula is as follows:
Figure G200910000806XD0000062
Preparation method: take by weighing the AMD3100 hydrobromate of 100 μ g, the adding prepared fresh 90Y (Ac) 3(acetic acid yttrium) heated one minute down at 80 ℃, and separation and purification can be used as the radiation treatment medicine.
Example 10, positron emitting tracer AMD3100 ( 18F) structural formula is as follows:
Figure G200910000806XD0000063
React as follows:
Figure G200910000806XD0000071
Preparation method: on the multi-functional synthesizer of commercial F-18, take by weighing 10mg nitro precursor, with the dissolving of 1mL acetonitrile, join in the F-18 ion behind the acetonitrile azeotropic water removing, under catalysis K.2.2.2, F-18 replaces nitro and generates intermediate, acidic hydrolysis, through the HPLC purifies and separates obtain AMD3100 ( 18In the structure of the medicine that F), obtains 18The position of substitution of F not only is confined to shown in the last figure, can be respectively all can on any one position of four the position of substitution of middle phenyl ring.
Example 11, positron emitting tracer AMD3100 ( 18The F ethyl), its structure is as follows:
Figure G200910000806XD0000072
Preparation method:
Figure G200910000806XD0000081
On the multi-functional synthesizer of F-18, take by weighing the 10mgOTs precursor, with the dissolving of 1mL acetonitrile, join through with the acetonitrile azeotropic water removing after the F-18 ion in, under K222 catalysis, F-18 replaces nitro and generates intermediate, acidic hydrolysis, through partly prepare the HPLC purifies and separates obtain AMD3100 ( 18The F ethyl), but this aliphatic chain not only is confined to ethyl, can contain for methyl, propyl group or longer alkane or other aliphatic 18The group of F, and the link position of aliphatic chain also not only is confined to the position as figure, can all can in nitrogenous six positions that replace hydrogen of macro ring.
Above-mentioned preparation method can also obtain Br-18 diagnosis PET medicine, and structure is as follows:
Figure G200910000806XD0000082
The aliphatic chain that contains Br-18 equally not only is confined to ethyl, can contain for methyl, propyl group or longer alkane or other aliphatic 18The group of Br, and the link position of aliphatic chain also not only is confined to the position as figure, can all can in nitrogenous six positions that replace hydrogen of macro ring.
Example 12, positron emitting tracer AMD3100 ( 76Br), its structure is as follows:
Figure G200910000806XD0000091
Preparation method:
Figure G200910000806XD0000092
On the multi-functional synthesizer of F-18, take by weighing 10mg iodine and replace precursor, dissolve with 1mLDMSO, join through with the acetonitrile azeotropic water removing after 76Br (NH4) in, under copper sulfate and the effect of sodium thiosulfate sodium, be heated to 196 ℃ of reactions under the acid condition, through partly prepare the HPLC purifies and separates obtain AMD3100 ( 76In the structure of the medicine that Br), obtains 76The position of substitution of Br not only is confined to shown in the last figure, can be respectively all can on any one position of four the position of substitution of middle phenyl ring.
Example 13, positron emitting tracer AMD3100 ( 11C)
Figure G200910000806XD0000101
Preparation method: on the multi-functional synthesizer of carbon-11, take by weighing 0.3mg hydroxyl precursor, use the 0.2mL acetone solution, add 10 μ L0.1N NaOH, feed synthetic 11C-Trifate methane, 80 ℃ of heating 1min, hydrolysis get final product through the HPLC separation, but this aliphatic chain not only is confined to methoxyl group, can contain for ethyoxyl, propoxyl group or longer alkane or other aliphatic 11The group of C, and the link position of aliphatic chain also not only is confined to the position as figure, but can be in the optional position of four the position of substitution of middle phenyl ring.
Example 14, positron emitting tracer AMD3100 ( 11C)
Figure G200910000806XD0000103
Preparation method: on the multi-functional synthesizer of C-11, take by weighing 0.3mg hydroxyl precursor, use the 0.2mL acetone solution, add 10 μ L 0.1N NaOH, feed synthetic 11C-Trifate methane, 80 ℃ of heating 1min get final product through the separation of C-18 post, but this aliphatic chain not only is confined to methyl, can contain for ethyl, propyl group or longer alkane or other aliphatic 11The group of C, and the link position of aliphatic chain also not only is confined to the position as figure, can all can in nitrogenous six positions that replace hydrogen of macro ring.
Figure G200910000806XD0000111

Claims (5)

1. the radiodiagnosis and the medicine of a chemokine receptors CXCR4 non-peptide antagonist, it is characterized in that, this medicine is to be parent and radioactive metal ion complexation with AMD3100 or to form with the positron radionuclide labelling, be used for diagnosis and treatment with the CXCR4 relevant disease, as the diagnosis and the treatment in AIDS, malignant tumor, arthritis and stem-cell therapy field.
2. the radiodiagnosis and the medicine of a kind of chemokine receptors CXCR4 non-peptide antagonist as claimed in claim 1 is characterized in that, AMD3100 can with the radioactive metal nucleic 64Cu, 68Ga, 99mTc, 111In or 186The Re complexation, as the medicine of radiodiagnosis (SPECT), its structure is as follows:
Wherein: M is the radioactive metal nucleic, 64Cu, 68Ga, 99mTc, 111In or 186Re.
3. the radiodiagnosis and the medicine of a kind of chemokine receptors CXCR4 non-peptide antagonist as claimed in claim 1 is characterized in that, AMD3100 and radioactive metal nucleic 64Cu, 90Y, 99mTc or 188The Re complexation, as follows as its structure of medicine of radiation treatment:
Wherein: M is the radioactive metal nucleic, 64Cu, 90Y, 99mTc or 188Re.
4. the radiodiagnosis and the medicine of a kind of chemokine receptors CXCR4 non-peptide antagonist as claimed in claim 1, it is characterized in that, the positron radionuclide that connects on the ring of the intermediary benzene of AMD3100 can be fluoro-18, bromo-76 or carbon-11, its position can be on four commutable optional positions on the middle phenyl ring, as the medicine of radiodiagnosis PET, its structure is as follows:
Figure F200910000806XC0000021
Wherein: X is for can be fluoro-18, bromo-76 or carbon-11.
5. the radiodiagnosis and the medicine of a kind of chemokine receptors CXCR4 non-peptide antagonist as claimed in claim 1, it is characterized in that, nitrogen-atoms on the macro ring of AMD3100 both sides can join aliphatic chain, the end of aliphatic chain is taken positron radionuclide fluoro-18, bromo-76 or carbon-11, as radiodiagnosis PET medicine.
CN 200910000806 2009-01-16 2009-01-16 Chemotactic factor receptor CXCR4 non-peptide antagonist medicaments for radiodiagnosis and treatment Pending CN101780286A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102408387A (en) * 2010-09-26 2012-04-11 韩南银 Metal complex with antitumor action
CN104066712A (en) * 2011-11-02 2014-09-24 协和发酵麒麟株式会社 Cationic lipid
CN106573877A (en) * 2014-08-07 2017-04-19 武田药品工业株式会社 Cationic lipid
EP3281643A4 (en) * 2015-04-07 2018-12-26 Kyungpook National University Industry-Academic Cooperation Foundation Radioactive probe for detecting hydrogen sulfide
CN110590744A (en) * 2019-07-03 2019-12-20 河南省人民医院 Micromolecule PET imaging agent of targeted chemokine receptor CXCR4

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102408387A (en) * 2010-09-26 2012-04-11 韩南银 Metal complex with antitumor action
CN104066712A (en) * 2011-11-02 2014-09-24 协和发酵麒麟株式会社 Cationic lipid
US10583206B2 (en) 2014-04-07 2020-03-10 Kyungpook National University Industry-Academic, Cooperation Foundation Radioactive probe for detecting hydrogen sulfide
CN106573877A (en) * 2014-08-07 2017-04-19 武田药品工业株式会社 Cationic lipid
US10252974B2 (en) 2014-08-07 2019-04-09 Takeda Pharmaceutical Company Limited Cationic lipid
CN106573877B (en) * 2014-08-07 2021-04-13 武田药品工业株式会社 Cationic lipids
EP3281643A4 (en) * 2015-04-07 2018-12-26 Kyungpook National University Industry-Academic Cooperation Foundation Radioactive probe for detecting hydrogen sulfide
CN110590744A (en) * 2019-07-03 2019-12-20 河南省人民医院 Micromolecule PET imaging agent of targeted chemokine receptor CXCR4
CN110590744B (en) * 2019-07-03 2021-11-02 河南省人民医院 Micromolecule PET imaging agent of targeted chemokine receptor CXCR4

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Application publication date: 20100721