CN109010852A - A kind of circular polypeptides class PET imaging agent and its preparation method and application targeting CD13 receptor - Google Patents
A kind of circular polypeptides class PET imaging agent and its preparation method and application targeting CD13 receptor Download PDFInfo
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- CN109010852A CN109010852A CN201811091414.4A CN201811091414A CN109010852A CN 109010852 A CN109010852 A CN 109010852A CN 201811091414 A CN201811091414 A CN 201811091414A CN 109010852 A CN109010852 A CN 109010852A
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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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
Abstract
The invention discloses a kind of circular polypeptides class PET imaging agents and its preparation method and application for targeting CD13 receptor.The present invention utilizes18F-NFP is carried out as radiochemistry label intermediate18F label, obtains the PET imaging agent of high-purity18F-cNGR, stability is good, water-soluble strong, and internal blood is removed fast, it is absorbed in the U87 model mice of APN/CD13 positive expression obvious, tumor focus position reproduced image contrast is high, and tumour resolution capability is strong, has good clinical application development prospect in terms of carrying out PET tumor imaging.
Description
Technical field
The present invention relates to a kind of circular polypeptides class PET imaging agents and its preparation method and application for targeting CD13 receptor.
Background technique
Malignant tumour is one of maximum public health problem in the whole world, to the very harmful of human health." 2017 Chinese cancers
Disease report " disclose the morbidity and dead data of China's cancer in 2013, report display China is cancer big country, cancer everybody
Number accounts for 40% or so of global cancer patient total number of persons, and there are about 10,000 people to make a definite diagnosis cancer daily in China, just has 7 people within average every 1 minute
It makes a definite diagnosis, this six kinds of lung cancer, gastric cancer, colorectal cancer, liver cancer, breast cancer, the cancer of the esophagus is most commonly seen in all cases of cancer, accounts for about complete
The 65% of portion's cases of cancer.
Tumor angiogenesis is tumour growth, the key link of invasion.Research shows that APN/CD13 is a kind of cross-film
Protease, it is related to extracellular matrix degradation, cell migration, angiogenesis and tumor invasion, many tumour cells, pericyte and
Certain stages of fibroblast and smooth muscle cell can also express CD13.Therefore, CD13 receptor is cancer target Journal of Sex Research
One promising target.NGR is can be with the tripeptides of a ν type integrin specific bond, receptor by what phage selection went out
With the Aminopeptidase N (APN/CD13) for adjusting revascularization and tumour growth function.NGR polypeptide can be with new-born blood vessel-specific
In conjunction with and have stronger affinity.18F-NFP is a kind of multiduty auxiliary group, be commonly used to label small molecule amino acid and
Polypeptide etc. has the compound of exposed amino structure.If with18F-NFP is that radiochemistry marks intermediate, is carried out to NGR polypeptide
Label, then be expected to obtain a kind of polypeptide PET imaging agent of selectively targeted CD13 receptor.
Summary of the invention
The purpose of the present invention is to provide a kind of circular polypeptides class PET imaging agents and preparation method thereof for targeting CD13 receptor
And application.
The technical solution used in the present invention is:
A kind of circular polypeptides class PET imaging agent targeting CD13 receptor, structural formula are as follows:
The preparation method of the circular polypeptides class PET imaging agent of above-mentioned targeting CD13 receptor, comprising the following steps:
1) it is bombarded using cyclotron18The aquatic production of O18F, then will18F conducts in anion-exchange column, then uses leacheate
It will18F elution is into reaction flask and carries out azeotropic water removing, adds 2 bromopropionic acid ethyl ester and solvent, sufficiently reacts, obtains 2-18F- ethyl propionate；
2) to 2-18F- ethyl propionate carry out basic hydrolysis, remove reaction dissolvent after again by bis- (the 4- nitre of hydrolysate, carbonic acid
Base phenyl) ester and solvent mixing, it sufficiently reacts, then carries out half preparation HPLC and isolate and purify, obtain18F-NFP；
3) will18F-NFP, circular polypeptides NGR, n,N-diisopropylethylamine and solvent mixing, sufficiently react, after being diluted with water
By Sep-Par C-18 column, it is rinsed with water C-18 column, then with ethanol rinse C-18 column, collects leacheate, obtain targeting CD13
The circular polypeptides class PET imaging agent of receptor.
Step 1) the leacheate by 4,7,13,16,21,24- six oxygen -1,10- diaza-bicyclo [8.8.8] hexacosane,
K2CO3Or KHCO3, water and acetonitrile composition.
Step 1) the reaction carries out at 95~105 DEG C, and the reaction time is 5~15min.
Step 2) the basic hydrolysis carries out at 95~105 DEG C, and the reaction time is 5~15min.
Step 2) the reaction carries out at 95~105 DEG C, and the reaction time is 5~15min.
The structural formula of step 3) the circular polypeptides NGR are as follows:
Step 3) the reaction carries out at 40~50 DEG C, and the reaction time is 15~25min.
The beneficial effects of the present invention are: the present invention utilizes18F-NFP is carried out as radiochemistry label intermediate18F label,
Obtain the PET imaging agent of high-purity18F-cNGR, stability is good, water-soluble strong, and internal blood is removed fastly, in APN/CD13 sun
Property expression U87 model mice in intake it is obvious, tumor focus position reproduced image contrast is high, and tumour resolution capability is strong, is carrying out
There is good clinical application development prospect in terms of PET tumor imaging.
Detailed description of the invention
Fig. 1 is embodiment 118The radioactivity HPLC map of F-cNGR.
Fig. 2 is embodiment 118PET of the F-cNGR in the U87 model mice of APN/CD13 positive expression images figure.
Specific embodiment
A kind of circular polypeptides class PET imaging agent targeting CD13 receptor, structural formula are as follows:
The preparation method of the circular polypeptides class PET imaging agent of above-mentioned targeting CD13 receptor, comprising the following steps:
1) it is bombarded using cyclotron18The aquatic production of O18F, then will18F conducts in anion-exchange column, then uses leacheate
It will18F elution is into reaction flask and carries out azeotropic water removing, adds 2 bromopropionic acid ethyl ester and solvent, sufficiently reacts, obtains 2-18F- ethyl propionate；
2) to 2-18F- ethyl propionate carry out basic hydrolysis, remove reaction dissolvent after again by bis- (the 4- nitre of hydrolysate, carbonic acid
Base phenyl) ester and solvent mixing, it sufficiently reacts, then carries out half preparation HPLC and isolate and purify, obtain18F-NFP；
3) will18F-NFP, circular polypeptides NGR, n,N-diisopropylethylamine and solvent mixing, sufficiently react, after being diluted with water
By Sep-Par C-18 column, it is rinsed with water C-18 column, then with ethanol rinse C-18 column, collects leacheate, obtain targeting CD13
The circular polypeptides class PET imaging agent of receptor.
Preferably, the step 1) leacheate is by 4,7,13,16,21,24- six oxygen -1,10- diaza-bicyclos [8.8.8] two
Hexadecane, K2CO3Or KHCO3, water and acetonitrile composition.
Preferably, the step 1) reaction carries out at 95~105 DEG C, and the reaction time is 5~15min.
Preferably, the step 1) solvent is acetonitrile.
Preferably, the concrete operations of the step 2) basic hydrolysis are as follows: add potassium hydroxide solution or sodium hydroxide solution
Enter to 2-18Reaction is hydrolyzed in F- ethyl propionate reaction solution.
Preferably, the step 2) basic hydrolysis carries out at 95~105 DEG C, and the reaction time is 5~15min.
Preferably, the step 2) reaction carries out at 95~105 DEG C, and the reaction time is 5~15min.
Preferably, the step 2) solvent is acetonitrile.
Preferably, step 2) described half prepares the condition of HPLC separation are as follows: C-18 column, mobile phase: A phase: 0.1% trifluoro second
The aqueous solution of acid, B phase: the acetonitrile solution of 0.1% trifluoroacetic acid, time gradient are 0~5min, 40%B phase；5~30min,
40%~90%B phase；30~40min, 90%~40%B phase.
Preferably, the structural formula of step 3) the circular polypeptides NGR (cNGR) are as follows:
Preferably, the step 3) reaction carries out at 40~50 DEG C, and the reaction time is 15~25min.
Preferably, the step 3) solvent is one of dimethyl sulfoxide, n,N-dimethylacetamide.
The present invention will be further explained combined with specific embodiments below and explanation.
Embodiment 1:
A kind of preparation method for the circular polypeptides class PET imaging agent targeting CD13 receptor, comprising the following steps:
1) it is bombarded using medical cyclotron18O water, passes through18O(p n)18F nuclear reaction production18F, then will18F conduction in
In anion-exchange column, activity is measured and with 1mL leacheate (by the 4 of 12mg, 7,13,16,21,24- six oxygen -1,10- phenodiazines pair
The K of ring [8.8.8] hexacosane+3mg2CO3+ 0.15mL water+1.35mL acetonitrile composition) it will18F is eluted into reaction flask, then to
It is constantly blown into high-purity helium in reaction flask and is heated to 110 DEG C of progress azeotropic water removings, dries up, adds the 2 bromopropionic acid second of 5mg
Ester and 1mL acetonitrile, 100 DEG C of reaction 10min, obtain 2-18F- ethyl propionate；
2) in 2-18The potassium hydroxide solution of 0.5mL concentration 0.1mol/L, 100 DEG C of hydrolysis are added in F- ethyl propionate
10min, solvent evaporated after reaction, then hydrolysate and 1.5mL are dissolved with bis- (4- nitrobenzophenone) esters of 40mg carbonic acid
(NPC) anhydrous acetonitrile mixing, 100 DEG C of reaction 10min, the acetum for adding 1mL mass fraction 5% terminate instead
Answer, then carry out half preparation HPLC isolate and purify (separation condition: C-18 column, mobile phase: A phase: the aqueous solution of 0.1% trifluoroacetic acid,
B phase: the acetonitrile solution of 0.1% trifluoroacetic acid, time gradient are 0~5min, 40%B phase；5~30min, 40%~90%B
Phase；30~40min, 90%~40%B phase), it obtains18F-NFP；
3) will18F-NFP and the 150 anhydrous DMSO solutions of μ L (wherein include the circular polypeptides NGR and 30 μ L of 50 μ g
DIPEA) mix, 40 DEG C of reaction 15min, then plus the dilution of 10mL water after by Sep-Par C-18 column, with 10mL water flushing C-18
Column, then with 2mL ethanol rinse C-18 column, leacheate is collected, obtain the circular polypeptides class PET imaging agent of targeting CD13 receptor
(18F-cNGR)。18The radioactivity HPLC map of F-cNGR is as shown in Figure 1.
Through calculating, combined coefficient 15%, radiochemical purity > 95%.
18The synthetic route of F-cNGR is as follows:
Embodiment 2:
A kind of preparation method for the circular polypeptides class PET imaging agent targeting CD13 receptor, comprising the following steps:
1) it is bombarded using medical cyclotron18O water, passes through18O(p n)18F nuclear reaction production18F, then will18F conduction in
In anion-exchange column, activity is measured and with 1mL leacheate (by the 4 of 12mg, 7,13,16,21,24- six oxygen -1,10- phenodiazines pair
The K of ring [8.8.8] hexacosane+3mg2CO3+ 0.15mL water+1.35mL acetonitrile composition) it will18F is eluted into reaction flask, then to
It is constantly blown into high-purity helium in reaction flask and is heated to 110 DEG C of progress azeotropic water removings, dries up, adds the 2 bromopropionic acid second of 7mg
Ester and 1mL acetonitrile, 100 DEG C of reaction 15min, obtain 2-18F- ethyl propionate；
2) in 2-18The potassium hydroxide solution of 0.5mL concentration 0.1mol/L, 100 DEG C of hydrolysis are added in F- ethyl propionate
15min, solvent evaporated after reaction, then hydrolysate and 1.5mL are dissolved with bis- (4- nitrobenzophenone) esters of 40mg carbonic acid
(NPC) anhydrous acetonitrile mixing, 100 DEG C of reaction 15min, the acetum for adding 1mL mass fraction 5% terminate instead
Answer, then carry out half preparation HPLC isolate and purify (separation condition: C-18 column, mobile phase: A phase: the aqueous solution of 0.1% trifluoroacetic acid,
B phase: the acetonitrile solution of 0.1% trifluoroacetic acid, time gradient are 0~5min, 40%B phase；5~30min, 40%~90%B
Phase；30~40min, 90%~40%B phase), it obtains18F-NFP；
3) will18F-NFP and the 200 anhydrous DMSO solutions of μ L (wherein include the circular polypeptides NGR and 30 μ L of 50 μ g
DIPEA) mix, 50 DEG C of reaction 15min, then plus the dilution of 10mL water after by Sep-Par C-18 column, with 10mL water flushing C-18
Column, then with 2mL ethanol rinse C-18 column, leacheate is collected, obtain the circular polypeptides class PET imaging agent of targeting CD13 receptor
(18F-cNGR)。
Through calculating, combined coefficient 18%, radiochemical purity > 95%.
Embodiment 3:
A kind of preparation method for the circular polypeptides class PET imaging agent targeting CD13 receptor, comprising the following steps:
1) it is bombarded using medical cyclotron18O water, passes through18O(p n)18F nuclear reaction production18F, then will18F conduction in
In anion-exchange column, activity is measured and with 1mL leacheate (by the 4 of 12mg, 7,13,16,21,24- six oxygen -1,10- phenodiazines pair
The K of ring [8.8.8] hexacosane+3mg2CO3+ 0.15mL water+1.35mL acetonitrile composition) it will18F is eluted into reaction flask, then to
It is constantly blown into high-purity helium in reaction flask and is heated to 110 DEG C of progress azeotropic water removings, dries up, adds the 2 bromopropionic acid second of 7mg
Ester and 1mL acetonitrile, 105 DEG C of reaction 10min, obtain 2-18F- ethyl propionate；
2) in 2-18The potassium hydroxide solution of 0.5mL concentration 0.1mol/L, 105 DEG C of hydrolysis are added in F- ethyl propionate
10min, solvent evaporated after reaction, then hydrolysate and 1.5mL are dissolved with bis- (4- nitrobenzophenone) esters of 40mg carbonic acid
(NPC) anhydrous acetonitrile mixing, 105 DEG C of reaction 10min, the acetum for adding 1mL mass fraction 5% terminate instead
Answer, then carry out half preparation HPLC isolate and purify (separation condition: C-18 column, mobile phase: A phase: the aqueous solution of 0.1% trifluoroacetic acid,
B phase: the acetonitrile solution of 0.1% trifluoroacetic acid, time gradient are 0~5min, 40%B phase；5~30min, 40%~90%B
Phase；30~40min, 90%~40%B phase), it obtains18F-NFP；
3) will18F-NFP and the 200 anhydrous DMSO solutions of μ L (wherein include the circular polypeptides NGR and 30 μ L of 50 μ g
DIPEA) mix, 40 DEG C of reaction 20min, then plus the dilution of 10mL water after by Sep-Par C-18 column, with 10mL water flushing C-18
Column, then with 2mL ethanol rinse C-18 column, leacheate is collected, obtain the circular polypeptides class PET imaging agent of targeting CD13 receptor
(18F-cNGR)。
Through calculating, combined coefficient 17%, radiochemical purity > 95%.
Test case:
Mice with tumor18The Micro PET of F-cNGR images test:
Test method: first allowing the U87 model mice 4h fasting for solids and liquids of APN/CD13 positive expression, then by the aobvious of embodiment 1
As agent18F-cNGR is injected in Mice Body (volume injected 0.1mL, radioactive activity 0.15mCi) by tail vein, allows mouse
Repose 40min, and the chloral hydrate anesthesia agent then at intraperitoneal injection 0.1mL mass fraction 7% makes mouse deep anaesthesia, to18F-
After 60min is completed in cNGR injection, Micro PET imaging is carried out, PET imaging figure is as shown in Figure 2.
As shown in Figure 2:18F-cNGR is gathered in tumor locus, the intake of tumor locus be apparently higher than muscle, bone, lung,
The devices such as brain are dirty or organize.Show18F-cNGR targeting specific is absorbed in tumor locus, and tumor uptake good contrast can clearly divide
Distinguish lesions position,18There is F-cNGR preferable specificity to image application prospect.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. a kind of circular polypeptides class PET imaging agent for targeting CD13 receptor, it is characterised in that: its structural formula are as follows:
2. the preparation method of the circular polypeptides class PET imaging agent of targeting CD13 receptor described in claim 1, it is characterised in that:
The following steps are included:
1) it is bombarded using cyclotron18The aquatic production of O18F, then will18F conducts in anion-exchange column, then will with leacheate18F
Azeotropic water removing is eluted in reaction flask and carried out, 2 bromopropionic acid ethyl ester and solvent are added, sufficiently reacts, obtains 2-18F- propionic acid
Ethyl ester；
2) to 2-18F- ethyl propionate carry out basic hydrolysis, remove reaction dissolvent after again by bis- (the 4- nitrobenzenes of hydrolysate, carbonic acid
Base) ester and solvent mixing, it sufficiently reacts, then carries out half preparation HPLC and isolate and purify, obtain18F-NFP；
3) will18F-NFP, circular polypeptides NGR, n,N-diisopropylethylamine and solvent mixing, sufficiently react, pass through after being diluted with water
Sep-Par C-18 column, is rinsed with water C-18 column, then with ethanol rinse C-18 column, collects leacheate, obtain targeting CD13 receptor
Circular polypeptides class PET imaging agent.
3. preparation method according to claim 2, it is characterised in that: the step 1) leacheate by 4,7,13,16,21,
24- six oxygen -1,10- diaza-bicyclo [8.8.8] hexacosane, K2CO3Or KHCO3, water and acetonitrile composition.
4. preparation method according to claim 2 or 3, it is characterised in that: step 1) it is described reaction at 95~105 DEG C into
Row, reaction time are 5~15min.
5. preparation method according to claim 2, it is characterised in that: the step 2) basic hydrolysis is at 95~105 DEG C
It carries out, the reaction time is 5~15min.
6. preparation method according to claim 2 or 5, it is characterised in that: step 2) it is described reaction at 95~105 DEG C into
Row, reaction time are 5~15min.
7. preparation method according to claim 2, it is characterised in that: the structural formula of step 3) the circular polypeptides NGR are as follows:
8. the preparation method according to claim 2 or 7, it is characterised in that: step 3) it is described reaction at 40~50 DEG C into
Row, reaction time are 15~25min.
9. the circular polypeptides class PET imaging agent of targeting CD13 receptor described in claim 1 is preparing answering in PET imaging agent
With.
10. the circular polypeptides class PET imaging agent of targeting CD13 receptor described in claim 1 is in preparation CD13 receptor expression level
Application in detection agent.
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Cited By (1)
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| CN112079900A (en) * | 2020-09-21 | 2020-12-15 | 中国工程物理研究院核物理与化学研究所 | Cyclic NGR polypeptide, radionuclide labeled molecular probe and application thereof |
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| CN103948947A (en) * | 2013-05-08 | 2014-07-30 | 南京市第一医院 | Radionuclide molecular probe using CD13 as molecular target and NGR as ligand, and labeling technique and application thereof |
| CN107019807A (en) * | 2017-03-06 | 2017-08-08 | 南方医科大学南方医院 | The polypeptide radiodiagnosis or medicine of a kind of GPC3 receptor targets |
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| CN103948947A (en) * | 2013-05-08 | 2014-07-30 | 南京市第一医院 | Radionuclide molecular probe using CD13 as molecular target and NGR as ligand, and labeling technique and application thereof |
| CN107019807A (en) * | 2017-03-06 | 2017-08-08 | 南方医科大学南方医院 | The polypeptide radiodiagnosis or medicine of a kind of GPC3 receptor targets |
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| CN112079900A (en) * | 2020-09-21 | 2020-12-15 | 中国工程物理研究院核物理与化学研究所 | Cyclic NGR polypeptide, radionuclide labeled molecular probe and application thereof |
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