CN101074231A - [18F] fluoraro-marked purine compound, its production and use - Google Patents
[18F] fluoraro-marked purine compound, its production and use Download PDFInfo
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Abstract
A (18F) fluorine-mark purine compound, its production and usage as report gene HSV1-tk PET molecular probe are disclosed. The structural formula is 2-amino-6-(18F)-fluorine-9-(4-hydroxy-3-methylol-butyl) purine.
Description
Technical field
The present invention relates to a kind of [
18F] purine nucleoside compounds of fluorine mark, particularly 2-amino-6-[
18F] fluoro-9-(4-hydroxyl-3-methylol-butyl) purine and radiological chemistry preparation method thereof, with and as the application of positron emission tomography (PET) (PET) molecular probe of reporter gene HSV1-tk (herpes simplex virus 1-Thymine deoxyriboside kinase gene).
Background technology
In recent years, along with people deepen continuously to the research synthetic and biological assessment of purine nucleoside and analogue thereof, find that this compounds has antitumor and antiviral activity clinically.By structure of modification to nucleoside analog, produce a series of tangible antiviral activity nucleoside analogs that have, become the important component part of antiviral class drug research.Simultaneously, chemical compound lot has physiologically active because of contain fluorine atoms, is introduced in the compound, and certain variation will take place for its physico-chemical property and physiologically active.Thereby the medicine that fluorochemicals is stronger as biological activity, selectivity is higher is widely used.Along with development of life science, the radio isotope F-18 of fluorine because positron and suitable transformation period (110min) are launched in its decay, makes the research of the bioactive compounds of F-18 mark have more deep meaning.These compounds as tracer agent and modern image instrument (as PET, be the positron emission computed tomography) combination, can realize some biological process not damageds, location, quantitative molecular video picture in the body, for biological process in the research body provides important means, while also provides new method for the research of pharmacokinetics and pharmacodynamics, is the research focus of current biological medicine.Nucleoside analog 9-(4-hydroxyl-3-methylol-butyl) guanine (be Penciclovir, structural formula is as shown in the formula shown in 6) is a kind of effective as selective inhibitor of simplexvirus class, is mainly used in the serious herpesvirus infection of treatment clinically.Penciclovir is carried out structural modification at present, synthesized the 9-[(4-fluorine)-3-hydroxymethyl butyl] guanine (is FHBG, structural formula is as shown in the formula shown in 7), 8-fluoro-9-(4-hydroxyl-3-hydroxymethyl butyl) guanine (is 8-Fluoropenciclovir, structural formula is as shown in the formula shown in 8) fluorochemicals, obtain fine drug effect, simultaneously it is carried out the F-18 mark, become the PET molecular probe of reporter gene HSV1-tk (herpes simplex virus 1-Thymine deoxyriboside kinase gene), realization is instructed the effect of gene therapy scheme optimization and evaluation gene therapy to the PET video picture of reporter gene HSV1-tk in the body.By structure and the active research to a kind of simplexvirus proteinoid HSV1-TK (herpes simplex virus 1-Thymine deoxyriboside kinase protein), purine C-6 position may be and HSV1-TK bonded reactive site.(Kim, D-K such as Kim; Lee, N; Kim, H-T; Im, G.-J; Kim, K-H.Bioorganic﹠amp; Medicinal Chemistry, 1999,7,565.) the introducing fluorine atom has synthesized 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine (6-Fluoropenciclovir on purine C-6 position, structural formula is as shown in the formula shown in 1), and it has been carried out esterification, obtain the Penciclovir prodrug that purine C-6 replaces with fluorine, and obtain certain drug effect.
The synthetic route of disclosed formula 1 compound is in the document:
But raw materials used formula 3 compounds are not conventional reagent in the first step in the said synthesis route, be difficult for buying, and because Trimethylamine 99 (TMA) boiling point lower (2～3 ℃), generally need be in application of sample under the cryogenic condensation and reaction, synthesis condition is relatively harsher, and the reaction times reaches 5 days simultaneously; And second step, according to literature method, the reaction side reaction product is many down at 80 ℃, and experiment is difficult to be repeated.
As seen, as formula 1 compound of on-radiation reference compound, and the preparation difficulty of formula 4 compounds of the precursor that serves as a mark, so influenced the preparation of radio-labeled compound of formula 1 compound and the 2-amino-6-[of the research of application, particularly F-18 mark thereof
18F] do not see so far fluoro-9-(4-hydroxyl-3-methylol-butyl) report is arranged by purine.
Summary of the invention
The objective of the invention is to solve above-mentioned problem, provide a kind of new [
18F] purine compound of fluorine mark.
Of the present invention [
18F] purine compound of fluorine mark, it is that structural formula is as shown in the formula the 2-amino-6-[shown in 5
18F] fluoro-9-(4-hydroxyl-3-methylol-butyl) purine.
That another object of the present invention provides is above-mentioned [
18F] preparation method of purine compound of fluorine mark.
Described preparation method is by precursor that formula 4 compound nucleosides chlorination ammonium salts are served as a mark, carry out routine [
18F] the fluorine mark.
Preferably, this preparation method comprises the following steps: to contain K
2CO
3, K
222,
18F-F
-Mixture and labelled precursor formula 4 compound nucleosides chlorination ammonium salts at N, in N-dimethylformamide (DMF) solvent, under heating condition, react, temperature of reaction is about 20～80 ℃, the reaction times is about 5～30 minutes.
More preferably, described temperature of reaction is 40～60 ℃, and the reaction times is 15～25 minutes.
Preparation method of the present invention is a single stage method radioactivity synthetic method, and it is a labelled precursor with formula 4 compound nucleosides chlorination ammonium salts, with F-18 ion single step reaction, obtains product.Its preferable synthetic route is as follows.
More preferably, a Silica Sep-pak (Plus) post is used in the separation and purification of product in the reaction, reaction mixture is by behind Silica Sep-pak (Plus) post, use this Silica Sep-pak (Plus) post of organic solvent drip washing again, after then solvent being dried up with nitrogen, obtain product formula 5 compounds in oil bath.
More preferably, the invention provides a kind of easier preparation labelled precursor formula 4 compounds, and as the novel method of formula 1 compound of on-radiation reference compound, its preferable synthetic route is as follows.
Wherein, formula 4 compounds can be by formula 3 compound 2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine and Trimethylamine 99 ethanolic soln at tetrahydrofuran (THF) (THF) and N, reacts in the N-dimethylformamide mixed solvent to make.
Preferably, described reaction may further comprise the steps: formula 3 compounds are dissolved in tetrahydrofuran (THF) (THF) and N, in the N-dimethylformamide mixed solvent, place-20～0 ℃ of salt ice-water baths, under the anhydrous and oxygen-free conditions such as logical nitrogen protection; Get the Trimethylamine 99 ethanolic soln and dropwise add above-mentioned system, stirring reaction slowly rises to room temperature, and reaction is spent the night.TLC follows the tracks of and reacts to the complete back of raw material primitive reaction stopped reaction, filters, and is dry under vacuum with the anhydrous diethyl ether washing, obtains white solid formula 4 compounds.
Wherein, tetrahydrofuran (THF) and N in the above-mentioned mixed solvent, the volume ratio of N-dimethylformamide is preferably 2～5: 1.
And for easy, the Trimethylamine 99 ethanolic soln adopts the commercially available prod among the present invention, and wherein Trimethylamine 99 and alcoholic acid volume ratio are 1: 2.
The said room temperature of the present invention is generally 10～25 ℃.
More preferably, formula 3 compounds can be sloughed the reaction of two ethanoyl through hydrolysis by the raw material formula 2 compound 2-amino that are easy to get-6-chloro-9-(4-acetoxy-3-acetyl-o-methyl butyl) purine and make.
Said hydrolysis reaction comprises formula 2 compound 2-amino-6-chloro-9-(4-acetoxy-3-acetyl-o-methyl butyl) purine is dissolved in THF, adds K
2CO
3Place 0～20 ℃ of following stirring reaction, TLC follows the tracks of and reacts complete to the raw material primitive reaction.Stopped reaction, rotary evaporation is removed reaction solvent, gets faint yellow solid, uses washing with alcohol, separates through silicagel column, and rotary evaporation removes and desolvates, and vacuum-drying obtains white solid formula 3 compounds.
Preferably, two ethanoyl are sloughed in adding methyl alcohol and water mixed solution hydrolysis in above-mentioned system, preserve the chlorine atom on 6 simultaneously, can obtain formula 3 compounds of high yield; The volume ratio of this first alcohol and water is preferably 1: 1.
And the preparation method of formula 1 compound 2-amino of the present invention-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine comprises formula 4 compounds is dissolved in N, and the N-dimethylformamide adds anhydrous potassium fluoride, places 20～60 ℃, carries out stirring reaction.TLC follows the tracks of and reacts complete to the raw material primitive reaction.After reaction finishes, filter, rotary evaporation is removed partial solvent, separates through silicagel column, and rotary evaporation removes and desolvates, and vacuum-drying obtains white solid formula 1 compound.
Made in the step of formula 4 compounds by formula 3 compounds above-mentioned, the present invention replaces Trimethylamine Anhydrous with the Trimethylamine 99 ethanolic soln, has avoided the severe condition of cryogenic condensation, and the reaction times also shortens (common one day just can) greatly.
And in the step of formula 4 compounds accepted way of doing sth 1 compound, the inventor finds that temperature of reaction is bigger to this reaction influence, and when temperature of reaction was lower than 60 ℃, nucleosides chlorination ammonium salt was stable, with a fluorination reagent reaction production 1 compound; But when temperature of reaction during greater than 60 ℃, then this nucleosides chlorination ammonium salt can decompose, and generates by product.
Certainly, formula 4 compounds among the present invention, formula 1 compound also can be prepared as disclosed method in the above-mentioned document by additive method.
This shows that preparation method's technology of the present invention is simple, particular requirements such as no high temperature, high pressure, common response equipment can be finished, and purifying products adopts methods such as filtration, post separation, and simple, product purity is higher.
Description of drawings
Fig. 1 is the uptake ratio lab diagram of formula 5 compounds of the present invention in cell in vitro C6 and C6-tk; Wherein, A: formula 5 compounds are at uptake ratio and the incubation time relation curve of cell C6 and C6-tk; B: the uptake ratio of formula 5 compounds and cell C6-tk concentration relationship figure.
Fig. 2 is formula 5 compounds of the present invention bio distribution figure in the tumor model nude mouse.
Fig. 3 is the PET 15min static image figure of formula 5 compounds of tumor model mouse.
Embodiment
Below will relevant details of the present invention be further described, but embodiment does not limit protection scope of the present invention by embodiment.
Synthesizing of embodiment 1 formula 3 compound 2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine
(358mg 1mmol), is dissolved in 12ml THF to modus ponens 2 compounds, adds 10ml K
2CO
3(150mg, 1mmol) methyl alcohol and water mixed solution (MeOH/H
2O volume ratio=1: 1), place 0 ℃ of following stirring reaction, TLC follows the tracks of (developping agent: 10% ethanol/dichloromethane, volume ratio=1: 9) and reacts complete to the raw material primitive reaction.Stopped reaction, rotary evaporation is removed reaction solvent, gets faint yellow solid, uses the 25ml washing with alcohol, again with a spot of THF dissolving.Separate through silicagel column (10% ethanol/dichloromethane, volume ratio=1: 9 are made leacheate), collect R
fValue is 0.36 component, and rotary evaporation removes and desolvates, and vacuum-drying obtains white solid formula 3 compounds, yield 78.4%.
Synthesizing of embodiment 2～3 formulas 3 compounds
Temperature of reaction is respectively 15 ℃ and 20 ℃, and is surplus with embodiment 1, obtains white solid formula 3 compounds, and yield is respectively 70.8%, 64.5%.
Synthesizing of embodiment 4 formulas 4 compound nucleosides chlorination ammonium salts
(813mg 3mmol) is dissolved in 40ml mixed solvent (THF/DMF volume ratio=3: 1) and places 0 ℃ of ice-water bath modus ponens 3 compounds, logical nitrogen protection.Get 9ml Trimethylamine 99 ethanolic soln and dropwise add above-mentioned system, stirring reaction.Reaction slowly rises to room temperature, and reaction is spent the night, and the adularescent solid generates.TLC follows the tracks of (developping agent: 10% ethanol/methylene, volume ratio=1: 9) and reacts complete to the raw material primitive reaction.Stopped reaction filters, and is dry under vacuum with anhydrous diethyl ether (10ml * 2) washing, obtains white solid formula 4 compounds, yield 90.5%.
Synthesizing of embodiment 5 formulas 4 compound nucleosides chlorination ammonium salts
(813mg 3mmol) is dissolved in 40ml mixed solvent (THF/DMF volume ratio=4: 1) and places-20 ℃ of salt ice-water baths modus ponens 3 compounds, logical nitrogen protection.Get 12ml Trimethylamine 99 ethanolic soln and dropwise add above-mentioned system, stirring reaction.Reaction slowly rises to room temperature, and reaction is spent the night, and the adularescent solid generates.Surplus with embodiment 4, obtain white solid formula 4 compounds, yield 86.8%.
Synthesizing of embodiment 6 formulas 1 compound 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine
(165mg 0.5mmol) is dissolved in 5ml DMF to modus ponens 4 compounds, and (240mg 5mmol), places 60 ℃ of stirring reactions, and TLC follows the tracks of (developping agent: 10% ethanol/methylene, volume ratio=1: 9) and reacts complete to the raw material primitive reaction to add anhydrous K F.After reaction finishes, filter, rotary evaporation is removed partial solvent, separates through silicagel column (leacheate is 10% methanol/dichloromethane solution, volume ratio=1: 9), collects R
fValue is 0.45 component, and rotary evaporation removes and desolvates, and vacuum-drying obtains white solid formula 1 compound, yield 87.3%.
Synthesizing of embodiment 7～8 formulas 1 compound 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine
Temperature of reaction is respectively 20 ℃, 40 ℃, and is surplus with embodiment 6, obtains formula 1 compound, and yield is respectively 70.8,72.6%.
Embodiment 9 formulas 5 compound 2-amino-6-[
18F] radioactivity of fluoro-9-(4-hydroxyl-3-methylol-butyl) purine is synthetic
Get 100 μ L[
18F] F
-Solution joins and includes K
222(10-12mg) and in the reaction flask of salt of wormwood (1-2mg), this reaction flask is immersed 90 ℃ of oil baths, feeds nitrogen (1mL/min) and dry up, add 500uL HPLC acetonitrile be evaporated to dried, triplicate.Add be dissolved in 0.5mL DMF in contain above-mentioned drying [
18F] F
-Reaction vessel in, add labelled precursor formula 4 compounds (3.8mg), 40 ℃ of following confined reactions 25 minutes, reaction finishes postcooling to room temperature, the DMF reaction solution that contains product with a 1mL syringe injection silica Sep-pak (Plus) post.Abandon the pouring fluid, and then with the 4mL mixed solvent (methyl alcohol: methylene dichloride=1: 1) flushing reaction flask, this silica Sep-pak (Plus) post of drip washing is collected leacheate in another container bottle then, is to dry up mixed solvent with nitrogen in 90～100 ℃ of oil baths.Be dissolved in 2ml phosphate buffer solution (PBS, pH=7.4) system again.Obtain product 2-amino-6-[
18F] fluoro-9-(4-hydroxyl-3-methylol-butyl) purine, get 100 μ L products and inject HPLC post, product retention time t
R=3.4 minutes, putting productive rate 40%, the radiochemicsl purity of final product is higher than 98%.
The radioactivity of embodiment 10 formulas 5 compounds is synthetic
Get 100 μ L[
18F] F
-Solution joins and includes K
222(10-12mg) and in the reaction flask of salt of wormwood (1-2mg), this reaction flask is immersed 100 ℃ of oil baths, feeds nitrogen (1mL/min) and dry up, add 500uL HPLC acetonitrile be evaporated to dried, triplicate.Add be dissolved in 1.0mL DMF in contain above-mentioned drying [
18F] F
-Reaction vessel in, add labelled precursor formula 4 compounds (5.2mg), 60 ℃ of following confined reactions 15 minutes, reaction finishes postcooling to room temperature, and is surplus with embodiment 11.Putting productive rate 47%, the radiochemicsl purity of final product is higher than 98%.
Raw material among this preparation method: formula 2 compound 2-amino-6-chloro-9-(4-acetoxy-3-acetyl-o-methyl butyl) purine is Changzhou Kangli Pharmaceutical Co., Ltd's product; Anhydrous tetrahydro furan (THF), N, N-dimethylformamide (DMF, extra dry), Kryptofix2.2.2 (K
222) purchase chemical reagents corporation in Acros; Anhydrous potassium fluoride, 33% Trimethylamine 99 (TMA) ethanolic soln are purchased in traditional Chinese medicines chemical reagents corporation; Other reagent is analytical pure and purchases in traditional Chinese medicines chemical reagents corporation, the not purified direct use of all reagent.[
18F] F
-Production be adopt whirlwind-30 magnetic resonance acceleator by small volume [
18O] H
2O finishes
18O (p, n)
18F nuclear reaction and getting.
The physico-chemical property and the spectroscopic data of final product of the present invention and main intermediate are as follows:
M.p.141.6～142.0 ℃; UV-vis (EtOH) λ max:223nm, 248nm and 310nm; IR (KBr) V:3320,3200,2930,1610,1570,1380,1060cm-1;
1H-NMR (DMSO-d
6) δ: 8.15 (s, 1H, C
8H), 6.90-6.80 (s, 2H, NH
2), 4.55-4.50 (m, 2H, OH), 4.05-4.15 (t, 2H, NCH
2, J=7.3Hz), 3.30-3.50 (m, 4H, OCH
2), 1.70-1.80 (m, 2H, CH
2CH), 1.40-1.50 (m, 1H, CH
2CH); MS m/z (%): 271 (M
+, 72), 240 (57), 170 (100).
m.p.168.1～170.5℃；UV-vis(EtOH)λmax：225nm，245nm，320nm；IR(KBr)V：3310，2920，1630，1570，1480，1320，1040cm-1；
1H-NMR(D
2O)δ：8.40(s，1H，C
8H)，4.20-4.30(t，2H，NCH
2，J＝7.42Hz)，3.70(s，9H，NCH
3)，3.55-3.65(m，4H，OCH
2)，1.85-1.90(m，2H，CH
2CH)，1.65-1.60(m，1H，CH
2CH)；MS?m/z(％)：280(M-CH
3Cl，92)，249(100)，191(80)。
Formula 1 compound 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine
m.p.173.5～175.4℃；UV(EtOH)λmax：306nm；IR(KBr)V：3320，3310，2930，1660，1570，1410，1220，1030，783，625cm-1；
1H-NMR(DMSO-d
6)δ：8.10(s，1H，C
8H)，6.85(s，2H，NH
2)，4.50-4.60(m，2H，OH)，4.15-4.05(t，2H，4′H-CH
2，J＝7.42)，3.45-3.30(m，4H，OCH
2)，1.80-1.70(m，2H，CH
2CH)，1.50-1.35(m，1H，CH
2CH)；
19F-NMR(DMSO-d
6)δ：-74.12(s，1F)；MS?m/z(％)：255(M
+，26)，224(27)，153(100)。
The cell in vitro experiment of experimental example 1 formula 5 compounds of the present invention
Insert fixed cell number (0.5 hundred ten thousand s') cell strain in 6 each hole of porocyte culture dish, C6-tk cell (the neuroglial cytoma C6 that contains the mouse source of HSV1-tk genetic expression is put in last three holes in every dish, take from the Shanghai Inst. of Tumor), C6 cell (the neuroglial cytoma in mouse source is put in following three holes, take from the Shanghai Inst. of Tumor), cultivate 24hr in 37 ℃, the cell of the preceding definite every dish of experiment on the same day is adherent growth all, to determine the cell well-grown.Experimental procedure is as follows:
1. formula 5 compounds that in each hole, add immobilization of radioactive activity 10 μ Ci;
2. (the C6 cell is cultivated in containing the two anti-DMEM nutrient solutions of 10% foetal calf serum, 1% penicillin-Streptomycin sulphate will to have added the cell culture fluid of formula 5 compounds, the C6-tk cell is cultivated in the DMEM nutrient solution of the G418 that contains the two anti-and 0.1mg/ml of 10% foetal calf serum, 1% penicillin-Streptomycin sulphate) under 37 ℃ of constant temperature, take out respectively in five different time points (0,30,60,120,180 minute) and to carry out the follow-up test step;
3. after incubation time finishes, abandon nutrient solution, (PBS pH=7.4) washes each hole, again with the PBS sucking-off, repeats 2～3 times to use the cold phosphoric acid buffer of 250 μ l again;
4. add 500 μ l0.25% pancreatin to each hole, the about 5min of digestion in 37 ℃, add 1mL substratum (the C6 cell is to contain 10% foetal calf serum, the two anti-DMEM nutrient solutions of 1% penicillin-Streptomycin sulphate, and the C6-tk cell is the DMEM nutrient solution that contains the G418 of the two anti-and 0.1mg/ml of 10% foetal calf serum, 1% penicillin-Streptomycin sulphate).Piping and druming is laid fully to guarantee cell gently, afterwards with the cell sucking-off, places corresponding test tube.Utilize 500 μ l phosphoric acid buffers to wash each hole afterwards again, place the front to fill the corresponding test tube of cell suspending liquid the phosphoric acid buffer sucking-off, repeat this and move twice so that this cell is fully collected;
5. get the 50 μ l solution blue indicating liquid counting cells of platform phenol number at each test tube that contains cell.Prepare in addition test tube add with step 1. in identical formula 5 compounds, and utilize cell culture fluid to supply 2.5ml the last cumulative volume, with foundation as adding total activity instrumentation definite value;
6. all test tubes are delivered to γ-counter meter, read activity, the analytical test data.
The expression of formula 5 compounds in C6 and C6-tk cell accounts for whole radioactive ratio (%dose/10 with the radioactivity amount of absorbing in per 1,000,000 cells
6Cells), its experimental result as shown in Figure 1.
Experimental result shows: formula 5 compounds of the present invention are hatched 30～180min at C6 cell and C6-tk cell, and formula 5 compounds can enter cell quickly C6-tk cellular uptake rate high 5.5～18.8 times than C6 cell, behind the 180min up to 8.6 ± 0.4%dose/10
6Cells, and the uptake ratio variation is little and lower in control group C6 cell, is up to 0.45 ± 0.03%dose/10
6Cells; Strengthen linear ratio (R with the increase of up-to-date style 5 compounds uptake ratio in cell in vitro and the concentration of C6-tk
2=0.947), the increase that shows the cellular uptake rate of formula 5 compounds is because the increase of the expression amount of HSV1-tk.This experimental results show that the C6-tk cell has specificity to absorb to formula 5 compounds, and its major cause is the expression that reporter gene HSV1-tk is arranged among the C6-tk, and in direct ratio with its expression amount.
The bio distribution experiment of experimental example 2 formula 5 compounds of the present invention
The establishment method of tumor model nude mice: be in the C6 of logarithm production phase and C6-tk cell through PBS washing, digestion, add in its culture medium solution, make its suspension.To test Balb/C nude mice anesthesia, the subcutaneous injection control group on the left leg top of Balb/C nude mice contains 1,000,000 C6 cells and substratum thereof then, and at 1,000,000 the C6-tk cells of subcutaneous injection experimental group and the substratum thereof on right leg top.Grow and used for formula 5 compound biological assessments and micro-PET video picture experiment behind the formation solid tumor in several days.
To 3 formula 5 compound formulations of having planted the tumor model nude mice tail vein injection 20 μ Ci of C6-tk and C6 cell, put to death behind the 15min, dissect immediately, gather interested organs and tissues: the heart, lung, kidney, liver, pancreas, stomach, spleen, small intestine, tumour (left side), tumour (right side), weigh respectively, count, carry out after the decay correction, the counting of each tissue sample is all counted relatively with standard.The result is expressed as %ID/g ± SD (radioactivity of every gram tissue accounts for the percentage composition of injected dose), is the relative absorption value of each internal organs to formula 5 compounds.Each internal organs to the relative absorption value of formula 5 compounds as shown in Figure 2.
Visible 5 compounds specific absorption in liver, kidney is higher among the figure.Absorption value is also than higher in C6-tk tumour and C6 tumour, be respectively 1.91+0.30 and 1.514 ± 0.20, its ratio is up to 1.69, formula 5 compounds have higher specificity to absorb in the C6-tk tumour of transfection reporter gene HSV1-tk, can attempt formula 5 compounds are used for the early stage PET video picture of reporter gene HSV1-tk.
The PET video picture of experimental example 3 formula 5 compounds of the present invention
PET video picture research and utilization R4Micro-PET (U.S. Concorde micro-system company limited, resolving power is approximately 1mm, height of bed 5.7cm, sweep length 7.8cm) obtaining 3D rebuilds, measuring result is analyzed by filtered back projection's method reconstruction coronal-plane, transverse section, sagittal plane faultage image through dispersion, counting, dead time correction at random.Model tumour nude mice injecting narcotic vetanarcol (0.2ml, concentration is 4mg/ml), after the anesthesia, tail vein injection probe-type 5 compound formulations 20 μ Ci behind 15min, are fixed on the video picture platform, scan 10min with micro-PET.Formula 5 compounds in the micro-PET video picture of the tumor model nude mice of having planted C6-tk and C6 cell as shown in Figure 3.
As seen from the figure, behind injecting type 5 compound 15min, can find out the difference of formula 5 compounds in C6-tk tumour and control group C6 tumour, its ratio is about 1.5.Formula 5 compounds can be used for the early stage PET video picture of reporter gene HSV1-tk.
Claims (10)
1, a kind of [
18F] purine compound of fluorine mark, it is that structural formula is as shown in the formula the 2-amino-6-[shown in 5
18F] fluoro-9-(4-hydroxyl-3-methylol-butyl) purine
2, the preparation method of purine compound as claimed in claim 1, it comprises by the following formula 4 compound nucleosides chlorination ammonium salts precursor that serves as a mark,
Carry out routine [
18F] the fluorine mark.
3, preparation method as claimed in claim 2 is characterized in that it comprises the following steps: to contain K
2CO
3, K
222,
18The mixture of F-F-and labelled precursor formula 4 compound nucleosides chlorination ammonium salts, react under heating condition in the N-dimethylformamide solvent at N, and temperature of reaction is about 20～80 ℃, and the reaction times is about 5～30 minutes.
4, preparation method as claimed in claim 3 is characterized in that described temperature of reaction is 40～60 ℃, and the reaction times is 15～25 minutes.
5, preparation method as claimed in claim 2 is characterized in that these formula 4 compounds can be by formula 3 compound 2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine and Trimethylamine 99 ethanolic soln
In organic solvent, react and make.
6, preparation method as claimed in claim 5 is characterized in that described reaction may further comprise the steps: formula 3 compounds are dissolved in tetrahydrofuran (THF) and N, in the N-dimethylformamide mixed solvent, place-20～0 ℃ of salt ice-water baths, logical nitrogen protection; Get the Trimethylamine 99 ethanolic soln and dropwise add above-mentioned system, stirring reaction slowly rises to room temperature, and reaction is spent the night.
7, preparation method as claimed in claim 6 is characterized in that tetrahydrofuran (THF) and N in this mixed solvent, and the volume ratio of N-dimethylformamide is 2～5: 1.
8, preparation method as claimed in claim 5 is characterized in that these formula 3 compounds are by formula 2 compound 2-amino-6-chloro-9-(4-acetoxy-3-acetyl-o-methyl butyl) purine
Slough two ethanoyl reactions through hydrolysis and make, this hydrolysis reaction may further comprise the steps: formula 2 compounds are dissolved in anhydrous tetrahydro furan, place under 0～20 ℃, the methyl alcohol and the water mixed solution that add salt of wormwood react.
9, as each described preparation method of claim 2～8, it is characterized in that its also comprise with [
18F] the fluorine labeled reactant product step that adopts Silica Sep-pak (Plus) post to carry out separation and purification.
10, as claimed in claim 1 [
18F] application of purine compound in the positron emission tomography (PET) molecular probe of preparation report hsv 1-Thymine deoxyriboside kinase gene of fluorine mark.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007101036142A CN100506822C (en) | 2006-05-17 | 2007-04-28 | [*F] fluoraro-marked purine compound, its production and use |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610026601 | 2006-05-17 | ||
| CN200610026601.5 | 2006-05-17 | ||
| CNB2007101036142A CN100506822C (en) | 2006-05-17 | 2007-04-28 | [*F] fluoraro-marked purine compound, its production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101074231A true CN101074231A (en) | 2007-11-21 |
| CN100506822C CN100506822C (en) | 2009-07-01 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570782A (en) * | 2012-07-23 | 2014-02-12 | 医影生物纳米技术(苏州)有限公司 | Nano molecular probe FMAU precursor, and preparation method thereof |
| CN104496991A (en) * | 2014-11-04 | 2015-04-08 | 常州康丽制药有限公司 | Preparation method for high-quality 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbutyl)purine |
| WO2022178840A1 (en) * | 2021-02-26 | 2022-09-01 | Seecure Taiwan Co. , Ltd. | Thiopurine-based compound, composition, method of preparation and applications |
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2007
- 2007-04-28 CN CNB2007101036142A patent/CN100506822C/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570782A (en) * | 2012-07-23 | 2014-02-12 | 医影生物纳米技术(苏州)有限公司 | Nano molecular probe FMAU precursor, and preparation method thereof |
| CN104496991A (en) * | 2014-11-04 | 2015-04-08 | 常州康丽制药有限公司 | Preparation method for high-quality 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbutyl)purine |
| WO2022178840A1 (en) * | 2021-02-26 | 2022-09-01 | Seecure Taiwan Co. , Ltd. | Thiopurine-based compound, composition, method of preparation and applications |
| CN115298178A (en) * | 2021-02-26 | 2022-11-04 | 聚天生医股份有限公司 | Thiopurine compound, composition, preparation method and application |
| JP2023518868A (en) * | 2021-02-26 | 2023-05-08 | ▲聚▼天生醫股▲ふん▼有限公司 | Thiopurine compounds, compositions, methods of preparation, and applications |
| CN115298178B (en) * | 2021-02-26 | 2023-09-01 | 聚天生医股份有限公司 | Thiopurine compound, composition, preparation method and application |
| JP7469504B2 (en) | 2021-02-26 | 2024-04-16 | ▲聚▼天生醫股▲ふん▼有限公司 | Thiopurine compounds, compositions, methods of preparation, and applications |
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| CN100506822C (en) | 2009-07-01 |
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