CN102746315A - Preparation method and use of 10-<11>C-methoxycamptothecin - Google Patents

Preparation method and use of 10-<11>C-methoxycamptothecin Download PDF

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CN102746315A
CN102746315A CN2011104379583A CN201110437958A CN102746315A CN 102746315 A CN102746315 A CN 102746315A CN 2011104379583 A CN2011104379583 A CN 2011104379583A CN 201110437958 A CN201110437958 A CN 201110437958A CN 102746315 A CN102746315 A CN 102746315A
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mocpt
preparation
methyl iodide
post
reaction
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董孟杰
刘振锋
王国林
张倩
李嘉俊
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Zhejiang University ZJU
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Abstract

The present invention provides a preparation method for 10-<11>C-methoxycamptothecin. According to the present invention, a cyclotron is adopted to carry out a <14>N(pi,alpha)<11>C reaction to produce <11>C; the <11>C reacts with oxygen inside a target to generate <11>C-carbon dioxide; the <11>C-carbon dioxide sequentially reacts with lithium aluminum hydride and hydroiodic acid to generate <11>C-methyl iodide; the <11>C-methyl iodide reacts with a weak alkali solution of 10-hydroxycamptothecin; and the resulting reaction product is separated by HPLC or a solid phase extraction C18 column to obtain the target product. With the method of the present invention, automated synthesis is easily achieved. In the prior art, <18>FDG, <11>C-choline, and other imaging agents used in clinic are generally metabolic imaging agents, do not have specificities, and can not distinguish inflammation from cancer. The 10-<11>C-methoxycamptothecin of the present invention is a positron imaging agent firstly adopting DNA topoisomerase I as a target point, and can be applied in preparations of tumor-specific imaging agents.

Description

A kind of Preparation method and use of 10-11C-MOCPT
Technical field
The invention belongs to field of medicaments, relate to a kind of positron emission fault (PET) developer and preparation method thereof, relate in particular to a kind of positron 10- 11The preparation method and its usage of C-MOCPT.
Background technology
The PET inspection is different from other inspection, and it depends on positron medicine (PET medicine), the purpose that relies on the positron drug specificity to concentrate and reach diagnosis and estimate in target organ.The topmost positron medicine of using in the current PE T inspection is 18The F-fluorodeoxyglucose ( 18FDG), 18FDG is as a kind of tumour metabolism class medicine, malignant tumour diagnose with differential diagnosis in brought into play enormous function, still 18FDG as not distinguishing inflammation and tumour, much is reported as false positive or false negative as a kind of non-specific relatively developer, about the diagnosis of tumour and research also need develop novel, have more specific developer.NSC 94600 is a kind of natural alkaloid that from the fruit of the distinctive plant camptotheca acuminata of China, extracts; Can be used as the specific anti cancer drug of S phase; Camptothecine compounds reaches the purpose of treatment malignant tumour through the activity that suppresses DNA topology isomerase I (TOPO I); Research has shown that NSC 94600 and natural and artificial-synthesis derivant have the anti-knurl effect in inside and outside of wide spectrum; In natural camptothecin derivative, 10-hydroxycamptothecine is a kind of more verivate of high reactivity and low toxicity that has, and is mainly used in primary hepatocarcinoma, the rectum cancer, bladder cancer, cancer of the stomach, chronic granulocyte clinically from the sick treatment of blood.
Summary of the invention
The purpose of this invention is to provide a kind of 10- 11The preparation method of C-methyl NSC 94600, said 10- 11The chemical formula of C-MOCPT be [ 11C]-C 21H 18N 2O 5, structural formula is:
Figure BDA0000124258370000011
Prepare through following 2 kinds of approach respectively:
(1) by the magnetic resonance acceleator warp 14N (p, α) 11The C reacted 11C, 11Oxygen in C and the target generates 11The C-carbonic acid gas ( 11CO 2), 11C-carbonic acid gas and lithium aluminium hydride (LiAlH 4) reaction, generate with hydroiodic acid HI (HI) reaction again 11The C-methyl iodide ( 11CH 3I), 11The C-methyl iodide ( 11CH 3I) weak caustic solution with 10-hydroxycamptothecine reacts, and separating perhaps with HPLC reactant, the separation of SPE C18 post obtains title product.
Synthetic route 1:
Figure BDA0000124258370000021
(2) by the magnetic resonance acceleator warp 14N (p, α) 11The C reacted 11C, 11Oxygen in C and the target generates 11The C-carbonic acid gas, 11C-carbonic acid gas and lithium aluminium hydride (LiAlH 4) reaction, generate with hydroiodic acid HI (HI) reaction again 11The C-methyl iodide ( 11CH 3I), 11The C-methyl iodide ( 11CH 3I) online Triflate-Ag post through 200 ℃ is converted into 11C-triflate-methane, 11The weak caustic solution reaction of C-triflate-methane and 10-hydroxycamptothecine, separating perhaps with HPLC reactant, the separation of SPE C18 post obtains title product.
Wherein the weak base selected for use of weakly alkaline solution is salt of wormwood, sodium hydrogencarbonate, and the tetra-n-butyl oxyammonia, Strontium carbonate powder, Trimethylamine 99 or triethylamine, solvent is selected methyl-sulphoxide for use, N, dinethylformamide, second eyeball, ethanol, methyl alcohol or acetone.
Synthetic route 2:
Figure BDA0000124258370000022
Separator column is the performance liquid C18 post of divergence type described in two kinds of preparing methods, and moving phase is the leacheate of second eyeball and water or the leacheate of ethanol and water, and separation obtains title product to reactant through HPLC.
The C18 post adopts Sep-pak Plus C18, Sep-pak Plus C18, and Sep-Pak Light C18 pillar or Oasisis HLB Plus pillar [being U.S. Waters Company products] perhaps also can be made the C18 pillar by oneself.
Of the present invention in addition-individual purpose provides 11The application of C-methyl NSC 94600 in preparation tumour pet imaging agent.
11The bio distribution experiment of C-methyl NSC 94600 and Micro-PET video picture show that having blood removes fast characteristics, and increased radioactivity mainly concentrates on liver, intestines, kidney, spleen.Micro-PET shows radioactivity dense gathering in liver of elder generation, and dense gathering in the liver sausage position of back, drug moiety passes through renal metabolism, brain, and muscle and lung's radioactivity are seldom, and be consistent with bio distribution.
The present invention provides compound method to realize that easily robotization is synthetic.At present used clinically 18FDG, 11Developers such as C-choline generally are metabolism class developers, do not have specificity, can not distinguish inflammation and tumour, and 10-of the present invention 11The C-MOCPT is to be the pet imaging agent of target spot with DNA topology isomerase I first, is the tumour-specific developer.
Description of drawings
Fig. 1 is 10- 11The performance liquid collection of illustrative plates of C-MOCPT, a are the radioactivity collection of illustrative plates, and b is a uv absorption spectrum.
Fig. 2 is 10- 11The little PET video picture of C-MOCPT animal in the normal mouse body.
Embodiment
The present invention combines accompanying drawing and specific embodiment to be further described.
Embodiment 1.10- 11The preparation of C-MOCPT
1. the preparation of standard substance 10-Methoxycamptothecine
Take by weighing 10-hydroxycamptothecine 513mg (1.41mmol), add acetone 50mL, add Anhydrous potassium carbonate 602mg (4.36mmol), add the about 0.4mL of methyl iodide (7.89mmol) rapidly, bathe 60 ℃ of stirrings outward.After passing through 13h approximately, raw material point is basic to disappear.Remove the reaction solution solvent under reduced pressure, add entry 45mL under the ice bath, this moment, PH was about 8～9, left standstill 1h, filtered, and filter residue is with a small amount of petroleum ether.Obtain thick product 450mg, thick product dissolves silica gel (100～200 order) column chromatography (methylene dichloride: methyl alcohol), get pure article 120mg faint yellow solid with an amount of chloroform-methanol.mp：251-254℃； 1HNMR(400MHz，DMSO-d6)：δ0.87(t，J＝7.26Hz，3H，CH 2CH 3)，1.86(m，2H，CH 2CH 3)，3.92(s，3H，OCH3)，5.20(s，2H，H-17)，5.40(s，2H，H-5)，6.50(s，1H，20-OH)，7.25(s，1H，H-14)，7.46(m，2H，H-9，11)，8.01(d，J＝9.89Hz，1H，H-12)，8.50(s，1H，H-7)；MS(ESI)：m/z?379(MH+)。
2.10- 11The preparation of C-MOCPT
Method one: by the accelerator warp 14N (p, α) 11The C reacted 11C, 11Oxygen in C and the target generates 11The C-carbonic acid gas, 11C-carbonic acid gas and lithium aluminium hydride (LiAlH 4) reaction, generate with hydroiodic acid HI (HI) reaction again 11The C-methyl iodide ( 11CH 3I), 11The C-methyl iodide ( 11CH 3I) be passed among the 300uL DMSO of a certain amount of 10-hydroxycamptothecine, add K2CO3 in the solution in advance, sealing, 60 degree heating 3-5min; Separation method 1: mixture advances HPLC and separates the separation condition of HPLC: C18 separator column, moving phase are V (water): V (second eyeball)=70: 30; 4min/mL, product appears in 8min, collects the back and adds 10mL water; Cross the C-18 post, get off, be diluted to 10% with the 3mL alcohol flushing.Separation method 2: add 10mL water, cross the C-18 post,, get off with the 3mL alcohol flushing again, be diluted to 10% with 1.5mL 50% alcohol flushing precursor.
Method two: by the accelerator warp 14N (p, α) 11The C reacted 11C, 11Oxygen in C and the target generates 11The C-carbonic acid gas, 11C-carbonic acid gas and lithium aluminium hydride (LiAlH 4) reaction, generate with hydroiodic acid HI (HI) reaction again 11The C-methyl iodide ( 11CH 3I), 11The C-methyl iodide ( 11CH 3I) online changing into 11C-Triflate-methane, 11C-Triflate-methane is passed among the 300uL DMSO of a certain amount of 10-hydroxycamptothecine, adds K2CO3 in the solution in advance, sealing, 60 degree heating 3-5min; Separation method 1: mixture advances HPLC and separates the separation condition of HPLC: C18 separator column, moving phase are V (water): V (second eyeball)=70: 30; 4min/mL, product appears in 8min, collects the back and adds 10mL water; Cross the C-18 post, get off, be diluted to 10% with the 3mL alcohol flushing.Separation method 2: add 10mL water, cross the C-18 post,, get off with the 3mL alcohol flushing again, be diluted to 10% with 1.5mL 50% alcohol flushing precursor.
The result: the structure of the standard substance of 10-Methoxycamptothecine through mass spectrum (ESI) and 1H NMR identifies confirmation.Analyze the 10-of preparation through HPLC 11The t of the standard substance of C-MOCPT and 10-Methoxycamptothecine RRT is consistent.Referring to Fig. 1.
10- 11C-MOCPT injecting fluid is colourless or faint yellow clear and bright solution; PH is about 6.0-7.5; Radiochemicsl purity is greater than 95%; Always proofread and correct that putting productive rate is 15-40%, the inspections of undue toxicity inspection, sterility test and bacterial endotoxin are undertaken by Pharmacopoeia of People's Republic of China said method of version in 2005.The undue toxicity inspection: 6 KM kind mouse, tail intravenously administrable 37MBq/ only observes 48h, and the mouse growth is normal, and no death and untoward reaction phenomenon take place, and dissect the back and observe, and do not see any organ damage.Sterility test and bacterial endotoxin inspection are all negative.
Embodiment 2.10- 11The C-MOCPT distributes in the normal mouse body.
Km kind mouse is divided into 4 groups at random, and 4 every group, tail vein injection is through the 10-of saline water dilution 11The C-MOCPT, every 1.85Mbq (0.2mL).Injection back is respectively at 1,15,45 and 60min put to death, eye is got blood, brain, lung, the heart, liver,spleen,kidney, intestines, muscle, bone respectively, measures radiocounting respectively and weighs, and calculates every gram and organizes percentage injection dose rate (%ID/g).
Table 1 has been summed up 11The C-MOCPT is in the intravital bio distribution of KM mouse, 11The C-MOCPT absorbs in KM mouse body rapidly, distributes extensively, removes soon at mouse body inner blood, and uptake ratio is the highest during 1min, reduces rapidly behind the 15min.When vein injects 11C-MOCPT 1min; Distribute at most with the heart, kidney, reflect that medicine passes through at first to get into heart, be transported to each organ of whole body fast; Most internal organs uptake ratio when 15min reaches mxm., after reduce gradually or be in metastable state; During 15min, liver, intestines, kidney, spleen tissue have the high radioactivity picked-up, and radioactivity all obviously reduces in the administration 60min, each internal organs.Drug main will be through the liver and gall metabolism, and the increased radioactivity behind the hepatic tissue 15min peaks, and is 7.31 ± 1.67%, and is the highest and remove slower in each tissue distribution; Next is an intestinal tissue, 15min the time, increased radioactivity is 2.74 ± 0.98%; Be reduced to 2.45 ± 0.51% during 60min, other tissue radiation property picked-ups are progressively increased relatively, and radioactivity is removed slower; If drug main is described through the Digestive tract metabolism, kidney is higher at one minute radioactive uptake, reduces very fast thereafter; Explain drug moiety discharge by urine after the metabolism in vivo through the renal metabolism NSC 107124 less, little to the urinary system pungency, renal function is not had influence.Other internal organs brain radioactive uptakes are lower all the time, explain that medicine can not pass through hemato encephalic barrier, lung, and flesh, the bone radioactive uptake is lower.
Table 1 11The C-MOCPT is at the intravital bio distribution %ID/g of normal mouse
Figure BDA0000124258370000051
Annotate: the mouse number is 4, and data are mean ± se in the table
Embodiment 3. 11The C-MOCPT is in the little PET video picture of animal of normal mouse
1. the little PET video picture of the animal of normal mouse
The fasting of KM kind mouse is 4-6 hour before the inspection, behind the tail vein injection 0.2mCi, carries out the Micro-PET video picture after the anesthesia, and continuous sweep 60min obtains image through CP.
2.10- 11The C-MOCPT is in the little PET video picture of the animal result of normal mouse
The result is referring to Fig. 2 for the little PET video picture of animal; The drug main that can visually see will develop at liver, can see liver behind the 12min, and enteron aisle and bladder all have development; Heart, lung, muscle, brain, bone radioactivity are developed very light; Explain that drug main will pass through the liver sausage metabolism, part is through renal metabolism, and is consistent with bio distribution.

Claims (6)

1. 10- 11The preparation method of C-MOCPT, said 10- 11The chemical formula of C-MOCPT be [ 11C]-C 21H 18N 2O 5, structural formula is:
Figure FDA0000124258360000011
It is characterized in that, obtain through following preparation process: by the magnetic resonance acceleator warp 14N (p, α) 11The C reacted 11C, 11Oxygen in C and the target generates 11The C-carbonic acid gas ( 11CO 2), 11C-carbonic acid gas and lithium aluminium hydride (LiAlH 4) reaction, generate with hydroiodic acid HI (HI) reaction again 11The C-methyl iodide ( 11CH 3I), 11The C-methyl iodide ( 11CH 3I) weak caustic solution with 10-hydroxycamptothecine reacts, and reactant is separated obtaining title product with HPLC separation or SPE C18 post,
Synthetic route:
Figure FDA0000124258360000012
2. 10- 11The preparation method of C-MOCPT, said 10- 11The chemical formula of C-MOCPT be [ 11C]-C 21H 18N 2O 5, structural formula is:
Figure FDA0000124258360000013
It is characterized in that, obtain through following preparation process: by the magnetic resonance acceleator warp 14N (p, α) 11The C reacted 11C, 11Oxygen in C and the target generates 11The C-carbonic acid gas, 11C-carbonic acid gas and lithium aluminium hydride (LiAlH 4) reaction, generate with hydroiodic acid HI (HI) reaction again 11The C-methyl iodide ( 11CH 3I), 11The C-methyl iodide ( 11CH 3I) online Triflate-Ag post through 200 ℃ is converted into 11C-triflate-methane, 11The weak caustic solution reaction of C-triflate-methane and 10-hydroxycamptothecine obtains title product with reactant with HPLC separation or the separation of SPE C18 post,
Synthetic route:
Figure FDA0000124258360000021
3. a kind of 10-according to claim 2 11The preparation method of C-MOCPT is characterized in that, the weak base that said weakly alkaline solution is selected for use is salt of wormwood, sodium hydrogencarbonate, tetra-n-butyl oxyammonia; Strontium carbonate powder, Trimethylamine 99 or triethylamine, solvent is selected methyl-sulphoxide for use, N; Dinethylformamide, second eyeball, ethanol, methyl alcohol or acetone.
4. a kind of 10-according to claim 1 and 2 11The preparation method of C-MOCPT is characterized in that, said separator column is the performance liquid C18 post of divergence type, and moving phase is the leacheate of second eyeball and water or the leacheate of ethanol and water.
5. a kind of 10-according to claim 1 and 2 11The preparation method of C-MOCPT is characterized in that, the C18 post is selected Sep-pak Plus C18 for use, Sep-pak Plus C18, Sep-Pak Light C18 pillar or Oasisis HLB Plus pillar.
6. according to a kind of 10-of claim 1 or the preparation of 2 said methods 11The application of C-MOCPT in preparation tumour pet imaging agent.
CN2011104379583A 2011-12-23 2011-12-23 Preparation method and use of 10-<11>C-methoxycamptothecin Pending CN102746315A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109180554A (en) * 2018-10-19 2019-01-11 广东石油化工学院 A kind of method of methylation reaction
CN109369506A (en) * 2018-12-12 2019-02-22 广东石油化工学院 A kind of method of selective N-methylation second level amide
CN113717189A (en) * 2021-10-08 2021-11-30 哈尔滨理工大学 Preparation method of 10-methoxy camptothecin

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109180554A (en) * 2018-10-19 2019-01-11 广东石油化工学院 A kind of method of methylation reaction
CN109180554B (en) * 2018-10-19 2022-04-29 广东石油化工学院 Methylation reaction method
CN109369506A (en) * 2018-12-12 2019-02-22 广东石油化工学院 A kind of method of selective N-methylation second level amide
CN109369506B (en) * 2018-12-12 2022-05-31 广东石油化工学院 Method for selectively N-methylating secondary amide
CN113717189A (en) * 2021-10-08 2021-11-30 哈尔滨理工大学 Preparation method of 10-methoxy camptothecin
CN113717189B (en) * 2021-10-08 2024-01-26 哈尔滨理工大学 Preparation method of 10-methoxy camptothecine

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Application publication date: 20121024