CN105963724B - A kind of radiolabeled tumor developer, preparation method and application - Google Patents
A kind of radiolabeled tumor developer, preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
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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
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
Contain the invention discloses a kind of radiolabeled tumor developer, preparation method and application, in structure and can be used for the alpha-amino acid derivatives structure of isotope labeling and the folate molecule of cancer target, radionuclide is18F, the alpha-amino acid derivatives structure are connected with folate molecule with specific chemical species.The purposes of PET imaging is used for the invention further relates to the preparation method of the compound and its in human or animal's body as Trace imaging agent, is especially used as tumor developer, has the advantages that prepare simple, cheap and targeting strong.
Description
Technical field
The invention belongs to Medical Imaging Technology fields, and in particular to a kind of18Tumor developer, the preparation method of F label
And application.
Background technique
A-amino acid is the structural unit of protein, plays vital work in neurotransmitter and the conversion of ATP energy
With.Nutriment necessary to a-amino acid is also tumour cell existence and is proliferated simultaneously, most tumours all can be to amino
Sour high intake, this will lead to the transfer of high-level tumour higher intake and tumour again.Amino acid is the signal point of tumor proliferation
Son also functions to the effect for reprograming metabolism network biomass accumulation relevant to tumour.
In addition, folacin receptor high expression in many tumor tissues, as oophoroma, kidney, uterine cancer, carcinoma of testis, the cancer of the brain,
Colon cancer, adenocarcinoma of lung etc..Folate molecule has very high selectivity to these tumours.
CN103827057A discloses a kind of quilt18The novel compound of F label and corresponding warp18The compound of F label
In itself, its their warp19The fluorinated analog of F and its they as reference standard purposes, prepare the side of such compound
Method, the composition comprising such compound, the kit comprising such compound or composition and such compound, composition
Or kit is used for the purposes of the diagnosing image by positron emission tomography Positron Emission Tomography imaging (PET).
CN101723850A discloses a kind of novel radioactive18F marks ArAA, disconnected for tumour positron emission
Layer (PET) imaging research, it is characterised in that: one end has F substituted alkoxy benzoyl structure；The other end has a-amino acid
Structure, substituent R 1 are located in alpha site of carboxyl group, and R1 is phenyl, benzyl, 3- indole methyl, and R2 is methoxyl group, n 1-5.R1 is benzene
Base, benzyl, 3- indole methyl, R2 are methoxyl group, n 1-5.
CN101723847A discloses one kind18F marks p-nitrophenyl benzoyl amino acid compound, it is characterized in that: together
When have 2-18F-4- nitrobenzene formyl and a-amino acid structure, and substituted base R is located in alpha site of carboxyl group, is hydrogen, methyl, second
Base, propyl, isopropyl, butyl, isobutyl group, benzyl, 2-methylmercaptoethyl, carboxyethyl, carboxylic propyl, phenyl, imidazolmethyl.Both ends
Structure is connected directly by amido bond.
CN102126985A is disclosed18F labelled precursor compound, further simultaneously discloses preparation method, successively include with
Lower step: the 1) synthesis of labelled precursor compound: by 3,4- dinitrobenzoic acid, amino alkynes, 1- (3- dimethylamino-propyl) -3-
Ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole are dissolved in dimethylformamide, are stirred to react；React resulting product
It is post-treated, obtain precursor compound；2) label of precursor compound.It is above-mentioned18F labelled precursor compound can use click
Method labeled amino acid, the polypeptide compounds of chemistry；Also it can be used as molecular image probe, be applied to PET and image.
Bioconjugate Chem., 2008,19,2462-2470 disclose it is a kind of with18The folacin compound of F label,
It is characterized in that: using18F-Then p-toluenesulfonyl anion on ion nucleophilic displacement of fluorine labelled precursor utilizes click
The method of chemistry marks folacin compound, and is applied to PET and is imaged.
However, in the above prior art, most small molecule Imaging probes often contain only a group with targeting,
The delay of target organ is generated for receptor or certain physical factors, but non-target organ may be because have similar receptor or have
The high intake same to probe of similar physical property, it is very high so as to cause target to non-target ratio value.
Summary of the invention
It is an object of the invention to overcome amino acid targeting not strong and folic acid is the high intake of kidney the problem of, simultaneously
The advantage that the intake of tumour height and folic acid for having both amino acid are absorbed in the targeting of tumour, provides a kind of folic acid and a-amino acid
Derivative coupling18F label tumor developer, preparation method and application, and by PET image be used for tumour or its
The diagnosis of his disease or curative effect evaluation.
The technical solution adopted by the present invention to solve the technical problems first is that:
It is a kind of18The tumor developer of F label, structural formula is as shown in following formula I:
The technical solution adopted by the present invention to solve the technical problems second is that:
It is a kind of above-mentioned18The preparation method of the tumor developer of F label, shown in the following reaction route of the preparation method:
Include:
1) in the first organic solvent, under purity titanium tetraethoxide catalysis, compound 1 and compound 2 according to molar ratio 1:1~
1.5 ratio, reaction is stayed overnight at room temperature；After addition saturated sodium chloride solution is quenched, diatomite filtering, filtrate takes organic phase,
Drying is washed, solvent is removed, crude product carries out silica gel with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio
Column chromatography purifying, obtains compound 3；
2) under inert gas shielding, in a second organic solvent, (1,3- dicyclohexyl -2- subunit) tertiary fourth oxygen copper (I) is urged
Under change, compound 3 and compound 4 react 20~48h according to the ratio of molar ratio 1:1.5~2.5 at -5~5 DEG C；It removes molten
Agent, crude product carry out silica gel chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio, obtain
Compound 5；
3) under inert gas shielding, in third organic solvent, under hydrogen chloride effect, the first of the equivalent of compound 5 and 5~15
Alcohol reacts 0.5~3h at room temperature, generates compound 6；
4) in the 4th organic solvent, under hydrogen chloride effect, compound 6 and KHF215~25h is reacted at room temperature, is removed
Solvent, crude product carry out silica gel chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio, obtain
To compound 7-1；
5) in the mixed solution for the pyridazine-hydrochloride buffer and DMF for being 1~3 in pH value, 5~20mCi's18F and compound
7-1 reacts 5~20min at 50~100 DEG C, generates compound 7-2, as compound shown in formula II；
6) in water, under the catalysis of copper sulphate and sodium ascorbate, compound 7-2 and compound 8 are reacted at 50~100 DEG C
5~20min generates compound 9, as shown in formula I18The tumor developer of F label.
In one embodiment: the step 5) includes:
A) will18F is eluted from anion trapping column with potassium carbonate, Kryptofix 2.2.2 mixed solution；
B) compound 7-1 is dissolved in N,N-dimethylformamide that volume ratio is 1:0.8~1.2 and pH value is 1~3 to rattle away
In piperazine-hydrochloride buffer；
C) step a) is mixed with the product of step b), 5~30min is reacted at 50~100 DEG C, it is cooling, then plus go in right amount
After ionized water dilution, with the mixed liquor of volume ratio 1:1.5~2.5 of boric acid and the PBS- ethanol solution of volume ratio 1:0.5~1.5
C18 column purification is carried out as eluent, obtains compound 7-2.
In one embodiment: first organic solvent, the second organic solvent, third organic solvent, the 4th organic solvent are
Tetrahydrofuran, toluene, Isosorbide-5-Nitrae-dioxane, one of n,N-Dimethylformamide, and can be identical or different.
In one embodiment: in the step 3), hydrogen chloride is Isosorbide-5-Nitrae-dioxane solution of the hydrogen chloride of concentration 4M.
In one embodiment: in the step 4), hydrogen cloride concentration 4M.
The technical solution adopted by the present invention to solve the technical problems third is that:
It is above-mentioned18Application of the tumor developer of F label in preparation tumour or inflammatory related disease imaging agent.
The technical solution adopted by the present invention to solve the technical problems fourth is that:
One kind can be used for preparing above-mentioned18The compound of the tumor developer of F label, structural formula is as shown in following formula II:
The technical solution adopted by the present invention to solve the technical problems fifth is that:
A kind of preparation method of compound shown in above-mentioned formula II, comprising:
A) will18F is eluted from anion trapping column with potassium carbonate, Kriptofix 2.2.2 mixed solution；
B) compound 7-1 is dissolved in N,N-dimethylformamide and pH value is in 1~3 pyridazine-hydrochloride buffer；
C) step a) is mixed with the product of step b), 5~30min is reacted at 50~100 DEG C, it is cooling, then plus go in right amount
After ionized water dilution, with the mixed liquor of volume ratio 1:1.5~2.5 of boric acid and the PBS- ethanol solution of volume ratio 1:0.5~1.5
C18 column purification is carried out as eluent, obtains compound 7-2.
Signified inert gas of the invention, such as nitrogen etc. avoid producing reaction for completely cutting off the air in experimental situation
It is raw to influence；The reaction carried out under inert gas shielding can carry out in glove box.
The technical program compared with the background art, it has the following advantages:
1. the present invention overcomes amino acid targeting in the prior art is not strong and folic acid is the high intake of kidney the problem of,
It is prepared by the way that folic acid to be coupled with alpha-amino acid derivatives18The tumor developer of F label, effectively increases marker
Polarity and water solubility are conducive to improve folate-targeted and increase tumor uptake, so that the tumor developer has both amino acid
The advantage that the intake of tumour height and folic acid are absorbed in the targeting of tumour, and the two does not interfere with each other, targeting is strong, Neng Gouxian
It lands and improves target to non-target ratio value, be verified by experiments, can get 5 or more target to non-target ratio value, and tumor/muscle ratio in mouse
Up to 9.20, biological assessment effect is good, is conducive to clinical expansion.
2. in preparation method of the invention, being coupled, being made by reacting amino acid derivativges using click with folic acid
It must react efficiently, purifying is simple, is conducive to large-scale production.
3. in preparation method of the invention, isotope labeling method used has marked capacity strong, the label time is short, label
Yield is high, the simple feature of step, and without anhydrous label and HPLC purifying.
Detailed description of the invention
Fig. 1 is of the invention18The tumor developer of F label is in the intracorporal PET imaging (2h after administration) of lotus KB tumor mouse.
Fig. 2 is of the invention18In the intracorporal PET imaging of lotus KB tumor mouse, (folic acid inhibits control to the tumor developer of F label
Group, 2h after administration).
Specific embodiment
The contents of the present invention are illustrated below by embodiment:
Embodiment 1: labelled precursor, that is, compound 7-1 and compound 7-2 synthesis
1) it in 10ml tetrahydrofuran, is added compound 1 (0.99g, 0.01mol), compound 2 (1.45g,
0.012mol), purity titanium tetraethoxide (4.56g, 0.02mol) is added, is stirred to react at room temperature overnight；It is dilute that 10ml ethyl acetate is added
It after releasing, adding 10ml saturated sodium chloride solution and is quenched, stir 5min, diatomite is filtered to remove insoluble matter, and filtrate takes organic phase,
It is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, removes solvent, the dichloromethane of crude product 10~20:1 of volume ratio
Alkane-ethyl acetate mixtures elution carries out silica gel chromatography, obtains compound 3,1.63g；
2) in glove box, compound 3 (0.2g, 1mmol) is added in 2ml toluene；Separately by compound 4 (0.51g,
It 2mmol) is dissolved in 2mL toluene, is added into the solution containing compound 3；Again by (1,3- dicyclohexyl -2- subunit) tertiary fourth oxygen
Copper (I) (36.6mg, 0.1mmol) is dissolved in 2mL toluene, is added into the solution containing compound 3 and compound 4；At 0 DEG C
After reacting 48h, the dilution of 10ml ethyl acetate is added, removes solvent, methylene chloride-acetic acid of crude product 10~20:1 of volume ratio
The elution of ethyl ester mixed liquor carries out silica gel chromatography, obtains compound 5,0.11g；
3) under nitrogen protection, in Isosorbide-5-Nitrae-dioxane solution of 0.25ml 4M hydrogen chloride, be added compound 5 (0.33g,
1mmol), methanol 0.41ml is stirred to react 1h at room temperature, removes solvent, is washed with the n-hexane of volume ratio 2:1-ether mixed liquor
Solid is washed, compound 6,0.22g is obtained；
4) be added 80 μ L n,N-Dimethylformamide in the Eppendorf pipe of 1.5mL, be added compound 6 (65mg,
8.48 μm of ol), the KHF of 3M240 μ L, 4M hydrochloride aqueous solution of aqueous solution, 20 μ L, 20 μ L water, vortex concussion mix, at room temperature
Placing response 20h, is removed in vacuum solvent, and crude product is eluted with the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio
Silica gel chromatography is carried out, compound 7-1,3.5mg are obtained.
Embodiment 2:18The preparation of tumor developer, that is, compound 9 of F label
(1) prepare compound 7-2
A) will18F is from anion trapping column QMA with potassium carbonate, Kriptofix 2.2.2 (K2.2.2) (mass ratio 5:1)
Mixed solution elutes, and obtains the K of 5~20mCi18F aqueous solution；
B) the 7.5 μ L of pyridazine-hydrochloride buffer that pH is 2.5, n,N-Dimethylformamide are added in 1.5mL centrifuge tube
7.5 μ L, the compound 7-1,1mg prepared in embodiment 1；
C) K for obtaining step a)18F aqueous solution (5~20mCi, 10 μ L) is added into the solution of step b), is heated to 60
10min is reacted at DEG C, it is cooling, then plus the dilution of 2ml deionized water after, carry out C18Sep-Pak cartridge column chromatography, first with
2ml deionized water drenches decontamination, then uses the mixed liquor of 0.5ml boric acid and the PBS- ethanol solution of 1ml volume ratio 1:1 as elution
Agent elutes lower product, obtains compound 7-2；It is analyzed using HPLC, Radiochemical yield 60%, radiochemical purity is
98%；
(2) it in the above-mentioned solution containing 7-2, is added compound 8 (1g), sodium ascorbate 0.1mg, anhydrous cupric sulfate
0.1mg is heated to 80 DEG C of reaction 15min, then by reactant by preparative HPLC, mobile phase is acetonitrile/water, isolatedization
Object 9 is closed, as shown in formula I18The tumor developer of F label.
Embodiment 3:18The bio distribution of the tumor developer (compound 9) of F label
The nude mice for selecting 18~20g, in nude mice forelimb oxter, injection about cell quantity is 5 × 106KB cell liquid modeling.
Feeding is carried out in the food that the last week of experiment should use weary folic acid instead.Every mouse is prepared by tail vein injection embodiment 218Tumor developer, that is, compound 9 of F label, injection dosage is 10 μ Ci/100 μ L (physiological saline), upon administration at 1h and 2h
Extremely, the main organs such as blood and the heart, liver, lung, kidney are taken, weighs and counts.Inhibit injecting in control group in folic acid18F label swells
10min injects 100 μ g folic acid and is inhibited before tumor imaging agent, and puts to death mouse after 2h is administered, and equally takes main organs
Weighing counts.As a result see Table 1 for details and 2.
It can be seen in table 1 that intake of the compound 9 in the highly expressed mouse tumor of folacin receptor and kidney is all higher, body
Good folacin receptor affinity is showed.And apparent retention of activity is all not observed in other non-target organs, energy
Enough obtain higher target to non-target ratio value (tumor/muscle ratio up to 9.20) (table 2).Inhibit by the excessive unmarked folic acid of injection
Afterwards, tumour and kidney intake are all substantially reduced and (reduce 82.5% and 68.2% respectively), it was demonstrated that the intake of the compound and folic acid
Receptor-specific is highly relevant.
Table 118F marked tumor imaging agent, that is, compound 9 the intracorporal bio distribution result of lotus KB tumor nude mice (%ID/g,
Mean ± SD, n=5)
Table 218F marked tumor imaging agent, that is, compound 9 is in the intracorporal target of lotus KB tumor nude mice/non-target ratio
Embodiment 4:18The PET imaging of the tumor developer (compound 9) of F label
Tumor inoculation method is with embodiment 3, when tumour grows to 0.5~1cm of diameter, can carry out imaging experiment.It is all
Imaging mouse the experiment weary folic acid food of the last week feeding to avoid the tetrahydrofolate components contained in food caused by experimental result
It influences.Every mouse is prepared by tail vein injection embodiment 218Tumor developer, that is, compound 9 of F label, injection dosage
For 100 μ Ci/100 μ L (physiological saline).2h after injecting radioactively labelled substance is imaged.
From figure 1 it appears that intake of the compound 9 in tumour and kidney is all higher, embody good folic acid by
Body affinity.And apparent retention of activity is all not observed in other non-target organs, can obtain higher target with
The clear image of non-target ratio.After inhibiting, tumour and kidney intake are all substantially reduced (Fig. 2), it was demonstrated that the compound is taken the photograph
It takes highly relevant with folacin receptor specificity.As a result it is detailed in attached Fig. 1 and 2.
Above data shows that use is prepared by the present invention18F marked tumor imaging agent has mark rate height, synthesizing efficient etc.
Advantage.In the application, target to non-target ratio value is high, and biological assessment effect is good, is conducive to clinical expansion.
The above is only the preferred embodiment of the present invention, the range implemented of the present invention that therefore, it cannot be limited according to, i.e., according to
Equivalent changes and modifications made by the invention patent range and description, should still be within the scope of the present invention.
Claims (9)
1. a kind of18The tumor developer of F label, it is characterised in that: its structural formula is as shown in following formula I:
2. one kind can be used for preparing shown in claim 118The compound of the tumor developer of F label, it is characterised in that: it is tied
Structure formula is as shown in following formula II:
3. a kind of described in claim 118The preparation method of the tumor developer of F label, it is characterised in that: the preparation method is such as
Shown in lower reaction route:
Include:
1) in the first organic solvent, under purity titanium tetraethoxide catalysis, compound 1 and compound 2 are according to molar ratio 1:1~1.5
Ratio, reaction is stayed overnight at room temperature；After addition saturated sodium chloride solution is quenched, diatomite filtering, filtrate takes organic phase, and washing is dry
It is dry, solvent is removed, crude product carries out silica gel column chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio
Purifying, obtains compound 3；
2) under inert gas shielding, in a second organic solvent, under (1,3- dicyclohexyl -2- subunit) tertiary fourth oxygen copper (I) catalysis,
Compound 3 and compound 4 react 20~48h according to the ratio of molar ratio 1:1.5~2.5 at -5~5 DEG C；Solvent is removed, slightly
Product carries out silica gel chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio, obtains chemical combination
Object 5；
3) under inert gas shielding, in third organic solvent, under hydrogen chloride effect, the methanol of the equivalent of compound 5 and 5~15 exists
0.5~3h is reacted at room temperature, generates compound 6；
4) in the 4th organic solvent, under hydrogen chloride effect, compound 6 and KHF215~25h is reacted at room temperature, removes solvent,
Crude product carries out silica gel chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1, obtains compound 7-
1；
5) in the mixed solution for the pyridazine-hydrochloride buffer and DMF for being 1~3 in pH value, 5~20mCi's18F and compound 7-1
5~20min is reacted at 50~100 DEG C, generates compound 7-2, as compound shown in formula II；
6) in water, under the catalysis of copper sulphate and sodium ascorbate, compound 7-2 and compound 8 react 5 at 50~100 DEG C~
20min generates compound 9, as shown in formula I18The tumor developer of F label.
4. according to claim 318The preparation method of the tumor developer of F label, it is characterised in that: the step 5) packet
It includes:
A) will18F is eluted from anion trapping column with potassium carbonate, Kriptofix 2.2.2 mixed solution；
B) compound 7-1 is dissolved in N,N-dimethylformamide that volume ratio is 1:0.8~1.2 and pH value is 1~3 pyridazine-salt
In acid buffer；
C) step a) is mixed with the product of step b), 5~30min is reacted at 50~100 DEG C, it is cooling, then plus deionization in right amount
Water dilution after, use the mixed liquor of volume ratio 1:1.5~2.5 of the PBS- ethanol solution of boric acid and volume ratio 1:0.5~1.5 as
Eluent carries out C18 column purification, obtains compound 7-2.
5. according to claim 318The preparation method of the tumor developer of F label, it is characterised in that: described first is organic
Solvent, the second organic solvent, third organic solvent, the 4th organic solvent are tetrahydrofuran, toluene, Isosorbide-5-Nitrae-dioxane, N, N-
One of dimethylformamide, and can be identical or different.
6. according to claim 318The preparation method of the tumor developer of F label, it is characterised in that: the step 3)
In, hydrogen chloride is Isosorbide-5-Nitrae-dioxane solution of the hydrogen chloride of concentration 4M.
7. according to claim 318The preparation method of the tumor developer of F label, it is characterised in that: the step 4)
In, hydrogen cloride concentration 4M.
8. a kind of preparation method of compound as claimed in claim 2, it is characterised in that: include:
A) will18F is eluted from anion trapping column with potassium carbonate, Kriptofix 2.2.2 mixed solution；
B) compound 7-1 is dissolved in N,N-dimethylformamide and pH value is in 1~3 pyridazine-hydrochloride buffer；
C) step a) is mixed with the product of step b), 5~30min is reacted at 50~100 DEG C, it is cooling, then plus deionization in right amount
Water dilution after, use the mixed liquor of volume ratio 1:1.5~2.5 of the PBS- ethanol solution of boric acid and volume ratio 1:0.5~1.5 as
Eluent carry out C18 column purification to get.
9. according to claim 118The tumor developer of F label is in preparation tumour or inflammatory related disease imaging agent
Application.
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