CN109369433A - A kind of 5-ALA derivative, synthetic method and the application of F-18 label - Google Patents

A kind of 5-ALA derivative, synthetic method and the application of F-18 label Download PDF

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CN109369433A
CN109369433A CN201811264446.XA CN201811264446A CN109369433A CN 109369433 A CN109369433 A CN 109369433A CN 201811264446 A CN201811264446 A CN 201811264446A CN 109369433 A CN109369433 A CN 109369433A
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庄晓青
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Abstract

This application discloses 5-ALA derivative, synthetic method and the applications of a kind of F-18 label.It is long that the application implements the radioactive probe radioactive half-life provided, stability and fat-soluble is all substantially higher in 5-ALA.Compared with 5-ALA, the 5-ALA derivative of F-18 label can form higher concentration in pathological tissues, and concentration is lower in normal tissue, and toxicity is also smaller.And because its is fat-soluble more preferable, the ability for penetrating blood-brain barrier is stronger, can accurately be positioned to general tumour tissue, become broad spectrum type tumor developer.

Description

A kind of 5-ALA derivative, synthetic method and the application of F-18 label
Technical field
This application involves organic compound synthesis technical field, in particular to a kind of 5-ALA of F-18 label Derivative, synthetic method and application.
Background technique
Before 5-ALA (5-aminolevulinic acid, 5-ALA) is the endogenous of human body heme catabolism Body substance is synthesized under the catalysis of 5-ALA synzyme in mitochondria by glycine and amber acyl coenzyme (Succinyl CoA). Itself without light sensitivity, but it be metabolized in vivo after can generate the protoporphysin Ⅸ with near-infrared fluorescent and light sensitivity (protoporphyrin Ⅸ, Pp Ⅸ).The forming process of protoporphysin Ⅸ is very slow in normal cell, and in ferrochelatase (Ferrochelatase) under the action of and Fe2+Ion, which is formed, does not have photoactive ferroheme.But in malignant cell The combined coefficient of protoporphysin Ⅸ is high and largely gathers, and issues near-infrared fluorescent (Near Infrared, NIR).Also, Pp Ⅸ It is a kind of very effective photosensitizer, photochemical reaction occurs under the irradiation of certain wavelength light in it, generates creating singlet oxygen and oxygen Compound, causes the damage of cell membrane, mitochondria and nucleic acid, to make cancer cell necrosis, apoptosis, plays the role for the treatment of [4]. Therefore 5-ALA is widely used in the diagnosis of various malignant tumours, treats the photodynamic therapy and light power diagnosis of tumour In the tumor resection of guiding.
In view of advantage of the 5-ALA in terms of tumor imaging: 1) small molecule compound；2) before photosensitizer protoporphyrin Pp Ⅸ Body；3) otherness of height is metabolized in tumour and normal tissue, if one can be constructed by radioisotope labeling With very highly sensitive near-infrared fluorescent-radionuclide image double mode probe, the whole body of targeting is carried out to tumour Imaging.
Many radionuclides have ideal physics, chemical property, but due to the molecule very little of 5-ALA, because This can only be with will not be marked the positron radionuclide that its molecular structure affects greatly.Suzuki et al. first reported It is carried out on 5 with the precursor that schiff bases activates11C methylation reaction, obtains11The radioactive probe of C flag11C-MALA.Then Their preliminary assessments11C-MALA is absorbed in kinds of tumor cells and tumor model, and is drawn a conclusion,11The intake of C-MALA It is highly relevant with the aggregation of Pp Ⅸ.Meanwhile from their data it can also be seen that, after injection in 1 minute to 60 minutes,11C- The tumour of MALA intake is increasing always than the ratio of muscle, and probably there is no reach most within the time period for this numerical value High point.But the nucleic for there was only 20 minutes for half-life period11For C, it has been the limit that 1 hour after injection, which is detected,. Pippin etc. passes through use13N is marked, and the structure for not changing 5-ALA completely synthesizes13N-5-ALA, reaction speed is fast and imitates Rate is high, and can observe the aggregation in tumour in Murine tumor model with PET.But it can be seen that from their data In Glioma Model in situ, the intake of intake and normal cerebral tissue in tumour brain tissue only has in the when ratio of 10 minute-peaks 1.3 or so, this is very big the reason is that the half-life period because of 13N only has 9.96 minutes, and the biological half-life of 5-ALA in vivo is about 1 hour, therefore it is extremely difficult to ideal effect.For radioactive probe ideal for one, its radioactive half-life is answered This is greater than the biological metabolism half-life period of the molecule in vivo, can just make have enough time to carry out body in the molecule of non-target organ in this way Interior transport, metabolism and external discharge, obtain high target/background ratio.
Summary of the invention
It the 5-ALA derivative for being designed to provide a kind of F-18 label of the application, synthetic method and answers With to solve the problems, such as radioactive probe half-life short in the prior art.
In a first aspect, according to an embodiment of the present application, a kind of 5-ALA derivative of F-18 label is provided, Including 18F-ALA, chemical structure are as follows:
Wherein, n=1-6.
Second aspect provides a kind of 5-ALA derivative of F-18 label according to an embodiment of the present application, Including 18F-O-ALA, chemical structure are as follows:
Wherein, n=2-4.
The third aspect provides a kind of 5-ALA derivative of F-18 label according to an embodiment of the present application Synthetic method, comprising:
5-ALA is soluble in water, pH value is adjusted to 8.5, and the two dimethyl dicarbonate fourths for being dissolved in dioxane are added dropwise Ester is stirred at room temperature 18h, extra di-tert-butyl dicarbonate is removed after reaction, aqueous solution is adjusted to acidity, is extracted with ethyl acetate Obtain 5-N- t-butoxycarbonyl amino levulic acid；
By the 5-N- t-butoxycarbonyl amino levulic acid, dimethylamino naphthyridine and glycol stir under ice bath, are added Carbodiimide, ice bath stirring 2h, room temperature continue to stir 48h, and solvent is spin-dried for after reaction, water is added, is extracted with ethyl acetate, Organic phase is cleaned with 10% NaHCO3 solution after collected organic layer, finally carries out post separation, obtains pale yellow powder shape HBA, the glycol include diethanol, two butanol or two hexanols；
The HBA is added in dry pyridine, paratoluensulfonyl chloride is added portionwise under ice bath, is then gradually restored to room Temperature is stirred overnight, and post separation after solution concentration, obtains precursor THBA after reaction；
Accelerator outflow comes18F-Ion is captured by QMA column, is then eluted to reaction tube with amino-polyether/potassium carbonate, is added Acetonitrile removes dry solvent repeatedly, is added in reaction tube the precursor THBA and is dissolved in dry acetonitrile, is heated at reflux and is reacted, instead Should after be added HCl solution heating deprotection group, after being diluted with water use solid-phase extraction column preliminary purification, finally use efficient liquid phase Chromatography carries out post separation, obtains18F-ALA。
Fourth aspect provides a kind of 5-ALA derivative of F-18 label according to an embodiment of the present application Synthetic method, including；
5-ALA is soluble in water, pH value is adjusted to 8.5, and the two dimethyl dicarbonate fourths for being dissolved in dioxane are added dropwise Ester is stirred at room temperature 18h, extra di-tert-butyl dicarbonate is removed after reaction, aqueous solution is adjusted to acidity, is extracted with ethyl acetate Obtain 5-N- t-butoxycarbonyl amino levulic acid；
By the 5-N- t-butoxycarbonyl amino levulic acid, dimethylamino naphthyridine, and, diethylene glycol, triethylene glycol It is stirred under ice bath with one of tetraethylene glycol, carbodiimide, ice bath stirring 2h is added, room temperature continues to stir 48h, after reaction Be spin-dried for solvent, water be added, is extracted with ethyl acetate, after collected organic layer with 10% NaHCO3Solution cleans organic phase, Post separation is finally carried out, the HEBA of pale yellow powder shape is obtained；
The HEBA is added in dry pyridine, paratoluensulfonyl chloride is added portionwise under ice bath, is then gradually restored to Room temperature is stirred overnight, and post separation after solution concentration, obtains precursor TEBA after reaction；
Accelerator outflow comes18F-Ion is captured by QMA column, is then eluted to reaction tube with amino-polyether/potassium carbonate, is added Acetonitrile removes dry solvent repeatedly, is added in reaction tube the precursor TEBA and is dissolved in dry acetonitrile, is heated at reflux and is reacted, instead Should after be added HCl solution heating deprotection group, after being diluted with water use solid-phase extraction column preliminary purification, finally use efficient liquid phase Chromatography carries out post separation, obtains18F-O-ALA。
5th aspect provides the 5-ALA derivative application of F-18 label according to an embodiment of the present application, For detecting tumour.
6th aspect provides the 5-ALA derivative application of F-18 label according to an embodiment of the present application, For detecting tumour.
From the above technical scheme, the 5-ALA that the embodiment of the present application provides a kind of F-18 label derives Object, synthetic method and application.It is long that the application implements the radioactive probe radioactive half-life provided, stability and fat-soluble all bright It is powerful and influential to be higher than 5-ALA.Compared with ALA, the 5-ALA derivative of F-18 label can be formed more in pathological tissues High concentration, and concentration is lower in normal tissue, toxicity is also smaller.And because of the fat-soluble more preferable of its, penetration rate of blood brain screen The ability of barrier is stronger, can accurately be positioned to general tumour tissue, become broad spectrum type tumor developer.
Specific embodiment
According to an embodiment of the present application, a kind of 5-ALA derivative of F-18 label is provided, including18F- ALA, chemical structure are as follows:
Wherein, n=1-6.
As n=1,18The chemical structure of F-ALA-1 are as follows:
18The compound identification data of F-ALA-1:
Mass spectrum (ES+) m/z:177.08
Hydrogen spectrum1H NMR(CDCl3):δ1.52(t,2H),δ2.74(t,2H),δ2.84(t,2H),δ3.81(t,2H),δ 4.28(t,2H),δ4.37(t,2H)。
As n=2,18The chemical structure of F-ALA-2 are as follows:
18The compound identification data of F-ALA-2:
Mass spectrum (ES+) m/z:205.11
Hydrogen spectrum1H NMR(CDCl3):δ1.49(m,2H),δ1.53(t,2H),δ1.62(m,2H),δ2.74(t,2H),δ 2.84(t,2H),δ3.81(t,2H),δ4.09(t,2H),δ4.13(t,2H)。
As n=3,18The chemical structure of F-ALA-3 are as follows:
18The compound identification data of F-ALA-3:
Mass spectrum (ES+) m/z:233.14
Hydrogen spectrum1H NMR(CDCl3): δ 1.43 (m, 2H), δ 1.49 (m, 2H), δ 1.53 (t, 2H), δ 1.62 (m, 2H), δ 2.74 (t, 2H), δ 2.84 (t, 2H), δ 3.84 (t, 2H), δ 4.13 (t, 2H).
As n=4,18The chemical structure of F-ALA-4 are as follows:
18The compound identification data of F-ALA-4:
Mass spectrum (ES+) m/z:261.17
Hydrogen spectrum1H NMR(CDCl3):δ1.29(m,6H),δ1.43(m,2H),δ1.49(m,2H),δ1.53(t,2H),δ 1.62(m,2H),δ2.74(t,2H),δ2.84(t,2H),δ3.81(t,2H),δ4.09(t,2H),δ4.13(t,2H)。
As n=5,18The chemical structure of F-ALA-5 are as follows:
18The compound identification data of F-ALA-5:
Mass spectrum (ES+) m/z:289.21
Hydrogen spectrum1H NMR(CDCl3):δ1.29(m,10H),δ1.43(m,2H),δ1.49(m,2H),δ1.53(t,2H),δ 1.62(m,2H),δ2.74(t,2H),δ2.84(t,2H),δ3.81(t,2H),δ4.09(t,2H),δ4.13(t,2H)。
As n=6,18The chemical structure of F-ALA-6 are as follows:
18The compound identification data of F-ALA-6:
Mass spectrum (ES+) m/z:317.24
Hydrogen spectrum1H NMR(CDCl3):δ1.26(m,4H),δ1.29(m,10H),δ1.43(m,2H),δ1.49(m,2H),δ 1.53(t,2H),δ1.62(m,2H),δ2.74(t,2H),δ2.84(t,2H),δ3.81(t,2H),δ4.09(t,2H),δ4.13 (t,2H)。
According to an embodiment of the present application, a kind of 5-ALA derivative of F-18 label is provided, including18F-O- ALA, chemical structure are as follows:
Wherein, n=2-4.
As n=2,18The chemical structure of F-O-ALA-2 are as follows:
18The compound identification data of F-O-ALA-2:
Mass spectrum (ES+) m/z:220.11
Hydrogen spectrum1H NMR(CDCl3):δ1.53(t,2H),δ2.74(t,2H),δ2.84(t,2H),δ3.57(t,2H),δ 3.65(t,2H),δ3.81(t,2H),δ4.20(t,2H),δ4.26(t,2H)。
As n=3,18The chemical structure of F-O-ALA-3 are as follows:
18The compound identification data of F-O-ALA-3:
Mass spectrum (ES+) m/z:264.14
Hydrogen spectrum1H NMR(CDCl3):δ1.53(t,2H),δ2.74(t,2H),δ2.84(t,2H),δ3.54(m,4H),δ 3.57(t,2H),δ3.65(t,2H),δ3.81(t,2H),δ4.20(t,2H),δ4.26(t,2H)。
As n=4,18The chemical structure of F-O-ALA-4 are as follows:
18The compound identification data of F-O-ALA-4:
Mass spectrum (ES+) m/z:308.16
Hydrogen spectrum1H NMR(CDCl3):δ1.53(t,2H),δ2.74(t,2H),δ2.84(t,2H),δ3.54(m,8H),δ 3.57(t,2H),δ3.65(t,2H),δ3.81(t,2H),δ4.20(t,2H),δ4.26(t,2H)。
According to an embodiment of the present application, a kind of 5-ALA derivative synthesizing process of F-18 label is provided, Include:
5-ALA is soluble in water, pH value is adjusted to 8.5, and the two dimethyl dicarbonate fourths for being dissolved in dioxane are added dropwise Ester is stirred at room temperature 18h, extra di-tert-butyl dicarbonate is removed after reaction, aqueous solution is adjusted to acidity, is extracted with ethyl acetate Obtain 5-N- t-butoxycarbonyl amino levulic acid；
By the 5-N- t-butoxycarbonyl amino levulic acid, dimethylamino naphthyridine and glycol stir under ice bath, are added Carbodiimide, ice bath stirring 2h, room temperature continue to stir 48h, and solvent is spin-dried for after reaction, water is added, is extracted with ethyl acetate, After collected organic layer with 10% NaHCO3Solution cleans organic phase, finally carries out post separation, obtains the HBA of pale yellow powder shape (6-hydroxyhexyl 5- ((tert-butoxycarbonyl) amino) -4-oxopentanoate), the glycol includes Diethanol, two butanol or two hexanols；
The HBA is added in dry pyridine, paratoluensulfonyl chloride is added portionwise under ice bath, is then gradually restored to room Temperature is stirred overnight, and post separation after solution concentration, obtains precursor THBA (6- (tosyloxy) hexyl5- ((tert- after reaction butoxycarbonyl)amino)-4-oxopentanoate)；
Accelerator outflow comes18F-Ion is captured by QMA column, is then eluted to reaction tube with amino-polyether/potassium carbonate, is added Acetonitrile removes dry solvent repeatedly, is added in reaction tube the precursor THBA and is dissolved in dry acetonitrile, is heated at reflux and is reacted, instead Should after be added HCl solution heating deprotection group, after being diluted with water use solid-phase extraction column preliminary purification, finally use efficient liquid phase Chromatography carries out post separation, obtains18F-ALA。
18F-ALA synthetic route is as follows.
With18For F-ALA-3, synthetic method is as follows:
1. the synthesis of precursor compound THBA.
The conjunction of A.Boc-5-ALA (5- ((tert-butoxycarbonyl) amino) -4-oxopentanoic acid) At.
5-ALA is dissolved in 5mL water, and adjusts pH value to 8.5 with the NaOH of 1N, is then added dropwise and is dissolved in 5mL dioxy six The di-tert-butyl dicarbonate ((Boc) of ring2O) (the 1-2 times of mole relative to 5-ALA), stirs 18h at room temperature.It is more after reaction Remaining (Boc)2O is extracted with ether and is removed, and aqueous solution is adjusted to acidity with the HCl solution of 1N, is then extracted with ethyl acetate to obtain Boc-5-ALA, vacuum distillation obtain colorless oil after being spin-dried for.
The synthesis of B.HBA.
Boc-5-ALA, dimethylamino naphthyridine (DMAP) and 1, bis- hexanol of 6- is according to the molar ratio of 1:1:1 under ice bath Stirring is added and Boc-5-ALA is with the carbodiimide of mole, and 2h is then stirred under ice bath, continues to stir later at room temperature 48h.Be spin-dried for solvent after reaction, water be added, is then extracted with ethyl acetate, after collected organic layer with 10% NaHCO3It is molten Liquid cleans organic phase.Finally carry out post separation (MeOH:CH2Cl2=40:1) obtain pale yellow powder shape HBA.
C. the synthesis of precursor THBA.
HBA is added in dry 5mL pyridine, the paratoluensulfonyl chloride of 2-3 times of mole is added portionwise under ice bath (TsCl), it is then gradually restored to room temperature, is stirred overnight.Post separation after solution concentration after reaction.
2. radioactive probe18The labelled synthesis of F-ALA-3.
Accelerator outflow comes18F-Ion is captured by QMA column, then uses K222/K2CO3It is eluted to reaction tube, adds acetonitrile anti- Dry solvent is removed again.Then the HBA for being added in reaction tube 5-20mg is dissolved in the dry acetonitrile of 1mL, is heated at reflux and is reacted.Instead Should after be added 2M HCl solution heating deprotection group, after being then diluted with water use solid-phase extraction column preliminary purification, finally use HPLC carries out post separation, finally obtains18Radiochemical purity > 95% of F-ALA-3.
18F-ALA-3 synthetic route is as follows:
According to an embodiment of the present application, a kind of 5-ALA derivative synthesizing process of F-18 label is provided, Including；
5-ALA is soluble in water, pH value is adjusted to 8.5, and the two dimethyl dicarbonate fourths for being dissolved in dioxane are added dropwise Ester is stirred at room temperature 18h, extra di-tert-butyl dicarbonate is removed after reaction, aqueous solution is adjusted to acidity, is extracted with ethyl acetate Obtain 5-N- t-butoxycarbonyl amino levulic acid；
By the 5-N- t-butoxycarbonyl amino levulic acid, dimethylamino naphthyridine, and, diethylene glycol, triethylene glycol It is stirred under ice bath with one of tetraethylene glycol, carbodiimide, ice bath stirring 2h is added, room temperature continues to stir 48h, after reaction Be spin-dried for solvent, water be added, is extracted with ethyl acetate, after collected organic layer with 10% NaHCO3Solution cleans organic phase, Post separation is finally carried out, HEBA (2- (2-hydroxyethoxy) the ethyl5- ((tert- of pale yellow powder shape is obtained butoxycarbonyl)amino)-4-oxopentanoate)；
The HEBA is added in dry pyridine, paratoluensulfonyl chloride is added portionwise under ice bath, is then gradually restored to Room temperature is stirred overnight, and post separation after solution concentration, obtains precursor TEBA (2- (2- (tosyloxy) ethoxy) after reaction ethyl5-((tert-butoxycarbonyl)amino)-4-oxopentanoate)；
Accelerator outflow comes18F-Ion is captured by QMA column, is then eluted to reaction tube with amino-polyether/potassium carbonate, is added Acetonitrile removes dry solvent repeatedly, is added in reaction tube the precursor TEBA and is dissolved in dry acetonitrile, is heated at reflux and is reacted, instead Should after be added HCl solution heating deprotection group, after being diluted with water use solid-phase extraction column preliminary purification, finally use efficient liquid phase Chromatography carries out post separation, obtains18F-O-ALA。
18F-O-ALA synthetic route is as follows.
With18For F-O-ALA-2, synthetic method is as follows:
1. the synthesis of precursor compound TEBA.
The synthesis of A.Boc-5-ALA.
5-ALA is dissolved in 5mL water, and adjusts pH value to 8.5 with the NaOH of 1N, is then added dropwise and is dissolved in 5mL dioxy six The di-tert-butyl dicarbonate ((Boc) of ring2O) (the 1-2 times of mole relative to 5-ALA), stirs 18h at room temperature.It is more after reaction Remaining (Boc)2O is extracted with ether and is removed, and aqueous solution is adjusted to acidity with the HCl solution of 1N, is then extracted with ethyl acetate to obtain Boc-5-ALA, vacuum distillation obtain colorless oil after being spin-dried for.
The synthesis of B.HEBA.
Boc-5-ALA, dimethylamino naphthyridine (DMAP) and diethylene glycol stir under ice bath according to the molar ratio of 1:1:1 The carbodiimide being added with mole is mixed, 2h is then stirred under ice bath, continues to stir 48h later at room temperature.React back spin Dry solvent, be added water, then extracted with ethyl acetate, after collected organic layer with 10% NaHCO3Solution cleaning is organic Phase.Finally carry out post separation (MeOH:CH2Cl2=40:1) obtain pale yellow powder shape HEBA.
C. the synthesis of precursor TEBA.
HEBA is added in dry 5mL pyridine, the paratoluensulfonyl chloride of 2-3 times of mole is added portionwise under ice bath (TsCl), it is then gradually restored to room temperature, is stirred overnight.Post separation after solution concentration after reaction.
2. radioactive probe18The labelled synthesis of F-O-ALA-2.
Accelerator outflow comes18F-Ion is captured by QMA column, then uses K222/K2CO3It is eluted to reaction tube, adds acetonitrile anti- Dry solvent is removed again.Then the TEBA for being added in reaction tube 5-20mg is dissolved in the dry acetonitrile of 1mL, is heated at reflux and is reacted. 2M HCl solution is added after reaction and heats deprotection group, solid-phase extraction column preliminary purification is used after being then diluted with water, finally Post separation is carried out with HPLC, is finally obtained18Radiochemical purity > 95% of F-O-ALA-2.
18F-O-ALA-2 synthetic route is as follows
According to an embodiment of the present application, the 5-ALA derivative application of F-18 label, the 5- ammonia are provided Base levulic acid derivative includes18F-ALA, for detecting tumour.
Tumor model is made using nude mice, mice with tumor anesthesia is placed on animal PET/CT, then from tail vein injection 0.1-0.5mCi's18F-ALA solution carries out PET/CT imaging after being metabolized 0.5-2 hours in vivo.
With AsPC-1 cell construction tumor model, from tail vein injection 0.1-0.5mCi's18F-ALA-3 probe, exists respectively The value that the γ of each organ in tumor mouse is counted, i.e. radiopharmaceutical 18F- are detected after injection after 10 minutes, 1 hour and 2 hours The amount and tumour of ALA-3 and the ratio of muscle, experimental result are as shown in table 1.
Table 1
10 minutes 60 minutes 120 minutes
Blood 4.56±1.34 1.14±0.47 0.96±0.11
Brain 0.62±0.21 1.02±0.33 1.24±0.18
Heart 2.78±0.41 1.48±0.09 0.96±0.09
Lung 4.21±0.62 2.64±0.29 1.26±0.20
Liver 9.67±0.63 3.32±0.52 2.37±0.31
Spleen 13.92±0.58 4.30±0.12 3.20±0.29
Pancreas 2.24±0.15 1.64±0.30 1.08±0.09
Stomach 2.99±0.47 1.24±0.31 1.02±0.08
Intestines 7.17±0.59 3.98±0.53 2.15±0.76
Kidney 74.30±7.97 38.64±5.20 18.48±3.24
Muscle 1.02±0.08 0.61±0.09 0.59±0.08
Bone 3.02±0.26 1.10±0.47 1.02±0.23
Tumour 3.98±0.74 5.89±0.65 5.94±0.38
Tumour/muscle 3.90±0.71 9.66±0.93 10.07±0.98
Seen from table 1,18F-ALA-3 shows in the internal distributed data of tumor mouse18F-ALA-3 has higher in tumour Intake, and the ratio of tumour and muscle is higher, can be used as the imaging agent of target tumor.
According to an embodiment of the present application, the 5-ALA derivative application of F-18 label, the 5- ammonia are provided Base levulic acid derivative includes18F-O-ALA, for detecting tumour.
With AsPC-1 cell construction tumor model, from tail vein injection 0.1-0.5mCi's18F-O-ALA-2 probe, respectively The value that the γ of each organ in tumor mouse is counted, i.e. radiopharmaceutical are detected behind 10 minutes after injection, 1 hour and 2 hours18F-O- The amount and tumour of ALA-2 and the ratio of muscle, experimental result are as shown in table 2.
Table 2
10 minutes 60 minutes 120 minutes
Blood 4.02±1.55 1.02±0.35 0.87±0.23
Brain 0.53±0.16 0.87±0.26 1.02±0.24
Heart 3.64±0.87 1.76±0.22 0.95±0.07
Lung 4.89±1.02 3.42±0.43 1.33±0.27
Liver 7.69±1.27 3.04±0.67 1.99±0.43
Spleen 11.34±2.04 3.89±0.46 2.87±0.22
Pancreas 2.36±0.75 1.56±0.45 1.01±0.06
Stomach 3.45±0.96 1.99±0.57 1.43±0.07
Intestines 8.78±1.69 4.84±1.24 2.96±0.24
Kidney 79.9±6.86 49.96±6.32 20.32±2.68
Muscle 1.32±0.07 0.66±0.08 0.52±0.06
Bone 3.45±0.31 1.14±0.55 0.99±0.35
Tumour 4.01±0.53 5.97±1.02 6.26±0.47
Tumour/muscle 3.04±0.35 9.05±1.24 12.04±0.66
As can be seen from Table 2,18F-O-ALA-2 probe shows respectively in vivo tumor mouse18F-O-ALA-2 has in tumour The ratio of higher intake, tumour and muscle is higher, can be used as the imaging agent of target tumor.
From the above technical scheme, the 5-ALA that the embodiment of the present application provides a kind of F-18 label derives Object, synthetic method and application.It is long that the application implements the radioactive probe radioactive half-life provided, stability and fat-soluble all bright It is powerful and influential to be higher than 5-ALA.Compared with ALA, the 5-ALA derivative of F-18 label can be formed more in pathological tissues High concentration, and concentration is lower in normal tissue, toxicity is also smaller.And because of the fat-soluble more preferable of its, penetration rate of blood brain screen The ability of barrier is stronger, can accurately be positioned to general tumour tissue, become broad spectrum type tumor developer.
Those skilled in the art will readily occur to its of the application after considering specification and practicing application disclosed herein Its embodiment.This application is intended to cover any variations, uses, or adaptations of the application, these modifications, purposes or Person's adaptive change follows the general principle of the application and including the undocumented common knowledge in the art of the application Or conventional techniques.The description and examples are only to be considered as illustrative, and the true scope and spirit of the application are by following Claim is pointed out.
It should be understood that the application is not limited to the precise structure that has been described above and shown in the drawings, and And various modifications and changes may be made without departing from the scope thereof.Scope of the present application is only limited by the accompanying claims.

Claims (6)

1. a kind of 5-ALA derivative of F-18 label, which is characterized in that including18F-ALA, chemical structure are as follows:
Wherein, n=1-6.
2. a kind of 5-ALA derivative of F-18 label, which is characterized in that including18F-O-ALA, chemical structure Are as follows:
Wherein, n=2-4.
3. a kind of 5-ALA derivative synthesizing process of F-18 label as described in claim 1, which is characterized in that Include:
5-ALA is soluble in water, pH value is adjusted to 8.5, and the di-tert-butyl dicarbonate for being dissolved in dioxane is added dropwise, 18h is stirred at room temperature, extra di-tert-butyl dicarbonate is removed after reaction, aqueous solution is adjusted to acidity, is extracted with ethyl acetate To 5-N- t-butoxycarbonyl amino levulic acid；
By the 5-N- t-butoxycarbonyl amino levulic acid, dimethylamino naphthyridine and glycol stir under ice bath, and carbon two is added Imines, ice bath stirring 2h, room temperature continue to stir 48h, and solvent is spin-dried for after reaction, water is added, is extracted with ethyl acetate, is collected After organic layer with 10% NaHCO3Solution cleans organic phase, finally carries out post separation, obtains the HBA of pale yellow powder shape, institute Stating glycol includes diethanol, two butanol or two hexanols；
The HBA is added in dry pyridine, paratoluensulfonyl chloride is added portionwise under ice bath, is then gradually restored to room temperature, It is stirred overnight, post separation after solution concentration, obtains precursor THBA after reaction；
Accelerator outflow comes18F-Ion is captured by QMA column, is then eluted to reaction tube with amino-polyether/potassium carbonate, is added acetonitrile Dry solvent is removed repeatedly, is added in reaction tube the precursor THBA and is dissolved in dry acetonitrile, is heated at reflux and is reacted, after reaction HCl solution is added and heats deprotection group, solid-phase extraction column preliminary purification is used after being diluted with water, finally uses high performance liquid chromatography Method carries out post separation, obtains18F-ALA。
4. a kind of 5-ALA derivative synthesizing process of F-18 label as claimed in claim 2, which is characterized in that Including；
5-ALA is soluble in water, pH value is adjusted to 8.5, and the di-tert-butyl dicarbonate for being dissolved in dioxane is added dropwise, 18h is stirred at room temperature, extra di-tert-butyl dicarbonate is removed after reaction, aqueous solution is adjusted to acidity, is extracted with ethyl acetate To 5-N- t-butoxycarbonyl amino levulic acid；
By the 5-N- t-butoxycarbonyl amino levulic acid, dimethylamino naphthyridine, and, diethylene glycol, triethylene glycol and four One of ethylene glycol stirs under ice bath, and carbodiimide, ice bath stirring 2h is added, and room temperature continues to stir 48h, be spin-dried for after reaction Solvent, be added water, extracted with ethyl acetate, after collected organic layer with 10% NaHCO3Solution cleans organic phase, finally Post separation is carried out, the HEBA of pale yellow powder shape is obtained；
The HEBA is added in dry pyridine, paratoluensulfonyl chloride is added portionwise under ice bath, is then gradually restored to room temperature, It is stirred overnight, post separation after solution concentration, obtains precursor TEBA after reaction；
Accelerator outflow comes18F-Ion is captured by QMA column, is then eluted to reaction tube with amino-polyether/potassium carbonate, is added acetonitrile Dry solvent is removed repeatedly, is added in reaction tube the precursor TEBA and is dissolved in dry acetonitrile, is heated at reflux and is reacted, after reaction HCl solution is added and heats deprotection group, solid-phase extraction column preliminary purification is used after being diluted with water, finally uses high performance liquid chromatography Method carries out post separation, obtains18F-O-ALA。
5. a kind of 5-ALA derivative application of F-18 label as described in claim 1, which is characterized in that be used for Detect tumour.
6. a kind of 5-ALA derivative application of F-18 label as claimed in claim 2, which is characterized in that be used for Detect tumour.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020087794A1 (en) * 2018-10-29 2020-05-07 庄晓青 F-18 labeled 5-aminolevulinic acid derivative, synthesis method therefor, and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101723850A (en) * 2008-10-10 2010-06-09 北京师范大学 Novel 18F labeled aromatic amino acids, preparation method and application thereof in tumor imaging

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856566A (en) * 1997-09-02 1999-01-05 Dusa Pharmaceuticals, Inc. Sterilized 5-aminolevulinic acid
CN109369433B (en) * 2018-10-29 2020-01-17 庄晓青 F-18 labeled 5-aminolevulinic acid derivative, and synthesis method and application thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101723850A (en) * 2008-10-10 2010-06-09 北京师范大学 Novel 18F labeled aromatic amino acids, preparation method and application thereof in tumor imaging

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ADAM B.PIPPIN: "Radiochemical synthesis and evaluation of 13N-labeled 5-aminolevulinic acid for PET imaging of gliomas", 《ACS MEDICINAL CHEMISTRY LETTES》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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