CN107674117A - The preparation method for the Dimer San A Cyclopeptide derivatives cancer of pancreas molecular probes that Cu 64 is marked - Google Patents

The preparation method for the Dimer San A Cyclopeptide derivatives cancer of pancreas molecular probes that Cu 64 is marked Download PDF

Info

Publication number
CN107674117A
CN107674117A CN201710844874.9A CN201710844874A CN107674117A CN 107674117 A CN107674117 A CN 107674117A CN 201710844874 A CN201710844874 A CN 201710844874A CN 107674117 A CN107674117 A CN 107674117A
Authority
CN
China
Prior art keywords
dimer
san
nota
cancer
marks
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710844874.9A
Other languages
Chinese (zh)
Other versions
CN107674117B (en
Inventor
李玉民
陈凯
王晓慧
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to CN201710844874.9A priority Critical patent/CN107674117B/en
Publication of CN107674117A publication Critical patent/CN107674117A/en
Application granted granted Critical
Publication of CN107674117B publication Critical patent/CN107674117B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a kind of preparation method of the Dimer San A Cyclopeptide derivatives cancer of pancreas molecular probes of Cu 64 marks, this method comprises the following steps：(1) NOTA Dimer Sansalvamide A are dissolved in acetonitrile, are configured to the polypeptide solution that concentration is 1 μ g/ μ L；⑵64CuCl2Middle addition acetic acid ammonia buffer solution is reacted, and obtains reaction solution64Cu(OAc)2；(3) polypeptide solution is added to reaction solution64Cu(OAc)2Middle heating, and the sustained oscillation during heating, obtain product64Cu‑NOTA‑Dimer‑Sansalvamide A；(4) product64Cu NOTA Dimer San dissolve through phosphate buffer, membrane filtration, produce64The Dimer Sansalvamide A Cyclopeptide derivatives cancer of pancreas molecular probes of Cu marks.The present invention first using NOTA Dimer San molecules as64The precursor of Cu marks, the target spot using Hsp90 as tumor imaging,64The new developers of NOTA Dimer San of Cu marks, the developer have the potential advantages of tumour-specific in clinical practice.

Description

The preparation of the Dimer-San A Cyclopeptide derivatives cancer of pancreas molecular probes of Cu-64 marks Method
Technical field
The present invention relates to the Dimer-San A cyclic peptide of a kind of preparation method of probe, more particularly to Cu-64 marks to derive The preparation method of thing cancer of pancreas molecular probe.
Background technology
Cancer of pancreas is the fifth-largest malignant tumour in the world, and its median survival interval is less than 6 months, and 5 years total survival rates are less than 6%, Only 10% patient is adapted to operative treatment, and its poor prognosis and the disease fail to early diagnose closely related.With the old-age group of China human mortality Change, the incidence of disease of the cancer of pancreas in China increased, and it is by as the main health problem in one, coming years China.
At present, the conventional image diagnosis of cancer of pancreas has ultrasound（Including EUS）, CT and MRI, but these structures Image is to diagnosis of pancreatic cancer poor specificity, the antidiastole of cancer of pancreas and chronic pancreatitis, especially mass pancreatitis It is medical imaging and clinical medicine problem urgently to be resolved hurrily for a long time.
18F-FDG PET/CT clinical practice, substantially increase the accuracy of diagnosis of pancreatic cancer.But18F-FDG is as one Kind tumour non-specificity developer, the limitation of its own are also evident from --- vacation in terms of the antidiastole of cancer of pancreas be present Positive and false negative.Meta analysis and research displays：18Sensitivity, the spy of F-FDG PET/CT antidiastoles cancers of pancreas and pancreatitis The opposite sex is respectively 90%, 84%.18Prepared by F-FDG passes through automatic chemistry synthesis module（chemistry process control Unit, CPCU）, it is automatically synthesized using software control.Synthetic method is with tetra--oxy-acetyls of 1,3,4,6- -2- oxygen-fluoroform Alkane sulfonyl-β-D- mannopyranoses（Abbreviation mannose triflate）For raw material, in phase transfer catalyst Kryptofix2.2.2 (ammonia Base polyethers 2.2.2) promote under, 18With the hydroxyl on mannose triflate 2 nucleophilic substitution, generation occur for F ion18F-FDG The precursor of protection type, slough acetyl protection base through acid or basic hydrolysis and obtain18F-FDG。18F-FDG PET/CT are as the non-spy of tumour Different in nature developer, obvious deficiency in terms of tumour early stage malignant and benign lesion diagnosis be present：False positive and false negative are simultaneously deposited, so as to lead The mistaken diagnosis of benign from malignant tumors diagnosis is caused with failing to pinpoint a disease in diagnosis.
In order to overcome18F-FDG deficiency, there is scholar to marked the molecular image of CA199 antibody fragments progress cancer of pancreas and examine It is disconnected, but radio-immuno-image whether uses radioactive nuclear mark monoclone antibody or its fragment, exist molecular weight compared with Greatly, blood is removed slow（4-20h）, the problem of being difficult to obtain higher T/NT ratios within a short period of time；Furthermore CA199 is Cancer of pancreas heterogenetic antigen, also there is obvious expression in pancreas inflammatory lesion.Tagged ligand molecular weight used in rii receptor Small, blood removes that fast, tissue penetration is strong, T/NT ratios are high, non-immunogenicity, has high sensitivity, high specificity and accurate The advantages that property is good, is one of most active research frontier of molecular nuclear medicine.
Heat shock protein 90（Heart shock protein 90, Hsp90）It is a kind of highly conserved general in living nature Store-through, have the albumen of particular molecule chaperone function, molecular weight is about 83~90KDa.Hsp90 contains three highly conserved knots Structure domain：That is N-terminal atriphos binding domain, central domain, C-terminal domain, in the form of homodimer exist, mainly with Cell cycle is related to apoptosis regulation.Research confirms that Hsp90 is in the Several Kinds of Malignancy cell including cancer of pancreas Overexpression, it is 2-10 times of normal cell, and generation with tumour, development, classification, by stages and prognosis is closely related； Hsp90 is activated in tumour cell matter and navigates to cell surface, and is only resided in normal cell in cytoplasm.Cause This, Hsp90 is of increasing concern as a potential oncotherapy research target spot, also turns into the molecular image of target for it and studies Lay a good foundation.
Sansalvamide A (abbreviation San A) be 1999 by U.S. Belofsky etc. from ocean Pseudomonas Fusarium In separate a kind of be made up of two leucines, a valine, a phenylalanine and an Alpha-hydroxy isocaproic acid Ring pentapeptide ester type compound, there is very high lipophilicity and significant anti-tumor capacity, it is to national cancer institute 60 kinds of cancer cell lines have significant antiproliferative activity, and to having including pancreatic carcinoma in interior kinds of tumor cells There is treatment targeting.Ester bond in San A molecules is transformed into amido link, gained compound is ring pentapeptide（Claim San A cyclic peptide）. Research is found, substitutes phenyl ring in San A cyclic peptide molecules to align hydrogen atom, gained San A rings using groups such as fluorine, chlorine, methoxyl groups The anti-tumor biological of peptide derivant is substantially better than San A.
San A and its derivative anti-pancreatic cancer activity research, the country still belongs to blank, and foreign study is more.There is scholar Think that San A have the important function for killing multiple pancreatic cancer cell lines system.Anticancer property of its derivative with uniqueness, and with The medicine of anti-pancreatic cancer does not have structural homology at present.Pan PS etc. have synthesized 31 kinds of San A Cyclopeptide derivatives, to two kinds of pancreases The active anticancer of gland cell system (being PL45 and BxPC-3 respectively) is studied, wherein the anti-pancreatic cancer effect of 6 kinds of derivatives Fruit is more than 140 times of clinical commonly used drug such as (e.g., 5-FU), and normal cell then has preferable tolerance to it.
Up to the present, the San A Cyclopeptide derivatives of synthesis have more than 100 to plant, and its antitumor activity difference is obvious.It is a large amount of right The research of San A Cyclopeptide derivatives structure-anticarcinogenic effect relation finds that, to ensure its higher active anticancer, the derivative must Two continuous D- amino acid and/or N- methoxyl groups must be contained.Pan etc. has synthesized 78 kinds of San A Cyclopeptide derivatives, wherein No. 1 Derivative（Abbreviation Diamer San A）, show most strong anti-pancreatic cancer（PL45、BxPC3）Activity, it is thin to cancer of pancreas PL45 The half inhibiting rate of born of the same parents（IC50）Only 1-20 nM, it is the most strong San A Cyclopeptide derivatives of the anti-pancreatic cancer activity of report.
64Cu (T1/2=12.7h) by International Atomic Energy Agency（IAEA）Referred to as " emerging PET nucleic ", there is wide application Prospect.With18F（T1/2 = 110 min）Compared Deng PET nucleic,64Cu has relatively long half-life period (T1/2=12.7 h), The imaging research of long period can be carried out, and is easy to the transport of long-range in nucleic.64Cu launches simultaneously β+Electronics（17%）With β-Electronics（39%）, can be used for PET imagings and radiation treatment, be expected to concentrate the diagnosis and treatment Study on Integration of radionuclide.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of Dimer- for the Cu-64 marks for effectively improving mark rate The preparation method of San A Cyclopeptide derivatives cancer of pancreas molecular probes.
To solve the above problems, the Dimer-San A Cyclopeptide derivatives cancer of pancreas point of Cu-64 marks of the present invention The preparation method of sub- probe, comprises the following steps：
(1) NOTA-Dimer-Sansalvamide A are dissolved in acetonitrile, are configured to the polypeptide solution that concentration is 1 μ g/ μ L；
(2) 37 ~ 111 MBq's64CuCl2The middle addition M of 300 μ L 0.1 and the acetic acid ammonia (NH of pH=5.54OAc) buffer solution Reacted, obtain reaction solution64Cu(OAc)2；
(3) polypeptide solution described in 5 ~ 10 μ g is added to the reaction solution64Cu(OAc)2In, in 45 DEG C of 45 min of heating, and Sustained oscillation during heating, obtains product64Cu-NOTA-Dimer-Sansalvamide A, referred to as64Cu-NOTA- Dimer-San, its structural formula are as follows：
；
(4) the product64Cu-NOTA-Dimer-San removes solvent with dry machine is hanged in 40oC, and with the phosphoric acid containing 5% DMSO Salt buffer（PBS）Dissolving, is most produced through 0.22 μm of membrane filtration afterwards64The Dimer-Sansalvamide A cyclic peptide of Cu marks Derivative cancer of pancreas molecular probe.
The step (4) dosage of middle phosphate buffer and the label64Cu-NOTA-Dimer-San ratio is 300~500 μL：5~10 μg.
The present invention has advantages below compared with prior art：
1st, the present invention is used as metal ion using NOTA-Dimer-San molecules first64Cu labelled precursor, using Hsp90 as imaging Target spot, structure64The new developers of NOTA-Dimer-San of Cu marks.
The present invention is with the most strong cyclic peptide Dimer-Sansalvamide A (letters of activity in Sansalvamide A derivatives Claim Dimer-San A) it is used as labelled precursor (IC50For 1-20 nM), its structural formula is as follows：
The labelled precursor is on the premise of the analog derivative important activity functional group is retained, by Dimer-San A molecules Phenyl ring on introduce amino, couple Isosorbide-5-Nitrae, the azo-cycle nonanes of 7- tri--Isosorbide-5-Nitrae, 7- triacetic acids（Isosorbide-5-Nitrae, 7-triazacyclononane-1, 4,7-triacetic acid, NOTA）Bifunctional chelating agent, after carrying out identification of its biological activity to it, realize positron emission Property nucleic64Cu carries out indirect labelling to it（64Cu-NOTA-Dimer-San, referred to as64Cu -NOTA-Dimer-San）.Research card In fact, San A and its Cyclopeptide derivatives are Hsp90 inhibitor, N-terminal and middle destructing domain of its selective binding in Hsp90, are led to Cross and prevent Hsp90 C-terminal domain from being combined with client protein downstream, be related to cell growth and tumor signal biography so as to disturb The multiple paths led, cause apoptosis of tumor cells, and the two is combined with high specific, high-affinity.
2nd, developer of the present invention64Target spots of the Cu-NOTA-San using Hsp90 as imaging, experiment card is absorbed through cell in vitro Real, it has higher Percentage bound with target spot, and extracorporeal blocking tests the specificity that further demonstrate the developer and targeted integration （Referring to Fig. 1 ~ 8）；Build nude mice pancreatic cancer models and carry out Micro-PET imagings, it is seen that tumor developer intake is obvious；Vein is noted 1 h after blocking agent is penetrated, then injects developer and is imaged, it is seen that tumor locus has no that developer absorbs, therefore experiment in vivo enters one Step confirms the specificity that the developer is combined with target spot Hsp90.
【Cell in vitro absorbs and blocking experiment】
PL45 cells are collected and planted to 24 orifice plates（0.5×105Cells/well）, put to the h of incubate box culture 24 (37oC-, 5% CO2)。
Non-blacked experiment adds the developer of same concentrations per hole（5 μCi/100 μL）；Kong Xianjia for blocking experiment Enter the certain density non-marked peptides of 100 μ L, the developer of same concentrations is added after 30 min of reaction, is at war with reference to anti- Should, to confirm developer and targeted integration whether there is specificity.By 24 orifice plate warm bath different times after sample-adding（0、15、30、 60、90、120 min）, the free developer of PBS rinsings, pancreatin digestion, after collecting cell, cell is detected in difference with gamma counter The intake situation of time developer.Above-mentioned experiment is repeated twice, and multiple holes are set per hole.
The certain density developer of high expression is absorbed in Fig. 1（64Cu-NOTA-Dimer-San）In the cell of different time Intake situation, during 60 min developer intake reach peak value, cell Percentage bound is 36.2 ± 6.8%；Relatively low curve is absorbed to represent Add cellular uptake after certain blocking agent to decline, cell Percentage bound is reduced to during 60min：23.2±4.2%.Two groups of data are examined through t Test, significant difference, P be present<0.05, illustrate developer64Cu-NOTA-Dimer-San is combined with target spot Hsp90 with special Property.
【The foundation of model of nude mice bearing tumor】
When pancreas cancer cell strain PL45 is in increased logarithmic phase, cell is collected in sterile working, and cell is injected in nude mice right shoulder Number 1 × 107/ only, etc. tumour length to the mm of volume 100 ~ 2003Shi Jinhang Micro-PET are imaged.6 tumor models are built altogether, its In 3 be served only for tumor imaging, 3 be served only for the imaging of tumour competition binding in addition.
【Tumor bearing nude mice images】
Imaged with Micro-PET toy scanners.Nude mice is imaged with after 2% isoflurane anesthesia by tail vein injection Agent（64Cu-NOTA-Dimer-San）100-200 μ Ci/ only, are placed in prone position and imaged respectively at 2 h, 4 h（See Fig. 2 ~ 4）.
64Cu-NOTA-Dimer San tumor imagings：The visible right side tumor position developer intake in Fig. 2 ~ 4 is increased.
【Tumor bearing nude mice competition binding images】
Nude mice 1 h before developer is injected, by the μ g blocking agents of tail vein injection 250, carry out prone position with 2 h, 4 h respectively Micro-PET is imaged.After the visible injection blocking agent in Fig. 5 ~ 7, due to blocking agent and the same target spot of developer competition binding, former tumour Height intake has no development.Developer is further confirmed by experiment in vivo64Cu-NOTA-Dimer-San and target spot Hsp90 is tied The specificity of conjunction.
【The external distribution experiments of tumor bearing nude mice】
Put to death after 6 nude mice 4h imagings, separation tumour, blood, the heart, liver, pancreas, spleen, kidney, gall-bladder, small intestine, be put into tubule, Weigh, gamma counter measurement radiocounting, the data obtained calculates %ID/g after correction for attenuation（percentage of Injected dose per gram of tissue, per g tissue injection dose numbers, for weighing histoorgan radioactivity point The height of cloth）, draw bar chart（Referring to Fig. 8）.
The %ID/g of non-blacked tumour is 4.66 ± 0.97, and the %ID/g of tumour is 2.13 ± 0.34 after blocking, and uses SPSS 22 softwares carry out independent samples t test, P to two groups of data<0.05, difference is statistically significant.It further demonstrate the imaging Agent is Hsp90 specificity developers.From Fig. 8 simultaneously as can be seen that the developer is mainly disappeared by liver, gall-bladder, intestines and stomach etc. Change system is drained, and the relative intake of pancreas background is relatively low；Secondly mainly drained by urinary system.
3rd, labeling method of the present invention is simple, it is not necessary to special chemistry synthesis module, and mark rate>97%.
4th, the precursor that the present invention marks is cyclic peptide dimer, and compared with linear monomer peptide, stability is high, imaging results It is good.
5th, present invention mark temperature is relatively low（45 ºC）, will not typically cause the destruction of labelled precursor.
6th, in the present invention64Cu launches β simultaneously+Electronics and β-Electronics, it can be used for PET imagings and radiation treatment,64Cu is marked The NOTA-Dimer-San of note has the potentiality of cancer of pancreas diagnosis and treatment integration.
Brief description of the drawings
The embodiment of the present invention is described in further detail below in conjunction with the accompanying drawings.
Fig. 1 is the present invention64Cu-NOTA-Dimer-San cellular uptakes are tested and extracorporeal blocking experimental result.
Fig. 2 is tumor bearing nude mice of the present invention64Cu-NOTA-Dimer San Micro-PET positive scintigraphies (2 h).
Fig. 3 is tumor bearing nude mice of the present invention64Cu-NOTA-Dimer San Micro-PET positive scintigraphies (4 h).
Fig. 4 is tumor bearing nude mice of the present invention64Cu-NOTA-Dimer San Micro-PET MIP scheme (4 h).
Fig. 5 is tumor bearing nude mice of the present invention64Cu-NOTA-Dimer San Micro-PET competition imagings (2 h).
Fig. 6 tumor bearing nude mices of the present invention64Cu-NOTA-Dimer San Micro-PET competition imagings (4 h).
Fig. 7 is tumor bearing nude mice of the present invention64Cu-NOTA-Dimer San Micro-PET competition imaging MIP figures (4 h).
Fig. 8 is tumor bearing nude mice extracorporeal biology distribution experiments of the present invention（4 h）.
Embodiment
The preparation method of the Dimer-San A Cyclopeptide derivatives cancer of pancreas molecular probes of the Cu-64 of embodiment 1 marks, bag Include following steps：
(1) NOTA-Dimer-Sansalvamide A are dissolved in acetonitrile, are configured to the polypeptide solution that concentration is 1 μ g/ μ L.
(2) 37 MBq's64CuCl2The middle addition M of 300 μ L 0.1 and the acetic acid ammonia (NH of pH=5.54OAc) buffer solution Reacted, obtain reaction solution64Cu(OAc)2。
(3) 5 μ g polypeptide solutions are added to reaction solution64Cu(OAc)2In, 45 min are heated in 45 DEG C, and in the mistake of heating Sustained oscillation in journey, obtains product64Cu-NOTA-Dimer-Sansalvamide A, referred to as64Cu-NOTA-Dimer-San.Through HPLC (high performance liquid chromatography) is analyzed and isolated and purified, and mark rate is>97%, its structural formula is as follows：
。
(4) product64Cu-NOTA-Dimer-San removes solvent with dry machine is hanged in 40oC, and with the phosphoric acid containing 5% DMSO Salt buffer（PBS）Dissolving, is most produced through 0.22 μm of membrane filtration afterwards64The Dimer-Sansalvamide A cyclic peptide of Cu marks Derivative cancer of pancreas molecular probe.
Wherein：The dosage and label of phosphate buffer64Cu-NOTA-Dimer-San ratio is 300 μ L：5 μg.
The preparation method of the Dimer-San A Cyclopeptide derivatives cancer of pancreas molecular probes of the Cu-64 of embodiment 2 marks, bag Include following steps：
(1) NOTA-Dimer-Sansalvamide A are dissolved in acetonitrile, are configured to the polypeptide solution that concentration is 1 μ g/ μ L.
(2) 111 MBq's64CuCl2The middle addition M of 300 μ L 0.1 and the acetic acid ammonia (NH of pH=5.54OAc) buffer Liquid is reacted, and obtains reaction solution64Cu(OAc)2。
(3) 10 μ g polypeptide solutions are added to reaction solution64Cu(OAc)2In, 45 min are heated in 45 DEG C, and in heating During sustained oscillation, obtain product64Cu-NOTA-Dimer-Sansalvamide A, referred to as64Cu-NOTA-Dimer-San。 Analyze and isolate and purify through HPLC (high performance liquid chromatography), mark rate is>97%, its structural formula is the same as embodiment 1.
(4) product64Cu-NOTA-Dimer-San removes solvent with dry machine is hanged in 40oC, and with the phosphoric acid containing 5% DMSO Salt buffer（PBS）Dissolving, is most produced through 0.22 μm of membrane filtration afterwards64The Dimer-Sansalvamide A cyclic peptide of Cu marks Derivative cancer of pancreas molecular probe.
Wherein：The dosage and label of phosphate buffer64Cu-NOTA-Dimer-San ratio is 500 μ L：10 μ g。
The preparation method of the Dimer-San A Cyclopeptide derivatives cancer of pancreas molecular probes of the Cu-64 of embodiment 3 marks, bag Include following steps：
(1) NOTA-Dimer-Sansalvamide A are dissolved in acetonitrile, are configured to the polypeptide solution that concentration is 1 μ g/ μ L.
(2) 74 MBq's64CuCl2The middle addition M of 300 μ L 0.1 and the acetic acid ammonia (NH of pH=5.54OAc) buffer solution Reacted, obtain reaction solution64Cu(OAc)2。
(3) 8 μ g polypeptide solutions are added to reaction solution64Cu(OAc)2In, 45 min are heated in 45 DEG C, and in the mistake of heating Sustained oscillation in journey, obtains product64Cu-NOTA-Dimer-Sansalvamide A, referred to as64Cu-NOTA-Dimer-San.Through HPLC (high performance liquid chromatography) is analyzed and isolated and purified, and mark rate is>97%, its structural formula is the same as embodiment 1.
(4) product64Cu-NOTA-Dimer-San removes solvent with dry machine is hanged in 40oC, and with the phosphoric acid containing 5% DMSO Salt buffer（PBS）Dissolving, is most produced through 0.22 μm of membrane filtration afterwards64The Dimer-Sansalvamide A cyclic peptide of Cu marks Derivative cancer of pancreas molecular probe.
Wherein：The dosage and label of phosphate buffer64Cu-NOTA-Dimer-San ratio is 400 μ L：8 μg.

Claims (2)

  1. The preparation method of the Dimer-San A Cyclopeptide derivatives cancer of pancreas molecular probes of 1.Cu-64 marks, comprises the following steps：
    (1) NOTA-Dimer-Sansalvamide A are dissolved in acetonitrile, are configured to the polypeptide solution that concentration is 1 μ g/ μ L；
    (2) 37 ~ 111 MBq's64CuCl2Middle addition M of the 300 μ L 0.1 and acetic acid ammonia buffer solution of pH=5.5 is reacted, Obtain reaction solution64Cu(OAc)2；
    (3) polypeptide solution described in 5 ~ 10 μ g is added to the reaction solution64Cu(OAc)2In, in 45 DEG C of 45 min of heating, and Sustained oscillation during heating, obtains product64Cu-NOTA-Dimer-Sansalvamide A, referred to as64Cu-NOTA- Dimer-San, its structural formula are as follows：
    ；
    (4) the product64Cu-NOTA-Dimer-San removes solvent with dry machine is hanged in 40oC, and with the phosphoric acid containing 5% DMSO Salt buffer dissolves, and is most produced afterwards through 0.22 μm of membrane filtration64The Dimer-Sansalvamide A cyclic peptide of Cu marks derives Thing cancer of pancreas molecular probe.
  2. 2. the preparation of the Dimer-San A Cyclopeptide derivatives cancer of pancreas molecular probes of Cu-64 marks as claimed in claim 1 Method, it is characterised in that：The step (4) dosage of middle phosphate buffer and the label64Cu-NOTA-Dimer-San Ratio be 300 ~ 500 μ L：5~10 μg.
CN201710844874.9A 2017-09-19 2017-09-19 Preparation method of Cu-64 labeled Dimer-San A cyclic peptide derivative pancreatic cancer molecular probe Active CN107674117B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710844874.9A CN107674117B (en) 2017-09-19 2017-09-19 Preparation method of Cu-64 labeled Dimer-San A cyclic peptide derivative pancreatic cancer molecular probe

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710844874.9A CN107674117B (en) 2017-09-19 2017-09-19 Preparation method of Cu-64 labeled Dimer-San A cyclic peptide derivative pancreatic cancer molecular probe

Publications (2)

Publication Number Publication Date
CN107674117A true CN107674117A (en) 2018-02-09
CN107674117B CN107674117B (en) 2021-03-05

Family

ID=61137208

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710844874.9A Active CN107674117B (en) 2017-09-19 2017-09-19 Preparation method of Cu-64 labeled Dimer-San A cyclic peptide derivative pancreatic cancer molecular probe

Country Status (1)

Country Link
CN (1) CN107674117B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117624278A (en) * 2024-01-25 2024-03-01 中国药科大学 Specific tumor diagnosis probe and imaging agent for targeting heat shock protein 90

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005034982A1 (en) * 2003-10-08 2005-04-21 Northwestern University Cyclic peptide antitumor agents
EP2010203A2 (en) * 2006-03-17 2009-01-07 San Diego State University Foundation Macrocyclic peptides and methods for making and using them
CN101801919A (en) * 2007-06-29 2010-08-11 都柏林伊丽莎白女皇神学院 The targeting diazo prodrugs of treatment gastrointestinal illness
CN106084005A (en) * 2016-06-15 2016-11-09 广州军区广州总医院 The Al of targeting somatostatin receptor18f NOTA PEG6tATE and its preparation method and application
CN106075484A (en) * 2016-06-28 2016-11-09 北京肿瘤医院 Isotopically labeled prostate specific membrane antigen targeted inhibition agent and preparation method thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005034982A1 (en) * 2003-10-08 2005-04-21 Northwestern University Cyclic peptide antitumor agents
EP2010203A2 (en) * 2006-03-17 2009-01-07 San Diego State University Foundation Macrocyclic peptides and methods for making and using them
CN101801919A (en) * 2007-06-29 2010-08-11 都柏林伊丽莎白女皇神学院 The targeting diazo prodrugs of treatment gastrointestinal illness
CN106084005A (en) * 2016-06-15 2016-11-09 广州军区广州总医院 The Al of targeting somatostatin receptor18f NOTA PEG6tATE and its preparation method and application
CN106075484A (en) * 2016-06-28 2016-11-09 北京肿瘤医院 Isotopically labeled prostate specific membrane antigen targeted inhibition agent and preparation method thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALEXANDER, L.D. 等: "Evaluation of Di-Sansalvamide A Derivatives: Synthesis, Structure-Activity Relationship, and Mechanism of Action", 《 JOURNAL OF MEDICINAL CHEMISTRY LETTER》 *
PETER LAVERMAN 等: "Optimized labeling of NOTA-conjugated octreotide with F-18", 《TUMOR BIOLOGY》 *
孙海辉: "PET和PET/CT在胰腺癌中的临床应用价值", 《武警医学院学报》 *
潘栋辉 等: "18F-RGD环肽二聚体的自动化合成及小动物PET显像", 《中华核医学与分子影像杂志》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117624278A (en) * 2024-01-25 2024-03-01 中国药科大学 Specific tumor diagnosis probe and imaging agent for targeting heat shock protein 90
CN117624278B (en) * 2024-01-25 2024-04-19 中国药科大学 Specific tumor diagnosis probe and imaging agent for targeting heat shock protein 90

Also Published As

Publication number Publication date
CN107674117B (en) 2021-03-05

Similar Documents

Publication Publication Date Title
CN105126128B (en) A kind of tumour VEGFR-3 molecular imagings agent and its application
HU230437B1 (en) Ethylenedicysteine(ec)-drug conjugates, preparations and methods for tissue-specific disease imaging
CN108434468B (en) Radioiodinated protein binding ligand and application thereof
CN104725473B (en) A kind of [18F] AlF marks PET polypeptide probes and preparation method thereof
CN106581700B (en) A kind of novel polypeptide radiopharmaceutical for targeting HER2 and its preparation method and application
CN114773433B (en) CD25 targeted polypeptide, molecular probe and application
CN113583089B (en) Tumor PD-L1 targeted PET imaging agent, labeling precursor, preparation method and application thereof
CN112043839A (en) Radioisotope-labeled polypeptide imaging agent targeting transferrin receptor and application thereof
CN110305187A (en) Prostate cancer PET diagnostic reagent68Ga-NOTA-ANCP-PSMA and its preparation method and application
CN110227169A (en) A kind of nuclear medicine drug of the rgd peptide of structural modification
CN111675750A (en) Tumor targeting peptide aiming at carcinoembryonic antigen related adhesion molecule CEACAM and application thereof
CN114989166B (en) Tumor KRAS G12C mutation targeting positron tracer agent, preparation method and application
CN112933249A (en) PD-L1 targeted bimodal molecular probe and preparation method and application thereof
CN110305186B (en) Prostate cancer PET diagnostic reagent68Ga-DOTA-ANCP-PSMA and preparation method and application thereof
CN117209476A (en) The method comprises the following steps of 99m Tc-labeled radioactive probe for targeting fibroblast activation protein and preparation method and application thereof
Xia et al. Application analysis of 124I-PPMN for enhanced retention in tumors of prostate cancer xenograft mice
CN107674117A (en) The preparation method for the Dimer San A Cyclopeptide derivatives cancer of pancreas molecular probes that Cu 64 is marked
CN107496943A (en) The preparation method for the Dimer San A Cyclopeptide derivatives cancer of pancreas molecular probes that F 18 is marked
CN115286693A (en) Tumor targeting peptide aiming at carcinoembryonic antigen related cell adhesion molecule CEACAM6 and application thereof
CN116036318A (en) PD-L1-targeted SPECT molecular imaging probe and preparation method and application thereof
CN108144073A (en) Radiolabeled tri-polyethylene glycol modified duramycin polypeptide drug targeting phosphatidylethanolamine
CN107586321A (en) The preparation method of the mark modification Dimer San A probes of F 18
CN108250276A (en) The preparation method of the Hsp90 inhibitor cancer of pancreas diagnosis and treatment integration molecular probes of Cu-64 labels
CN105611948B (en) For the diagnosticum for the treatment of of cancer effect
CN107021998B (en) Positron nuclide labeled polypeptide for tumor imaging

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant