CN108144073A - Radiolabeled tri-polyethylene glycol modified duramycin polypeptide drug targeting phosphatidylethanolamine - Google Patents
Radiolabeled tri-polyethylene glycol modified duramycin polypeptide drug targeting phosphatidylethanolamine Download PDFInfo
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- CN108144073A CN108144073A CN201711458719.XA CN201711458719A CN108144073A CN 108144073 A CN108144073 A CN 108144073A CN 201711458719 A CN201711458719 A CN 201711458719A CN 108144073 A CN108144073 A CN 108144073A
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Classifications
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- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Molecular Biology (AREA)
- Optics & Photonics (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to a radiolabeled tri-polyethylene glycol modified duramycin polypeptide drug targeting phosphatidylethanolamine, which consists of a pharmacophore (-Dur), a pharmacokinetic group (PEG3) and a combined radioactive chelating group (R), and the structural formula of the drug is shown in the following formula. The polypeptide drug has excellent in vivo pharmacokinetic properties; the preparation method comprises the steps of one-step reaction and small column separation and purification. The invention also relates to the application of the polypeptide medicament in the preparation of PET imaging medicaments.
Description
【Technical field】
Three polyethylene glycol of radioactive label (PEG3) modification the present invention relates to targeting phosphatidyl-ethanolamine (PE) is durable mould
Plain (Duramycin, Dur) polypeptide drugs (R-PEG3-Dur, wherein R=- [Mm+] NOTA or R=- [Nn+] DOTA), system
Preparation Method and its application in positron emission fault (PET) developer is prepared.
【Background technology】
Apoptosis is body by spontaneous, the orderly phenomena of mortality of cell that specific mechanism regulates and controls closely, it occurs
In stages such as embryonic development, immune defense and Cell Homeostasis, there is extensive biological significance.Apoptosis equally also assists in
A variety of normal physiologicals, pathologic process and much disease incidence mechanism.Abnormal apoptosis can cause a variety of diseases, such as autoimmunity
Property disease, nerve retrograde affection, myocardial infarction etc..Many antineoplaston means (such as chemotherapy, radiotherapy) are swollen by promoting
Apoptosis of tumor come achieve the purpose that treat tumour [1,2].Accordingly, it is desirable to find a kind of non-invasive, functional point
Sub- imaging technique come detect the generation of Apoptosis and assess apoptosis degree.
It is one of important feature of molecular level of Apoptosis that the inner membrance of cell membrane, which turns up, phosphatidylserine (PS) and
Phosphatidyl-ethanolamine (PE) accounts for a big chunk ratio on mammalian cell membrane inner membrance on cell membrane inner membrance in phospholipid
Example.In vivo the research of detection Apoptosis focuses primarily upon targeting PS developers now.Have now been found that annexin V
(Annexin V) and two (2,2 '-bipyridine methyl amine-Zn2+Class complex (DPAZn2) etc. can be special with epicyte surface PS
Property combine, label specificity AnnexinV and micromolecular compound DPAZn2 can be applicable to apoptosis imaging research.Wherein, [99mTc]
Annexin V are widely used to clinical research [1,2].
PE is second of most abundant phosphatide in mammalian cell membrane, accounts for about the 20% of total phospholipids.As PS, just
PE is distributed in the internal layer of cell membrane lipid bilayer under normal state, rarely occurs in normal live cells surface.In Apoptosis, PE leads to
It crosses lipid bilayer and outer membrane is shifted to by inner membrance, be exposed to apoptotic cell film surface；To keep film integrality, PE can also enter necrosis
In cell.Thus, PE is also a kind of recruit's target [3,4] that cannot distinguish between apoptotic cell and non-viable non-apoptotic cell.Duramycin
(Duramycin, Dur) is the minimum known peptide of molecular weight with definite three-dimensional binding site, with PE have high-affinity and
Specificity.At present, it is external succeeded in developing single photon emission computed tomography (SPECT) imaging medicament [99mTc] Duramycin,
For antineoplaston curative effect evaluation, heart ischemia reperfusion damage, atherosclerotic plaque assessment, acute and chronic pulmonary lesion and
Radiation injury etc. [4,5].Recently, it is domestic also have [68Ga] three azacyclo- nine alkyl diacetoxyl (NOTA)-Duramycin positive electricity
The research report [3] of sub- emission tomography (PET) imaging.Compared with marking Annexin V, label Duramycin has following bright
Aobvious advantage：1) Duramycin molecular weight is only 2000, and much smaller than Annexin V, internal blood removes very fast, radioactive background
It is relatively low, be conducive to improve early stage imaging quality；2) PE rich content (about 20%) in cell membrane phospholipid, content are the 2 of PS
Times；3) liver radioactivity intake is relatively low, and liver and kidney radioactivity are removed comparatively fast, and abdomen increased radioactivity is relatively low, is conducive to lower abdomen
Imaging；4) Duramycin is small-molecular peptides, without immunogenicity [3,4].[68Ga] NOTA-Duramycin with label small point
Sub- DPAZn2 classes complex is compared, and liver radioactivity intake is relatively low, and liver and kidney radioactivity are removed comparatively fast.But68Ga half-life period compared with
Short (67.71min), and lung and bone intake radioactivity are higher [3]；In addition, [68Ga] NOTA-Duramycin is purified, leads to
Often containing a certain amount of68GaCl3, influence PET imaging quality.It develops high-purity and half-life period is longer18F (109.8min) is marked
Duramycin is very necessary.In this way, we with [18F] -4- nitrobenzophenone -2- fluoropropionic acids ester ([18F] NFP) synthesis [18F]
FPDuramycin[6].However, [18F] FPDuramycin radioactive uptakes in liver and kidney are higher, and building-up process is complicated, no
Convenient for Fully automated synthesis.
Bibliography：
1. the progress .2011 of Huang graceful, Wang Hongliang, Tang Gang China Apoptosis small molecule PET developers, 24 (4):
240-245.
2. yuan Gong Jun, Nie great Hong, Tang Gang China clinics are put with the apoptosis of tumor cells nucleus medical imaging agent progress worlds
Penetrate medicine Journal of Nuclear Medicine, 2017,41 (4):271-277.
3. yellow refined, square latitude, Tian Wei, Wang Feng, Li Shaohua, Fu Tong, Meng Qingle, king is from positive68Ga-NOTA-Duramycin is real
Test the label of research and bio distribution China's nuclear medicine and molecular image magazine, 2012,32 (4):286-290.
4.Zhao M,Li Z,Bugenhagen S.99mTc-Labeled duramycin as a novel
phosphatidylethanolamine-binding molecular probe.J Nucl Med,2008,49:1345–
1352.
5.Elvas F,·Stroobants S,·Wyffels L.Phosphatidylethanolamine
targeting for cell death imaging in early treatment response evaluation and
disease diagnosis.Apoptosis,2017,22:971–987.
6.Yao S,Hu K,Tang G,Liang X,Du K,Nie D,Jiang S,Zang L.Positron
emission tomography imaging of cell death with[18F]FPDuramycin.Apoptosis,2014,
19:841-850.
【Invention content】
The present invention is just to provide for a kind of excellent pharmacokinetic properties, prepares simple, putting yield height, it can be achieved that certainly
A variety of three polyethylene glycol of positron-emitting radionuclides label (PEG3) modification of the targeting phosphatidyl-ethanolamine (PE) of dynamic metaplasia production
Duramycin (Duramycin) polypeptide drugs：R-PEG3-Dur, wherein R=[Mm+] NOTA-, i.e. polypeptide drugs are [Mm+]
NOTA-PEG3-Dur；Or R=[Nn+] DOTA-, i.e. polypeptide drugs are [Nn+]DOTA-PEG3-Dur.Introduce three polyethylene glycol
(PEG3) it is pharmacokinetics base, R-PEG3-Dur can be assigned with more excellent pharmacokinetic properties.
The invention further relates to a variety of three polyethylene glycol of positron-emitting radionuclides label of targeting phosphatidyl-ethanolamine (PE)
(PEG3) preparation method of duramycin (Duramycin) polypeptide drugs is modified.68Ga half-life period is shorter (67.71min), uncomfortable
In long-distance transportation；And18F、64Cu and89Zr half-life period is longer, respectively:109.8min, 12.7h and 78.4h are conducive to postpone
Imaging.
The key for radiating synthetic polypeptide medicaments R-PEG3-Dur is its precursor NOTA-PEG3-Dur or DOTA-PEG3-Dur
Preparation.The preparation difficulty of precursor raw material NOTA-PEG3-Dur or DOTA-PEG3-Dur are big, considerably complicated and cumbersome, price
Also it is fairly expensive.Thus, the present invention also relates to the pro-drug NOTA-PEG3-Dur or DOTA- of radiation synthetic polypeptide medicaments
The preparation method of PEG3-Dur.
Three polyethylene glycol of radioactive label (PEG3) modification the invention further relates to targeting phosphatidyl-ethanolamine (PE) is durable
Application of mycin (Duramycin) polypeptide drugs in positron emission fault (PET) developer is prepared.
The invention is realized in this way.
- NOTA and-the DOTA homologue that be structure similar, by adjusting pH value of solution, reach the different isotopic ions of label
Purpose, but its chelating isotopic ion is different.- NOTA and-DOTA can be combined68Ga3+With64Cu2+, but-NOTA can also chela
Close Al3+, it is used for18F-Label forms [Al18F]2+；And-DOTA is unable to stable bond [Al18F]2+, but it can stable bond89Zr4+
With177Lu ions.
The present invention uses and has obtained national inventing patent mandate (Patent No.：ZL201410521021.8 self-control synthesis)
Instrument, using NOTA-PEG3-Du as precursor, respectively with68Ga3+、[Al18F]2+、64Cu2+Generation chelatropic reaction is simultaneously pure through small post separation
Change, can be made into polypeptide PET drugs [Mm+]NOTA-PEG3-Dur(Mm+=68Ga3+,[Al18F]2+,64Cu2+)；With DOTA-PEG3-
Dur is precursor, respectively with68Ga3+、64Cu2+With89Zr4+Chelatropic reaction occurs and through small column separating purification, can be made into polypeptide PET medicines
Object [Nn+]DOTA-PEG3-Dur(Nn+=68Ga3+,64Cu2+,89Zr4+).It is more that the implementation of patent of the present invention solves Duramycin
Peptide precursor prepares problem, also further solves the difficulty of one-step method automated production radioactivity Duramycin polypeptide PET drugs
Topic.
The present invention relates to the preparations of the precursor NOTA-PEG3-Dur and DOTA-PEG3-Dur of polypeptide drugs R-PEG3-Dur.
It is formed after Dur modifications PEG3 after Dur-PEG3-NH2, NOTA-NHS or DOTA-NHS be dissolved in dimethyl sulfoxide, in diisopropylethylamine
In reacted with Dur-PEG3-NH2 1 hour, isolated and purified with preparation HPLC and collect product peak, precursor is obtained after freeze-dried
Polypeptide NOTA-PEG3-Dur or DOTA-PEG3-Dur.The N-terminal that theoretically PEG3 can be modified simultaneously in Dur dissociates-NH2 and Lys-
On NH2, but N-terminal-NH2 steric hindrances of dissociating are quite big, thus preferentially the Lys-NH2 less with steric hindrance is combined PEG3, most
The polypeptide precursor NOTA-PEG3-Dur or DOTA-PEG3-Dur of locator qualification Lys-NH2 is obtained afterwards.Its chemical yield is about
30%, purity is more than 95%.
The present invention relates to polypeptide PET drug R-PEG3-Dur, wherein R=- [Mm+] NOTA, i.e. polypeptide drugs are [Mm+]
NOTA-PEG3-Dur, such as [68Ga]NOTA-PEG3-Dur、[18F] AlF-NOTA-PEG3-Dur and [64Cu]NOTA-PEG3-Dur
Radiation synthesis.Using NOTA-PEG3-Dur as precursor, in faintly acid such as pH4.0 or so and 100-110 DEG C with68GaCl3Occur
Chelatropic reaction, through Sep-Pakplus C18 pillars or the small column separating purifications of HLB, can produce [68Ga] NOTA-PEG3-Dur injections
Liquid, reaction equation are shown in synthetic route 1A；Using NOTA-PEG3-Dur as precursor, in faintly acid such as pH4.0-4.5 and 100-110 DEG C
When and Al18After chelatropic reaction occurs for F, through Sep-Pak plus C18 pillars or the small column separating purifications of HLB, can prepare [18F]
AlF-NOTA-PEG3-Dur parenteral solutions, reaction equation are shown in synthetic route 1B；Using NOTA-PEG3-Dur as precursor, in faintly acid such as
PH4.0-5.6 and at 100-110 DEG C with64CuCl2After chelatropic reaction occurs, through Sep-Pak plus C18 pillars or HLB pillars
It isolates and purifies, can prepare [64Cu] NOTA-PEG3-Dur parenteral solutions, reaction equation is shown in synthetic route 1C.
Reaction equation 1. [68Ga]NOTA-PEG3-Dur(A)、[18F] AlF-NOTA-PEG3-Dur (B) and [64Cu]NOTA-
PEG3-Dur (C) synthetic route.
The present invention also relates to polypeptide PET drug R-PEG3-Dur, wherein R=- [Nn+] DOTA, i.e. polypeptide drugs are [Nn+]
DOTA-PEG3-Dur, such as [68Ga]DOTA-PEG3-Dur、[64Cu] DOTA-PEG3-Dur and [89Zr] DOTA-PEG3-Dur
Radiation synthesis.Using DOTA-PEG3-Dur as precursor, in faintly acid such as pH4.0 or so and 100-110 DEG C with68GaCl3Chela occurs
Reaction is closed, through Sep-Pakplus C18 pillars or the small column separating purifications of HLB, can produce [68Ga] DOTA-PEG3-Dur parenteral solutions,
Reaction equation is shown in synthetic route 2A；Using DOTA-PEG3-Dur as precursor, in faintly acid such as pH4.0-5.6 and 100-110 DEG C
With64CuCl2After chelatropic reaction occurs, through Sep-Pakplus C18 pillars or the small column separating purifications of HLB, can prepare [64Cu]
DOTA-PEG3-Dur parenteral solutions, reaction equation are shown in synthetic route 2B；Using DOTA-PEG3-Dur as precursor, in faintly acid such as
PH6.0-7.5 and at 100-110 DEG C with89ZrCl4After chelatropic reaction occurs, through Sep-Pakplus C18 pillars or HLB pillars point
From purifying, can prepare [89Zr] DOTA-PEG3-Dur parenteral solutions, reaction equation is shown in synthetic route 2C.
Reaction equation 2. [68Ga]DOTA-PEG3-Dur(A)、[64Cu] DOTA-PEG3-Dur (B) and [89Zr]DOTA-PEG3-
Dur (C) synthetic route.
[68Ga]NOTA-PEG3-Dur、[18F]AlF-NOTA-PEG3-Dur、[64Cu]NOTA-PEG3-Dur、[68Ga]
DOTA-PEG3-Dur、[64Cu] DOTA-PEG3-Dur and [89Zr] DOTA-PEG3-Dur parenteral solutions be in colourless or pale yellow transparent
Solution, pH value is between 5.0-7.0.With18F-For starting material, [18F] AlF-NOTA-PEG3-Dur do not correct putting yield about
It is 30%.With68GaCl3For starting material, [68Ga] NOTA-PEG3-Dur and [68Ga] DOTA-PEG3-Dur do not correct putting production
Rate is more than 50%.[64Cu] NOTA-PEG3-Dur and [64Cu] DOTA-PEG3-Dur do not correct putting yield more than 70%.
[89Zr] DOTA-PEG3-Dur do not correct putting yield more than 20%.When the Radiochemical purity of these polypeptides PET medicaments injections is total
Between about 40min, measured through radioactivity HPLC and radioactivity TLC, radiochemical purity is all higher than 95%.
In animal body [68Ga] NOTA-PEG3-Dur bio distributions show that kidney gathers radioactivity highest, liver has appropriateness
Radioactive uptake, blood radioactivity are removed comparatively fast, and other tissue forceps take radioactivity relatively low, and radioactivity is gathered most in midbrain
It is low.With reported [68Ga] NOTA-Duramycin compares, [68Ga] NOTA-PEG3-Dur radioactive uptake summaries in liver
Height, but lung and bone intake radioactivity are relatively low.With [68Ga] NOTA-Duramycin and [68Ga] NOTA-PEG3-Dur compares,
[18F] AlF-NOTA-PEG3-Dur shows more excellent pharmacokinetic properties, in addition to kidney accumulation radioactivity is higher, other tissues
Organ intake radioactivity is all relatively low, and blood radioactivity is removed comparatively fast.Other radioactive polypeptide drug R-PEG3-Dur performance with
[68Ga] NOTA-PEG3-Dur or [18F] the similar pharmacokinetic properties of AlF-NOTA-PEG3-Dur.In addition, a variety of models
Animal PET imaging show [18F] AlF-NOTA-PEG3-Dur can be used for the liver fibrosis related with PE and pulmonary fibrosis imaging prison
It surveys, antineoplaston curative effect monitoring, inflammation diagnosis and anti-inflammatory treatment monitoring and the heart and brain blood such as atheromatous plaque and myocardial infarction
The antidiastole of pipe disease.Because neurodegenerative disease is directed to PE, thus [18F] AlF-NOTA-PEG3-Dur is also expected to use
It is imaged in neurodegenerative disease PET.In addition, [18F] AlF-NOTA-PEG3-Dur is not absorbed in tumour or low intake, and
It can highly be absorbed in inflammation, thus [18F] AlF-NOTA-PEG3-Dur can distinguish tumour and inflammation, in the discriminating of tumour and inflammation
In terms of diagnosis better than the most frequently used PET drugs [18F] fluorodeoxyglucose ([18F] FDG), it is that a kind of very potential be converted into is faced
The cell death polypeptide PET drugs of bed application.In addition, other radioactive polypeptide drug R-PEG3-Dur also and [18F]AlF-
NOTA-PEG3-Dur has similar biological function and PET imaging results.Various metals isotope labeling PEG3-Dur is further
It expands and images application category with cell deaths of the PE in relation to lesion.
[M of the present inventionm+] NOTA-PEG3-Dur and [Nn+] DOTA-PEG3-Dur, it has the advantage that：(1)
After PEG3 modifications Duramycin, its more excellent pharmacokinetic properties is assigned.(2)-NOTA or-DOTA is introduced, and can not only be realized
Use nucleic68Ga is marked, and can use half-life period longer nucleic18F、64Cu2+And89Zr4+Label, and can be further with treatment nucleic
Such as177Lu is marked.(3)[Mm+] NOTA-PEG3-Dur can be used68Ga3+、[Al18F]2+With64Cu2+Respectively with NOTA-PEG3-Dur mono-
Step reaction and small column separating purification are made；[Nn+] DOTA-PEG3-Dur can be used68Ga3+、64Cu2+With89Zr4+Respectively with DOTA-
PEG3-Dur single step reactions and small column separating purification are made.Preparation method is simple, can be realized with simple synthesizer its high yield and
High-purity Fully automated synthesis meets clinic PET imaging needs.(4) liver fibrosis and pulmonary fibrosis is caused to be supervised for chemicotherapy treatment
It surveys, inflammation diagnoses and anti-inflammatory treatment monitoring, antineoplaston curative effect monitoring and cardiovascular and cerebrovascular disease diagnosis offer are novel excellent
Targeting PE cell death PET drugs.
【Description of the drawings】
Fig. 1 is the HPLC collection of illustrative plates (A) of precursor NOTA-PEG3-Dur and mass spectrogram (B).
Fig. 2 for [18F] AlF-NOTA-PEG3-Dur radioactivity TLC (A) and HPLC (B) analysis collection of illustrative plates.It is to put to scheme upper figure in B
Penetrating property collection of illustrative plates；Figure below is uv-spectrogram.
Fig. 3 for [18F] distribution of AlF-NOTA-PEG3-Dur vivo biodistributions.
Fig. 4 for [68Ga] distribution of NOTA-PEG3-Dur vivo biodistributions.
Fig. 5 be through treatment processing animal model injection [18F] AlF-NOTA-PEG3-Dur (A and B) and [18F] after FDG (C)
During 60min, tumour/muscle radioactive uptake ratio.A. lotus S180 mice with tumor group；Lotus A549 Pulmonary carcinoma nude mice models group (B and C)
(n=3).
Fig. 6 for [18F] AlF-NOTA-PEG3-Dur normal muscle tissues, inflammatory tissue and infection musculature in
Intake is compared.
Fig. 7 for Liver Fibrosis Model animal [18F] AlF-NOTA-PEG3-Dur PET images.A. model group；B. control group.
Fig. 8 for Liver Fibrosis Model animal [18F] FDG (A) and [18F] AlF-NOTA-PEG3-Dur (B) PET imaging compare
Figure.
Fig. 9 for pulmonary fibrosis model animal [18F] AlF-NOTA-PEG3-Dur PET imaging figures.
【Specific embodiment】
The synthesis of 1 precursor NOTA-PEG3-Dur of embodiment.
Dur-PEG3-NH2, Isosorbide-5-Nitrae, tri- azacyclo-s of 7- nine alkyl-N ', N "-diacetoxyl-N- are formed after Dur modifications PEG3
Acetyl group succimide ester (NOTA-NHS) or Cyclen-N ', N " N " '-triacetic acid base-N- second
After acyl group succimide ester (DOTA-NHS) is dissolved in dimethyl sulfoxide, at room temperature in diisopropylethylamine with Dur-PEG3-NH2
Reaction 1-2 hours is isolated and purified with preparation HPLC and collects product peak, and final products NOTA-PEG3- is obtained after freeze-dried
Dur or DOTA-PEG3-Dur.Finished product is more than 95% (retention time t through HPLC purity assaysR=8.4, Figure 1A)；ESI-MS:
[M-2H]2-=1242.0 (m/z), i.e. molecular weight (Mr.) 2486 are calculated:2485.00 i.e. NOTA-PEG3-Dur molecular weight
(Mr.2485)=- Dur molecular weight (Mr.2011)+- PEG3 molecular weight (Mr.189)+- NOTA molecular weight (Mr.286) (Figure 1B).
The ESI-MS of DOTA-PEG3-Dur:[MH]+=2586.40 (m/z) are calculated:2587.00.
Embodiment 2 [18F] AlF-NOTA-PEG3-Dur radiation synthesis
Passed through by cyclotron18O(p,n)18F nuclear reactions production18F-, in N2Under airborne band, it is captured in Sep-Pak
In QMA anion pillars,18O- water is collected in returnable bottle.It will be in QMA pillars with 0.4mL physiological saline18F-It elutes into bottle
In, 50-100 μ L is taken to add in reaction bulb.NOTA-PEG3-Dur (50 μ g/ μ L) 50 μ L are taken, add in 2mMAlCl36 μ L of solution, 4 μ
300 μ L of L glacial acetic acid and acetonitrile after mixing, are transferred in reaction bulb.After stirring, 10min or so is reacted in 100-110 DEG C of heating.
Cooling is added in physiological saline 8mL to reaction bulb, and mixing is transferred in HLB pillars or SEP-PAK C18 pillars.In reaction bulb
After solution has all shifted, pillar is rinsed with 10mL waters for injection, dries up pillar.Finally, with ethyl alcohol 1.5-2.0mL eluted products
And collected in receiving bottle after sterilised membrane filter, the product solution containing 5% ethyl alcohol is diluted to physiological saline, is met
It is required that [18F] AlF-NOTA-PEG3-Dur parenteral solutions.[18F] AlF-NOTA-PEG3-Dur do not correct Radiochemical yield and is
20-40%, total generated time that radiates is 35min.
Embodiment 3 [68Ga] NOTA-PEG3-Dur radiation synthesis
200 μ L of NOTA-PEG3-Dur (50 μ g/ μ L) 50 μ L and 1.25M sodium acetate solution are sequentially added in reaction tube.
From68Ge/68It is eluted in Ga generators with 0.05M hydrochloric acid 4mL68Ga3+Into the reaction tube, mixing adjusts pH value of solution to 4.0,100 DEG C
Heating reaction 10min or so.Cooling is added in physiological saline 4mL to reaction bulb, and mixing is transferred to HLB pillars or SEP-PAK
In C18 pillars.After solution in reaction bulb has all shifted, pillar is rinsed with 10mL waters for injection, dries up pillar.Then, it uses
Ethyl alcohol 1.5-2.0mL eluted products are simultaneously collected into after sterilised membrane filter in receiving bottle, are diluted to physiological saline containing 5% second
The product solution of alcohol, obtain it is satisfactory [68Ga] NOTA-PEG3-Dur parenteral solutions.[68Ga] NOTA-PEG3-Dur do not correct
It is 50% that Radiochemical yield, which is more than, and total generated time that radiates is 30min.
Embodiment 4 [68Ga] DOTA-PEG3-Dur radiation synthesis
200 μ L of DOTA-PEG3-Dur (50 μ g/ μ L) 50 μ L and 1.25M sodium acetate solution are sequentially added in reaction tube.
From68Ge/68It is eluted in Ga generators with 0.05M hydrochloric acid 4mL68Ga3+Into the reaction tube, mixing adjusts pH value of solution to 4.0,100 DEG C
Heating reaction about 10min.Cooling is added in physiological saline 4mL to reaction bulb, and mixing is transferred in HLB pillars.Treat reaction bulb
After middle solution has all shifted, pillar is rinsed with 15mL waters for injection, dries up pillar.Then, it with 1.5 eluted products of ethyl alcohol and passes through
It is collected into receiving bottle after sterilised membrane filter, is diluted to the product solution containing 5% ethyl alcohol with physiological saline, is met the requirements
[68Ga] DOTA-PEG3-Dur parenteral solutions.[68Ga] DOTA-PEG3-Dur do not correct Radiochemical yield and is more than for 60%, always
Radiation generated time is 30min.
Embodiment 5 [64Cu] NOTA-PEG3-Dur radiation synthesis
Sequentially added in reaction tube NOTA-PEG3-Dur (50 μ g/ μ L) 100 μ L and64CuCl2Solution 0.100-1.0mL,
PH 4.0-5.6 are adjusted to sodium acetate solution, react at room temperature 15min.Finally with normal saline dilution and after sterilised membrane filter filters
Be collected into receiving bottle, obtain it is satisfactory [64Cu] NOTA-PEG3-Dur parenteral solutions.[68Ga] the non-schools of NOTA-PEG3-Dur
It is 65% that positive Radiochemical yield, which is more than, and total generated time that radiates is 30min.
Embodiment 6 [64Cu] DOTA-PEG3-Dur radiation synthesis
Sequentially added in reaction tube DOTA-PEG3-Dur (50 μ g/ μ L) 100 μ L and64CuCl2Solution 0.100-1.0mL,
PH 4.0-5.6 are adjusted to sodium acetate solution, react at room temperature 15min.Finally with normal saline dilution and after sterilised membrane filter filters
Be collected into receiving bottle, obtain it is satisfactory [64Cu] DOTA-PEG3-Dur parenteral solutions.[68Ga] the non-schools of DOTA-PEG3-Dur
It is 70% that positive Radiochemical yield, which is more than, and total generated time that radiates is 30min.
Embodiment 7 [89Zr] DOTA-PEG3-Dur radiation synthesis
Sequentially added in reaction tube DOTA-PEG3-Dur (50 μ g/ μ L) 50 μ L and89Zr Cl4Solution 0.100-1.0mL,
PH 6.0-7.5 are adjusted to sodium acetate solution.30-100 DEG C of heating reaction 10min.Cooling adds in physiological saline 4mL to reaction bulb
In, mixing is transferred in HLB pillars or SEP-PAK C18 pillars.After solution in reaction bulb has all shifted, noted with 10mL
It penetrates and is rinsed with water pillar, dry up pillar.Then, reception is collected into ethyl alcohol 1.5-2.0mL eluted products and after sterilised membrane filter
Bottle in, be diluted to the product solution containing 5% ethyl alcohol with physiological saline, obtain it is satisfactory [89Zr]DOTA-PEG3-Dur
Parenteral solution.[89Zr] DOTA-PEG3-Dur do not correct Radiochemical yield and is more than for 20%, and total generated time that radiates is 30min.
The measure of 8 product purity of embodiment
Putting for polypeptide PET medicaments injections is measured with radioactivity high performance liquid chromatography (HPLC) and thin-layered chromatography (TLC)
Penetrate chemical purity.With the on-radiation standard items [M of determining structuren+] NOTA-PEG3-Dur and [Nn+] DOTA-PEG3-Dur, point
Not with corresponding radioactive polypeptide [Mn+] NOTA-PEG3-Dur and [Nn+] DOTA-PEG3-Dur parenteral solutions are injected into HPLC together
In or point sample row TLC together, to determine whether its retention time or Rf value Rf consistent, and confirmation prepares the true of parenteral solution
Property, its radiochemical purity is all higher than 95% (Fig. 2) after measured.
HPLC analysis conditions：Splitter is C18 analytical columns, and mobile phase is the acetonitrile solution of 0.1% trifluoroacetic acid (TFA)：
The aqueous solution of 0.1%TFA, row gradient elution：During 0min, the aqueous solution of acetonitrile solution/0.1%TFA containing 0.1%TFA：2/
98；When being gradually raised to 8min, the aqueous solution of acetonitrile solution/0.1%TFA of 0.1%TFA：10/90；When being raised again to 20min,
The aqueous solution of acetonitrile solution/0.1%TFA of 0.1%TFA：80/20.Flow velocity is 1mL/min, ultraviolet detection wavelength 210nm and
254nm。
TLC methods detect [Mn+] NOTA-PEG3-Dur and [Nn+] DOTA-PEG3-Dur parenteral solutions radiochemical purity.It takes
One silica gel plate, is put into behind shielding lead glass, and a little radioactive sample and its standard items (concentration 0.5mg/ are drawn with capillary
ML), gently put together on silica gel plate at one 1.5cm of distance, electricity consumption blowing drying.It is chromatographed, is unfolded in chromatography cylinder
Agent is methanol：1.0M ammonium acetate=50:50 (V/V) are dried up after chromatography with hot-air, using radioactivity TLC scanner row thin layers
Scanning.After scanning, with iodine staining TLC plates, the Rf value Rf of radioactive sample and standard items is detected.Representative [18F]AlF-
NOTA-NOC parenteral solution radioactivity TLC and HPLC analysis results are shown in Fig. 2A and Fig. 2 B.
The measure of 9 vivo biodistribution of embodiment distribution
Normal kunming mice 25, without fasting for solids and liquids before administration.Every mouse through tail vein injection [18F]AlF-NOTA-
PEG3-Dur or [68Ga] NOTA-PEG3-Dur parenteral solutions 0.74-1.48MBq (20-40 μ Ci), after administration respectively 5,10,20,
30th, five time points of 60min put to death, and each put 5 mouse.Blood sample is taken by eyeball, other histoorgans is separately taken to be weighed,
Numeration takes tissue to include the heart, lung, liver, kidney, stomach, small intestine, full brain and muscle.The tissue cut passes through decontamination, weighs, counts,
Initial data passes through correction for attenuation, and acquired results account for the percentage (%DI/g of injection dosage with per gram of tissue：Average value scholar's standard
Difference) it represents.[18F] AlF-NOTA-PEG3-Dur vivo biodistributions distribution be shown in Fig. 3.From the figure 3, it may be seen that kidney intake [18F]AlF-
NOTA-PEG3-Dur highests, and the residence time is longer, illustrates that it is mainly drained through kidney-bladder approach.Secondly, it is radiated in blood
Property intake it is higher, but remove it is also very fast.Liver and small intestine intake radioactivity are relatively low, and other histoorgan intake radioactivity are lower,
Wherein brain capture radioactivity is minimum.The result shows that [18F] AlF-NOTA-PEG3-Dur have excellent pharmacokinetic properties.
[68Ga] NOTA-PEG3-Dur vivo biodistributions distribution be shown in Fig. 4.As shown in Figure 4, kidney intake [18F]AlF-
NOTA-PEG3-Dur highests, and the residence time is longer, illustrates that it is mainly drained through kidney-bladder approach.Secondly, it is radiated in blood
Property intake it is higher, but remove it is also very fast.Liver and bone have appropriate radioactive uptake, and the residence time is longer.Other organizers
Official's intake radioactivity is relatively low, and wherein brain capture radioactivity is minimum.The result shows that：[68Ga] NOTA-PEG3-Dur with [18F]AlF-
NOTA-PEG3-Dur is the same, it may have preferable pharmacokinetic properties.
10 antineoplaston animal model tumour of embodiment/non-target tissue's ratio measurement
Experimental animal kunming mice and nude mice perform unified management, standard per cage 5 mouse of stable breeding in animal experimental center
Condition be 25 DEG C of room temperature, humidity 50%.
Kunming mice：In 18-22g female KM mouse right fore transaxillary positions, it is 2 × 10 that cell concentration, which is subcutaneously injected,7/
The culture medium of ml, be inoculated with mouse fibrosarcoma S180 cells, continue to cultivate, be measured with vernier caliper, when mouse tumor grow to
During diameter 0.5-1.0cm, kunming mice is divided into two groups：A oncocyte death groups：Intraperitoneal injection of cyclophosphamide solution
(cyclophosphamide, CTX are dissolved in physiological saline, 100mg/kg), as oncotherapy group model；B control groups：Abdominal cavity
Interior injecting normal saline makees blank control.
Nude mice：In 4 week old mouse right fore transaxillary positions, it is 5 × 10 that cell concentration, which is subcutaneously injected,6The culture medium of/ml, point
Not Jie Zhong humanized's lung cancer A549 and SPCA-1 cell strain, continue culture with spare.When nude mouse tumor length to diameter 0.5-1.0cm
When, nude mice is divided into two groups：A, death of neoplastic cells group, tail vein injection cisplatin solution (cisplatin diluted in
Saline, 3mg/kg) it is 5 days continuous, it is oncotherapy group model；B, control group, to nude mice tail vein injection saline to make
Blank control.
By Chemotherapeutic treatments handle tumor model, injection [18F] 60 after AlF-NOTA-PEG3-Dur when put to death animal,
Solution takes tissue of interest, measures liver mass and radiocounting, calculates tumour/muscle radioactivity ratio, is as a result shown in figure
5.The result shows that [18F] tumor tissues that handle in untreated of AlF-NOTA-PEG3-Dur handle without intake through treatment
Tumor group be woven with high intake；Compared with the tumor model of untreated processing, after treatment is handled [18F]AlF-NOTA-
The tumour of PEG3-Dur/muscle radioactive uptake ratio significantly increases, and after treatment is handled [18F] tumour/muscle of FDG puts
Penetrating property intake ratio is substantially reduced, illustrate [18F] AlF-NOTA-PEG3-Dur available for antineoplaston monitor.
11 inflammatory animal model of embodiment makes
0.2mL turpentine oil is injected under aseptic condition at mouse right thigh muscle, 3-4 days right legs is taken muscle abscess person occur
Enter to be selected as aseptic inflammation model.Equally, under aseptic condition at mouse right thigh muscle Escherichia Coli Injection, 2 hours rear right-legs
There is muscle abscess person to enter to be selected as infection model.
Above-mentioned inflammatory model, injection [18F] 60 after AlF-NOTA-PEG3-Dur when put to death animal, solution takes interested group
It knits, measures muscle tissue weight and radiocounting, calculate inflammatory tissue/muscle radioactivity ratio, be as a result shown in Fig. 6.As a result
Show [18F] AlF-NOTA-PEG3-Dur has high intake in aseptic inflammation tissue and infection muscle, and in normal muscle tissues
Without intake or low intake；Aseptic inflammation tissue/normal muscle and infection musculature/normal muscle radioactive uptake ratio are more than
4.5/1.0 and [18F] AlF-NOTA-PEG3-Dur in tumor tissues without intake.So as to illustrate [18F]AlF-NOTA-
PEG3-Dur can be used for inflammatory phenomena, and can distinguish tumor tissues and inflammatory tissue.
12 hepatic fibrosis rats modelling of embodiment
Thioacetamide has hepatotoxicity wind agitation, genotoxicity and immunotoxicity, and liver endite inflammatory cell is caused after exposed rats
Infiltration, hemorrhagic necrosis form center fiber interval or the portal fibrous septum in center in liver.Modeling ultra-pure water (control
Group) with thioacetamide (thiacetamide, TAA) (model group) be configured to a concentration of 4%TAA solution according to proper proportion,
By 200mg/kg TAA solution in rat femoribus internus abdominal subcutaneous injection, 2 times a week, week 4 weeks -12 time.Model group liver
Fibrosis formation is confirmed through pathologic finding.
13 pulmonary fibrosis in rats of embodiment makes
24 rats are randomly divided into pulmonary fibrosis group and control group, every group 12.Pulmonary fibrosis is established by literature method
Rat model is as follows：It is preoperative to the progress of SD rats to weigh, with 2% yellow Jackets abdomen is carried out by 0.225ml/kg
Chamber injecting anesthetic；After anaesthetizing successfully, rat supine position is on operating table and fixing its four limbs and head, with 75% alcohol to big
Mouse neck area row routine disinfection.Patient, with operating scissors row longitudinal cut, then cuts skin and passivity point at neck center
From muscle, tissue, finally expose tracheae.0.1ml bleomycins liquid (5mg/kg weight) is extracted with 1mL syringes, will be injected
Device syringe needle replaces with 7 number sword-shaped needles, and transtracheal cartilage czermak space is pierced into tracheae, and bleomycin liquid is slowly injected into tracheal strips.
The upright and rotation status of mouse plate is kept in injection process, bleomycin liquid is made to enter intrapulmonary by tracheae rapidly, and in intrapulmonary
It is evenly distributed.Rat is lieed down after the completion of Intratracheal instillation administration again, layer-by-layer suture muscle and skin.It is postoperative that rat is placed in guarantor
On temperature pad, rat is made to keep right lateral position, and the vital sign of close observation rat, waits for the natural revival of rat.With more than
Operating procedure is identical, and control rats give the physiological saline of single tracheal strips perfusion equivalent.Model group liver fibrosis forms warp
Pathologic finding confirms.
14 animal pattern PET of embodiment is imaged
Model group and control group, every group 3, injected respectively by tail vein [18F] AlF-NOTA-PEG3-Dur parenteral solutions
In (0.2mL, about 150-300 μ Ci/ are only) to model mouse body.10min is through being injected intraperitoneally 5% chloraldurate (6mL/ before imaging
Kg model mouse) is anaesthetized, fixed plate adhesive tape is placed on and fixes, body temperature is kept with heating cushion.After CT scan, in injection developer not
Collection PET data is checked and accepted with the time, after software (Inevon Research Workplace 4.1) row correction for attenuation, iteration weight
Build image.The area-of-interest (ROIs) of the tissues such as lesion tissue and brain, muscle is sketched the contours of, measures the radiation of region of interest tissue
Property count and volume, calculate per gram of tissue injection dosage percentage (%ID/g).
For Liver Fibrosis Model group, the radioactive uptakes such as Liver fibrosis tissue/brain, Liver fibrosis tissue/muscle are calculated
Relative ratio.Representative PET image results (Fig. 7 and Fig. 8) display：[18F] AlF-NOTA-PEG3-Dur liver groups in model mouse
It knits radioactive uptake and is apparently higher than hepatic tissue radioactive uptake in control group, Liver fibrosis tissue/normal liver tissue radioactivity is taken the photograph
Take ratio=12/1 (Fig. 7), and [18F] FDG Liver fibrosis tissues/normal liver tissue radioactive uptake ratio=2.5/1 (Fig. 8).
The result shows that [18F] AlF-NOTA-PEG3-Dur for liver fibrosis imaging be substantially better than [18F] FDG, while also illustrate [18F]
AlF-NOTA-PEG3-Dur can be used for curative effect evaluation.
For pulmonary fibrosis model group, the radioactive uptakes such as pulmonary fibrosis tissue/brain, Liver fibrosis tissue/muscle are calculated
Relative ratio.Representative PET imagings (Fig. 9) display：[18F] AlF-NOTA-PEG3-Dur lung tissue radioactivity in model mouse takes the photograph
It takes and is apparently higher than lung tissue radioactive uptake in control group, pulmonary fibrosis tissue/normal lung tissue's radioactive uptake ratio=6/1
(Fig. 9), and [18F] FDG pulmonary fibrosis tissue/normal lung tissue's radioactive uptake ratio=1.5/1.The result shows that [18F]AlF-
NOTA-PEG3-Dur for pulmonary fibrosis imaging be substantially better than [18F] FDG, while also illustrate [18F]AlF-NOTA-PEG3-Dur
Available for pulmonary fibrosis curative effect evaluation.
The above embodiment of the present invention preliminary test shows that involved radioactive label PEG3 modifies duramycin (R-
PEG3-Dur) be [18F] AlF-NOTA-PEG3-Dur analogs, ought to have similar physicochemical property and bioactivity.They
Preparation method is simple, easily realizes automated production, is respectively provided with excellent pharmacokinetic properties, and imaged available for liver fibrosis,
Pulmonary fibrosis imaging, differentiates tumour and inflammation and antineoplaston curative effect evaluation at inflammatory phenomena, is very promising targeting PE
Cell death PET drugs.It should be understood that it for those of ordinary skills, can be improved according to the above description
Or transformation, and all these modifications and variations should all belong to the protection domain of appended claims of the present invention.
Claims (10)
1. the three polyethyleneglycol modified duramycin polypeptide drugs of radioactive label of one kind targeting phosphatidyl-ethanolamine, by drug effect base
Group-Dur, pharmacokinetics base-PEG3 and combination radioactivity chelate group-R form polypeptide PET drug R-PEG3-Dur, wherein R=
[Mm+] NOTA- or [Nn+] DOTA-, structural formula is：
Wherein, R=[Mm+] NOTA- marks isotopic ion Mm+=68Ga3+, [Al18F] 2+ or 64Cu2+；Or R=- [Nn
+] DOTA-, label isotopic ion Nn+=68Ga3+, 64Cu2+ or 89Zr4+.
2. polypeptide drugs according to claim 1, it is characterised in that：R=[Mm+] NOTA-, i.e. polypeptide drugs are [Mm+]
NOTA-PEG3-Dur, label radionuclide ion Mm+ are：68Ga3+, [Al18F] 2+ or 64Cu2+；Or R=[Nn+]
DOTA-, i.e. polypeptide drugs are [Nn+] DOTA-PEG3-Dur, and label radionuclide ion Mn+ is：68Ga3+, 64Cu2+ or
89Zr4+。
3. the preparation method of the polypeptide drugs described in claims 1 or 2, it is characterised in that be made using the following method：With NOTA-
PEG3-Du is precursor raw material, chelatropic reaction occurs with 68Ga3+, [Al18F] 2+, 64Cu2+ respectively and through small column separating purification,
Polypeptide PET drugs [Mm+] NOTA-PEG3-Dur, Mm+=68Ga3+, [Al18F] 2+, 64Cu2+ is made；Or with DOTA-PEG3-
Dur is precursor raw material, chelatropic reaction occurs with 68Ga3+, 64Cu2+ and 89Zr4+ respectively and through small column separating purification, can be made into
Polypeptide PET drugs [Nn+] DOTA-PEG3-Dur, Nn+=68Ga3+,64Cu2+,89Zr4+。
4. polypeptide drugs preparation method according to claim 3, it is characterised in that described precursor raw material NOTA-PEG3-Dur
Or DOTA-PEG3-Dur is made using the following method：Dur-PEG3-NH2 is formed after Dur modifications PEG3, respectively with being dissolved in diformazan Asia
Tri- azacyclo-s of 1,4,7- nine the alkyl-N ', N ' of sulfone-diacetoxyl-N- acetyl group succimide ester NOTA-NHS or 1,4,7,
It is different to add in a small amount of two by 10- tetraazacyclododecanands-N ', N " N " '-triacetic acid base-N- acetyl group succimide ester DOTA-NHS
Propylethylamine, in alkalescence, reacts 1-2 hours to solution, is isolated and purified with preparation HPLC and collect product peak, through cold at room temperature
Be lyophilized it is dry after, you can obtain Precursor Peptide NOTA-PEG3-Dur or DOTA-PEG3-Dur respectively.
5. the preparation method of the polypeptide drugs described in claims 1 or 2, it is characterised in that described [68Ga]NOTA-PEG3-Dur
It is made using the following method：What described precursor raw material NOTA-PEG3-Dur was eluted with using 0.05M hydrochloric acid68GaCl3Solution is in weak acid
Under the conditions of, the lower reaction about 10min of 100-110 DEG C of heating, with HLB pillars or the small column separating purifications of SEP-PAK C18, met
It is required that [68Ga] NOTA-PEG3-Dur parenteral solutions；Described [68Ga] DOTA-PEG3-Du is made using the following method：Precursor is former
Expect what DOTA-PEG3-Dur was eluted with using 0.05M hydrochloric acid68GaCl3Solution is under mild acid conditions, is reacted under 100-110 DEG C of heating
About 10min, with HLB pillars or the small column separating purifications of SEP-PAK C18, obtain it is satisfactory [68Ga] DOTA-PEG3-Dur notes
Penetrate liquid.
6. the preparation method of radioactive polypeptide drug described in claims 1 or 2, it is characterised in that described [18F]AlF-NOTA-
PEG3-Dur is synthesized using the following method：Described precursor raw material NOTA-PEG3-Du is in AlCl3In the presence of with18F-Or [Al18F]2+
Reaction, reaction condition：In 50 μ g/ μ L of NOTA-PEG3-Dur solution, 50 μ L, 2mM AlCl are sequentially added36 μ L of solution, 4 μ L
300 μ L of glacial acetic acid and acetonitrile are transferred to containing of being eluted from QMA pillars18F-In the reaction bulb of physiological saline 50-100 μ L, mix
Solution is in subacidity, 100 DEG C of heating reaction about 10min, through HLB pillars or the small column separating purifications of SEP-PAK C18, ethyl alcohol after even
1.5-2.0mL eluted products, with normal saline dilution into the solution containing 5% ethyl alcohol to get to it is satisfactory [18F]AlF-
NOTA-PEG3-Dur parenteral solutions.
7. the preparation method of radioactive polypeptide drug described in claims 1 or 2, it is characterised in that described [64Cu]NOTA-
PEG3-Dur or [64Gu] DOTA-PEG3-Dur, it synthesizes using the following method：Described precursor raw material NOTA-PEG3-Dur50 μ g/ μ
100 μ L of L with64CuCl2Solution 0.100-1.0mL is adjusted to pH 4.0-5.6 with sodium acetate solution, and incubation at room temperature 15min reactions obtain
To it is satisfactory [64Cu] NOTA-PEG3-Dur parenteral solutions；Or 50 μ g/ μ L100 μ L of precursor raw material DOTA-PEG3-Dur and64CuCl2Solution reaction, obtain it is satisfactory [64Gu] DOTA-PEG3-Dur parenteral solutions.
8. the preparation method of radioactive polypeptide drug described in claims 1 or 2, it is characterised in that described [89Zr]DOTA-
PEG3-Dur is synthesized using the following method：Described precursor raw material DOTA-PEG3-Dur 50 μ g/ μ L, 50 μ L with89ZrCl4Solution
0.100-1.0mL is adjusted to pH 6.0-7.5,100 DEG C of heating reaction about 10min, through HLB pillars or SEP-PAK with sodium acetate solution
The small column separating purifications of C18, ethyl alcohol 1.5-2.0mL eluted products, with normal saline dilution into the solution containing 5% ethyl alcohol to get to
Satisfactory [89Zr] DOTA-PEG3-Dur parenteral solutions.
9. the three polyethyleneglycol modified duramycin polypeptide of radioactive label of the targeting phosphatidyl-ethanolamine of one of claim 1-3
Drug is preparing neurodegenerative disease, headstroke, thrombus, atheromatous plaque, myocardial infarction and antineoplaston curative effect prison
Application in the PET imaging Early Identification diagnosing developing agents of survey.
10. the three polyethyleneglycol modified duramycin of radioactive label of the targeting phosphatidyl-ethanolamine of one of claim 1-3 is more
Peptide medicine is imaged with cell death or apoptosis process in preparation with antidiastoles of the PS in relation to lesion with curative effect monitoring PET
Application in agent.
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