CN110483278A - The fluoro- 3- of 2,2- bis-18F- fluoropropionic acid and its synthetic method and application - Google Patents

The fluoro- 3- of 2,2- bis-18F- fluoropropionic acid and its synthetic method and application Download PDF

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CN110483278A
CN110483278A CN201910720483.5A CN201910720483A CN110483278A CN 110483278 A CN110483278 A CN 110483278A CN 201910720483 A CN201910720483 A CN 201910720483A CN 110483278 A CN110483278 A CN 110483278A
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唐刚华
张占文
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Abstract

The invention discloses the fluoro- 3- of 2,2- bis-18F- fluoropropionic acid and its synthetic method and application.The fluoro- 3- of 2,2- bis- of the invention18F- fluoropropionic acid, for precursor, is total to two-step reaction synthesis through nucleophilic fluorination reaction and hydrolysis with bromo- 2, the 2- difluoro ethyl propionate of 3-.The fluoro- 3- of 2,2- bis- of the invention18F- fluoropropionic acid pharmacodynamics, pharmacokinetics and in terms of show to stablize in vivo not defluorinate, have with11C- acetate (11C-AC excellent pharmacokinetic properties similar in) are a kind of High sensitivities, special and safely and effectively Novel PET imaging agent, have wide application prospect in the Positron emission tomography agent drug of preparation tumour lipid metabolism.

Description

The fluoro- 3- of 2,2- bis-18F- fluoropropionic acid and its synthetic method and application
Technical field
The present invention relates to Positron emission tomography agent technical fields, and in particular to 2,2- bis- fluoro- 3-18F- fluoropropionic acid (3-18F-FPA、3-[18F] FPA) and its synthetic method and application.
Background technique
Positron emission fault (positron emission tomography, PET) be at present it is only can be on living body It shows biomolecule metabolism, receptor and the movable New video technology of neurotransmitter, has been widely used in the diagnosis of a variety of diseases With antidiastole, state of an illness judgement, therapeutic evaluation, organ function research and new drug development etc..
11C- acetate (11It C-AC is) for measuring heart and brain oxidative metabolism, kinds of tumors (such as urinary tumor, incidence Cancer, hepatocellular carcinoma etc.) lipid metabolism positron emission fault (positron emission tomography, PET) imaging Agent is higher than 2- to the detection sensitivity for including the tumours such as urinary tumor, head-neck carcinoma, hepatocellular carcinoma18F-2- deoxidation-D- grape Sugar (18F-FDG、[18F]FDG).But11C half-life period is shorter, and half-life period is only 23.4min, need to be provided immediately by accelerator, and not It can be carried out delayed imaging.
18F- fluoroacetate (18F-FAC) it is11The analog of C-AC, can overcome the disadvantages that11The deficiency of C-AC, and have been used for forefront The PET of gland cancer transfer and glioma images research, and has shown that preferable application prospect, has and replaces11C-AC's becomes Gesture.
However,18F-FAC have internal defluorinate and with11The limitation of the different internal pharmacokinetic properties of C-AC Property.And 2-18F- fluoropropionic acid (18F-FPA、2-[18F] FPA) it overcomes11C-AC and18The limitation of F-FAC is shown very well Potential applicability in clinical practice, but it is shown as the defect of no optical activity racemic mixture, in pharmacodynamics, pharmacokinetics and toxicology etc. Aspect stereoselectivity is poor.
Summary of the invention
The object of the invention is in order to overcome current 2-18F- fluoropropionic acid (18F-FPA) racemic mixture is in medicine Effect learns, pharmacokinetics and toxicology etc. the poor disadvantage of stereoselectivity, provide a kind of internal stabilization not defluorinate, have with11Excellent pharmacokinetic properties and High sensitivity similar in C-AC and special Novel PET imaging agent, i.e. 2,2- bis- fluoro- 3 -18F- fluoropropionic acid (3-18F-FPA、3-[18F]FPA)。
The object of the invention is also to provide synthesize the fluoro- 3- of 2,2- bis- described above18The method of F- fluoropropionic acid.
Another object of the present invention, which also resides in, provides the fluoro- 3- of 2,2- bis- described above18F- fluoropropionic acid is preparing positive electricity Application in sub- emission tomography developer drug.
The purpose of the present invention is achieved through the following technical solutions.
The fluoro- 3- of 2,2- bis-18F- fluoropropionic acid, chemical structural formula is as shown in formula Ι:
Bio distribution is the result shows that the fluoro- 3- of 2,2- bis-18F- fluoropropionic acid (3- [18F] FPA) it shows as in blood most High increased radioactivity, and over time, the process gradually slowly declined is shown as, is one in Cardiac Manifestation Relatively high radioactive uptake and slowly removing.3-[18F] FPA brain, lung, liver, spleen, muscle, stomach, intestines, bone etc. organize A relatively medium or slightly lower radioactive uptake is shown as in organ, removing is slower, sends out in vivo without defluorinate phenomenon It is raw.
By 3- [18F]FPA、2-[18F] FPA and [18F] FDG shows 3- to the PET of 145 tumour of prostate cancer DU imaging [18F] radioactive uptake of the FPA in tumour be apparently higher than 2- [18F] FPA and [18F]FDG；Moreover, 3- [18F] FPA tumour/ The ratio of the ratio of muscle (T/M) and tumour/liver (T/L) obviously higher than 2- [18F] FPA and [18F]FDG。
Meanwhile by 3- [18F]FPA、2-[18F] FPA and [18F] FDG shows the PET of prostate cancer PC-3 tumour imaging 3-[18F] radioactive uptake of the FPA in tumour be apparently higher than 2- [18F] FPA and [18F]FDG。
The synthesis fluoro- 3- of 2,2- bis-18The method of F- fluoropropionic acid, with bromo- 2, the 2- difluoro ethyl propionate of 3- for precursor, Through nucleophilic fluorination reaction and hydrolysis synthesis.
Preferably, the synthetic method, specifically comprises the following steps:
(1) nucleophilic fluorination reacts synthetic intermediate:
With bromo- 2, the 2- difluoro ethyl propionate of 3- for precursor, under the catalytic action of catalyst, with [K/K222]+18F-(ammonia Base polyethers potassium compound) nucleophilic fluorination reaction occurs, obtain intermediate 2, the fluoro- 3- of 2- bis-18F- fluoropropionic acid ethyl ester；
(2) hydrolysis synthesizes target product:
The fluoro- 3- of intermediate 2,2- bis-18F- fluoropropionic acid ethyl ester obtains target product through hydrolysis, i.e., described 2, the 2- bis- Fluoro- 3-18F- fluoropropionic acid；
Specific synthetic route is as shown in reaction equation Ι:
It is furthermore preferred that the synthetic method, in step (1), the catalyst is selected from amino-polyether catalyst, including 4, 7,13,16,21,24- six oxa- -1,10- diazabicyclo [8,8,8] hexacosane (Kryptofix2.2.2, K222).
Still more preferably, the mass ratio of the precursor and the catalyst is 1:6.5~7.5.
It is furthermore preferred that the synthetic method, in step (1), the nucleophilic fluorination reaction is to react 5 at 85~110 DEG C ~15min, further preferably 110 DEG C reaction 10min.
It is furthermore preferred that the synthetic method, in step (2), the hydrolysis is carried out in alkaline condition, hydrolytic reagent choosing With the alkaline solution including sodium hydroxide solution.
It is furthermore preferred that the synthetic method, in step (2), the hydrolysis is reacted using On-column hydrolysis.
Still more preferably, the fluoro- 3- of 2,2- bis- of the invention18F- fluoropropionic acid radiation synthetic method is simple, activation It is higher to learn yield, is convenient for Fully automated synthesis, can be used18F-FDG Fully automated synthesis instrument is completed under the control of the computer, is specifically included Following steps:
(1)18F-F-Trapping；(2) solvent evaporates；(3) fluorination reaction；(4) it is trapped in column；(5) in column basic hydrolysis；(6) in With with isolate and purify, obtain 3-18F-FPA injection.
The fluoro- 3- of 2,2- bis- of the invention18In the synthetic method of F- fluoropropionic acid, it is with bromo- 2, the 2- difluoro ethyl propionate of 3- Precursor, in catalyst 4,7,13,16,21,24- six oxa- -1,10- diazabicyclo [8,8,8] hexacosane Under (Kryptofix2.2.2, K222) effect, with [K/K222]18Nucleophilic fluorination reaction occurs for F, and further occurrence is in column after reaction Hydrolysis obtains 3-18F-FPA, and can realize full-automatic synthesis.Wherein, with18F-For starting material, 3-18F-FPA does not decline Correction down putting yield is 20-30%, and total Radiochemical purity time is 35min (n=10), and specific activity is not less than 3.7 × 1010Bq/ mmol；It is detected through radioactivity HPLC (high performance liquid chromatography),18F-Retention time (Rt) is about 5.5min, with its standard items 3-19F- FPA retention time is consistent.The 3- of full-automation synthesis18F-FPA injection be in colorless cleared solution, pH value between 6.0-7.5, And 3- is measured through radioactivity HPLC18The radiochemical purity of F-FPA is greater than 98%.
The fluoro- 3- of 2,2- bis-18Application of the F- fluoropropionic acid in preparation Positron emission tomography agent drug.
Preferably, in the application, the Positron emission tomography agent drug includes for measuring lung cancer, forefront The Positron emission tomography agent drug of the lipid metabolisms such as gland cancer, hepatoma or brain tumor.
Preferably, in the application, the Positron emission tomography agent drug includes for measuring heart and brain lipid The Positron emission tomography agent drug of metabolism.
Compared with prior art, the invention has the advantages that and the utility model has the advantages that
The fluoro- 3- of 2,2- bis- of the invention18F- fluoropropionic acid (3- [18F] FPA) overcome current 2-18F- fluoropropionic acid (18F- FPA) the defect of racemic mixture, pharmacodynamics, pharmacokinetics and in terms of show to stablize not defluorinate in vivo, have With11C- acetate (11C-AC excellent pharmacokinetic properties similar in) are a kind of High sensitivities, special and safely and effectively new Type PET imaging agent has wide application prospect in the Positron emission tomography agent drug of preparation tumour lipid metabolism；And The fluoro- 3- of 2,2- bis-18F- fluoropropionic acid can effectively realize Fully automated synthesis, be conducive to its extensive synthesis and application.
Detailed description of the invention
Fig. 1 is 3- of the invention in embodiment 118The process flow chart of F-FPA Fully automated synthesis；
Fig. 2 a is the 3- that embodiment 1 synthesizes18The HPLC analysis of spectra of F-FPA before purification；
Fig. 2 b is the 3- that embodiment 1 synthesizes18The HPLC analysis of spectra of F-FPA after purification；
Fig. 3 is 3- of the invention in embodiment 318F-FPA is in normal mouse vivo biodistribution distribution results figure；
Fig. 4 is the PET comparison imaging figure of 145 cell strain nude mice model of lotus prostate cancer DU in embodiment 4；
Fig. 5 is the PET comparison imaging figure of lotus Human Prostate Cancer PC-3 Cell Line strain nude mice model in embodiment 4.
Specific embodiment
Technical solution of the present invention is described in further detail below in conjunction with specific embodiments and drawings, but the present invention Protection scope and embodiment it is without being limited thereto.
It uses18F-FDG Fully automated synthesis instrument is improved TRACERlab FX F-N Fully automated synthesis instrument, comprising: (1) It directly will be accelerator-produced18F-Target water transfer conduit is connected with V10,18F-Target water is delivered directly to be placed in radioactivity prospecting In Sep-Pak light QMA pillar in device, exhaust needle is inserted into No. 16 bottles；(2) small using Sep-Pak light QMA Column, Sep-Pak plus C18 pillar, Sep-PakAl2O3Pillar and Sep-Pak SCX pillar replace complete point of import high price From purification column, (anion exchange pillar contains PS-H+、PS-HCO3、Al2O3With HR-P column), it is isolated and purified；(3) it edits simultaneously It improves18F-F-Separation, fluorination hydrolysis and column separating purification program.
Wherein, PET trace cyclotron and TRACERlab FX F-N Fully automated synthesis instrument, it is public purchased from U.S. GE Department；Sep-Pak light QMA pillar, Sep-Pak plus C18 pillar and Sep-Pak Al2O3Pillar is purchased from the U.S. Waters company；Sep-Pak SCX pillar is self-control.
Using18F-FDG Fully automated synthesis instrument completes 3- under the control of the computer18F-FPA automated production, flow chart ginseng As shown in Figure 1, key step includes:
(1)18F-F-Trapping.Passed through by PET trace cyclotron18O(p,n)18F nuclear reaction production18F-F-, in N2 Airborne leukorrhagia, by the Sep-Pak light QMA anion pillar being placed in radioactive activity measuring meter,18F-F-It is trapped in small In column,18O- water is collected in returnable bottle.
(2) solvent evaporates.In N2Under effect, K is contained in headpin2CO3It, will with the acetonitrile solution of K22218F-F-Elute into In confined reaction bottle, heating mixed solution to 60~95 DEG C, evaporated under reduced pressure obtains dry [K/K222]18F, waste liquid is by being placed in Cold-trap in liquid nitrogen absorbs.
(3) fluorination reaction.In N2Under gas effect, bromo- 2, the 2- difluoro ethyl propionate acetonitrile solution of precursor -3- in No. 3 bottles It is pressed into reaction flask, heating reaction.After the completion of fluorination reaction, it is concentrated under reduced pressure, it is cooling.
(4) it is trapped in column.In N2Under airflow function, fluorinated intermediates and H in No. 2 bottles2O mixed liquor is transmitted over two Sep-Pak plus C18 pillar and a Sep-Pak Al2O3In pillar, intermediate 2, the fluoro- 3- of 2- bis-18F- fluoropropionic acid second Ester is trapped by Sep-Pak plus C18 pillar.With H in No. 4 bottles2O washs pillar, and uses N2Drying, the waste liquid containing acetonitrile-water are received Collection is in waste bottle.
(5) in column basic hydrolysis.NaOH solution is pressed into reaction flask in kingpin, and is loaded into two SepPak plus In C18 pillar, hydrolysis.
(6) it neutralizes and isolates and purifies.Product in water elution Sep-Pak plus C18 pillar in No. 6 bottles, passes through Sep- In Pak SCX pillar and NaOH solution, leacheate is in N2Under atmospheric pressure effect, collect after sterilised membrane filter is handled in sterile product In bottle, 3- is obtained18F-FPA injection.
Embodiment 1
1.1 synthetic route
The fluoro- 3- of 2,2- bis- of the invention18F- fluoropropionic acid (3-18F-FPA before) being with the bromo- 2,2- difluoro ethyl propionate of 3- Body, through nucleophilic fluorination and in column hydrolysis two-step reaction synthesis.
Specifically, 3-18The synthetic route of F-FPA is as shown in reaction equation Ι:
Wherein, with bromo- 2, the 2- difluoro ethyl propionate of 3- for precursor, in 4,7,13,16,21,24- six oxa- -1 of catalyst, Under 10- diazabicyclo [8,8,8] hexacosane (Kryptofix2.2.2, K222) effect, with [K/K222]18Fluorine occurs for F Change reaction, generates intermediate 2, the fluoro- 3- of 2- bis-18F- fluoropropionic acid ethyl ester.The fluoro- 3- of intermediate 2,2- bis-18F- fluoropropionic acid ethyl ester It is carried out after column hydrolysis by with sodium hydroxide solution, after isolating and purifying, crosses sterilised membrane filter, obtain 3-18F-FPA injection.
1.2 Fully automated synthesis
3- is prepared using On-column hydrolysis18F-FPA, Fully automated synthesis process are shown in Fig. 1, wherein18O- water is collected in In returnable bottle, waste liquid is absorbed by the cold-trap being placed in liquid nitrogen, and the waste collection of the water containing acetonitrile is in waste bottle, and manufactured goods are through sterile The V in sterile product bottle is collected after filter membrane processing1-V13V1,-V6, it is valve, Al2O3, C-18, SCX be respectively Sep-Pak Al2O3Pillar, Sep-Pak plus C18 pillar and Sep-Pak SCX pillar.
Using18F-FDG Fully automated synthesis instrument completes 3- under the control of the computer18F-FPA automated production, specifically includes that
(1)18F-F-Trapping.Passed through by PET trace cyclotron18O(p,n)18F nuclear reaction production18F-F-, in N2 Airborne leukorrhagia, by the Sep-Pak light QMA anion pillar being placed in radioactive activity measuring meter,18F-F-It is trapped in small In column,18O- water is collected in returnable bottle.
(2) solvent evaporates.In N2Under effect, K containing 3mg in headpin2CO3With the acetonitrile solution of 13mg K222 (1.0mL), will18F-F-It elutes in confined reaction bottle, heating mixed solution to 95 DEG C, evaporated under reduced pressure obtains dry [K/ K222]18F, waste liquid are absorbed by the cold-trap being placed in liquid nitrogen.
(3) fluorination reaction.In N2Under gas effect, bromo- 2,2- difluoro ethyl propionate (2mg) acetonitrile of precursor -3- in No. 3 bottles Solution (1mL) is pressed into reaction flask, and 15min is reacted in 110 DEG C of heating.After the completion of fluorination reaction, it is concentrated under reduced pressure, it is cooling.
(4) it is trapped in column.In N2Under airflow function, fluorinated intermediates and H in No. 2 bottles2O mixed liquor (10mL) is passed through by transmission Cross two Sep-Pak plus C18 pillars and a Sep-Pak Al2O3In pillar, intermediate 2, the fluoro- 3- of 2- bis-18F- fluoro Ethyl propionate is trapped by Sep-Pak plus C18 pillar.With the H in No. 4 bottles2O (10mL) washs pillar, and uses N2Drying, contains The waste collection of acetonitrile-water is in waste bottle.
(5) in column basic hydrolysis.NaOH solution (1.0mL, 2mol/mL) is pressed into reaction flask in kingpin, and is loaded into two In a Sep Pak plus C18 pillar, the Hydrolysis At Room Temperature reaction time is 2min.
(6) it neutralizes and isolates and purifies.Product in water (10mL) elution Sep-Pak plus C18 pillar in No. 6 bottles, leads to It crosses in Sep-Pak SCX pillar and NaOH solution, leacheate is in N2Under atmospheric pressure effect, collect after sterilised membrane filter is handled in nothing In bacterium product bottle, 3- is obtained18F-FPA injection.
Standard items 2, the fluoro- 3- of 2- bis-19F- fluoropropionic acid (3-19F-FPA) according to 3-18The similar method system of F-FPA It is standby, and its structure is confirmed by mass spectrum (MS).
1.3 radiation composite results
PET drug 3-18F-FPA, for precursor, hydrolyzes two steps through nucleophilic fluorination and in column with bromo- 2, the 2- difluoro ethyl propionate of 3- Reaction, and use18F-FDG Fully automated synthesis instrument realizes its full-automation synthesis.With18F-For starting material, 3-18F-FPA does not decline Correction down putting yield is 20-30%, and total Radiochemical purity time is 35min (n=10), and specific activity is not less than 3.7 × 1010Bq/ mmol。
2 product quality inspection of embodiment
2.1 radiochemicsl purity detection methods
With the standard items 3- for the determination structure that embodiment 1 synthesizes19The 3- that F-FPA and embodiment 1 synthesize18F-FPA injection It is injected into high performance liquid chromatograph together, to determine whether its retention time is consistent.
HPLC analysis condition:
Analytical column is ZORBAX Eclipse XDB-C18 column, and mobile phase is the acetonitrile solution and 0.1%TFA of 0.1%TFA Aqueous solution.Row gradient elution: when 0min, aqueous solution=2/98 acetonitrile solution/0.1%TFA containing 0.1%TFA；Gradually rise When to 8min, aqueous solution=10/90 acetonitrile solution/0.1%TFA of 0.1%TFA；When being raised again to 20min, 0.1%TFA's Aqueous solution=80/20 acetonitrile solution/0.1%TFA.Flow velocity is 1mL/min, ultraviolet detection wavelength 210nm.
2.2 quality test results
It is detected through radioactivity HPLC,18F-Retention time (Rt) is about 5.5min, 3-18F-FPA and its standard items 3-19F- The retention time of FPA is consistent.3-18F-FPA injection is in colorless cleared solution, and pH value is between 6.0-7.5.It is efficient with radioactivity Liquid chromatogram (HPLC) measures 3-18The radiochemical purity of F-FPA injection, can by Fig. 2 a and Fig. 2 b as shown in Fig. 2 a and Fig. 2 b Know, measures 3- through radioactivity HPLC18The radiochemical purity of F-FPA is greater than 98%.
3 3- of embodiment18F-FPA vivo biodistribution distribution experiments
3.1 vivo biodistribution measures of spread
Measure the 3- that embodiment 1 synthesizes18F-FPA is in the intracorporal bio distribution of normal kunming mice.
Taking weight is healthy kunming mice 20 of 20~25g, is randomly divided into 5 groups, 4 mouse of each time point.Abdominal cavity After injecting 5% chloraldurate (6mL/kg) anesthetized mice, tail vein injection 0.2mL contains 0.37-0.55MBq (10-15 μ Ci) 3-18F-FPA injection, 5,30,60,90 and 120min is grouped after injection, and after removal eyeball takes blood, cervical dislocation is put to death Mouse.The tissue of interest samples such as brain, heart, lung, liver, spleen, pancreas, kidney, stomach, small intestine, right thigh muscle and humerus are taken after dissection This, weighing measures radiocounting with γ calculating instrument, and all measurement data deduct background, are then averaged calculating through decaying Uptake ratio %ID/g in different time periods after correction.
Biodistribution result in 3.2 Mice Bodies
3-18F-FPA is shown in Fig. 3 in normal mouse vivo biodistribution distribution results.Vivo biodistribution distribution shows small as shown in Figure 3 Tail vein injection 3-18After F-FPA, 3- [18F] FPA shows as highest increased radioactivity in blood, from the 4.14 of 5min 3.65 ± 0.54%ID/g of ± 0.32%ID/g to 120min shows as the process gradually slowly declined.5min kidney It is dense poly- to show as apparent radioactivity, relatively quick excretion is shown as in 30min, from 3.55 ± 0.76%ID/g of 5min 2.68 ± the 0.31%ID/g for dropping to 30min is a relatively slow decline process from 30min to 120min.In In 120min, Cardiac Manifestation is a relatively high radioactive uptake and slowly removes.3-[18F] FPA is in brain, lung, liver Show as a relatively medium or slightly lower radioactive uptake in the histoorgans such as dirty, spleen, muscle, stomach, intestines, bone, remove compared with Slowly, there is no defluorinate phenomenon in vivo.
4 3- of embodiment18F-FPA small animal position emission tomography (PET)/CT imaging experiment
4.1 small animal position emission tomography (PET)s/CT developing method
Small animal position emission tomography (PET)-the CT (Siemens) of model mice is imaged: after intraperitoneal injection amobarbital (5mL/kg) anesthesia, by Tail vein injection imaging agent 100-150 μ Ci (0.2mL, about 3.7-5.5MBq), go respectively for three days on end [18F] FDG, the conjunction of embodiment 1 At 3- [18F]FPA、2-[18F] FPA scanning.After CT scan, (30,60,90min) acquire PET data, warp in different time points After correction for attenuation, iterative approximation obtains cross section, sagittal plane, coronal-plane faultage image and PET/CT blending image.Use software (Inevon Researc PET Workplace 4.1) sketches the contours of the area-of-interests such as tumor locus, muscle (ROIs), passes through The radiocounting and volume (default per gram of tissue density is 1g/mL) for measuring region of interest tissue, obtain region of interest tissue Per gram of tissue injection dosage percentage (%ID/g).
4.2 small animal position emission tomography (PET)s/CT image results
3-[18F]FPA、2-[18F] FPA and [18F] FDG is shown in Fig. 4 to the PET of 145 tumour of prostate cancer DU imaging.By Fig. 4 Shown 3- [18F]FPA、2-[18F] FPA and [18F] FDG shows in injection 3- the PET of 145 tumour of prostate cancer DU imaging [18F]FPA、2-[18F] FPA and [18F] 90min after FDG, the radioactive uptake in tumour is respectively 5.60 ± 0.29,3.50 ± 0.36 and 0.62 ± 0.10%ID/g, 3- [18F] radioactive uptake of the FPA in tumour be apparently higher than 2- [18F] FPA and [18F] FDG, difference are statistically significant (P < 0.05).3-[18F]FPA、2-[18F] FPA and [18F] FDG takes the photograph in the radioactivity of liver Respectively 5.30 ± 0.48,5.00 ± 0.18 and 0.70 ± 0.12%ID/g is taken, is respectively 2.70 in the radioactive uptake of muscle ± 0.16,2.50 ± 0.17 and 1.30 ± 0.15%ID/g, injection 3- [18F]FPA、2-[18F] FPA and [18F] 90min after FDG The ratio of tumour/muscle (T/M) is respectively 2.07 ± 0.22,1.40 ± 0.09 and 0.48 ± 0.15, tumour/liver (T/L) Ratio is respectively 1.06 ± 0.07,0.70 ± 0.08 and 0.89 ± 0.12,3- [18F] FPA T/M and T/L ratio obviously higher than 2-[18F] FPA and [18F] FDG, difference is statistically significant (P < 0.05).
[18F]FPA、2-[18F] FPA and [18F] FDG is shown in Fig. 5 to the PET of prostate cancer PC-3 tumour imaging.As shown in Figure 5 3-[18F]FPA、2-[18F] FPA and [18F] FDG to the PET of prostate cancer PC-3 tumour imaging show injection 3- [18F]FPA、 2-[18F] FPA and [18F] 90min after FDG, the radioactive uptake in tumour is respectively 4.10 ± 0.21,3.70 ± 0.36 Hes 3.20 ± 0.33%ID/g, 3- [18F] radioactive uptake of the FPA in tumour be apparently higher than 2- [18F] FPA and [18F] FDG, 3- [18F] FPA with [18F] radioactive uptake difference of the FDG in tumour is statistically significant (P < 0.05).3-[18F]FPA、2- [18F] FPA and [18F] FDG in the radioactive uptake of liver is respectively 4.00 ± 0.45,3.60 ± 0.29 and 3.80 ± 0.41% ID/g, respectively 1.70 ± 0.23,1.80 ± 0.28 and 1.20 ± 0.22%ID/g in muscle, injection 3- [18F]FPA、2- [18F] FPA and [18F] ratio of 90min T/M is respectively 2.41 ± 0.25,2.06 ± 0.32 and 2.67 ± 0.19 after FDG, T/L Ratio be respectively 1.03 ± 0.06,1.03 ± 0.13 and 0.84 ± 0.11.
3-[18F]FPA、2-[18F] FPA and [18F] FDG prostate cancer DU 145 and PC-3 cell strain tumour comparison PET imaging result of study show 3- [18F] imaging results of the FPA in two kinds of cell strain tumours be superior to 2- [18F] FPA, and Difference is more obvious in 145 cell strain of DU.3-[18F] FPA compensate for 2- [18F] FPA takes the photograph in 145 cell strain tumour of DU Take relatively low deficiency, prostate cancer PET imaging in show be it is a kind of than 2- [18F] the more potential positive electron of FPA is short Chain fatty acid metabolic imaging agent.
In summary, the fluoro- 3- of 2,2- bis- of the invention18F- fluoropropionic acid pharmacodynamics, pharmacokinetics and in terms of Stereoselectivity is good, in vivo stable not defluorinate, have with11Excellent pharmacokinetic properties similar in C-AC and height spirit Quick and special optical activity has extensive in the Positron emission tomography agent drug that preparation includes brain tumor lipid metabolism Application prospect.
Above embodiments are only preferred embodiment of the invention, are only that further detailed to technical solution of the present invention work Description, but protection scope of the present invention and embodiment are without being limited thereto, any without departing under spirit of the invention and principle Change, combination, deletion, replacement or modification for being made etc. are included in protection scope of the present invention.

Claims (10)

1.2,2- two fluoro- 3-18F- fluoropropionic acid, which is characterized in that chemical structural formula is as shown in formula Ι:
2.2,2- two fluoro- 3-18The synthetic method of F- fluoropropionic acid, which is characterized in that before being with bromo- 2, the 2- difluoro ethyl propionate of 3- Body is synthesized through nucleophilic fluorination reaction and hydrolysis.
3. synthetic method according to claim 2, which is characterized in that specifically comprise the following steps:
(1) nucleophilic fluorination reacts synthetic intermediate:
With bromo- 2, the 2- difluoro ethyl propionate of 3- for precursor, under the catalytic action of catalyst, with [K/K222]+18F-Nucleophilic occurs Fluorination reaction obtains intermediate 2, the fluoro- 3- of 2- bis-18F- fluoropropionic acid ethyl ester；
(2) hydrolysis synthesizes target product:
The fluoro- 3- of intermediate 2,2- bis-18F- fluoropropionic acid ethyl ester obtains target product through hydrolysis, i.e., described 2, the 2- bis- fluoro- 3 -18F- fluoropropionic acid；
Specific synthetic route is as shown in reaction equation Ι:
4. synthetic method according to claim 3, which is characterized in that in step (1), the catalyst is selected from amino-polyether Catalyst, including 4,7,13,16,21,24- six oxa- -1,10- diazabicyclo [8,8,8] hexacosanes.
5. synthetic method according to claim 3 or 4, which is characterized in that in step (1), the nucleophilic fluorination reaction is In 85~110 DEG C of 5~15min of reaction.
6. synthetic method according to claim 3, which is characterized in that in step (2), the hydrolysis is in alkaline condition It carries out, hydrolytic reagent selects the alkaline solution including sodium hydroxide solution.
7. the synthetic method according to claim 3 or 6, which is characterized in that in step (2), the hydrolysis is used The reaction of column Hydrolyze method.
8.2,2- two fluoro- 3-18Application of the F- fluoropropionic acid in preparation Positron emission tomography agent drug.
9. application according to claim 8, which is characterized in that the Positron emission tomography agent drug includes to be used for Measurement includes lung cancer, prostate cancer, hepatoma or the Positron emission tomography agent drug of brain tumor lipid metabolism.
10. application according to claim 8, which is characterized in that the Positron emission tomography agent drug includes using In the Positron emission tomography agent drug of measurement heart and brain lipid metabolism.
CN201910720483.5A 2019-08-06 2019-08-06 The fluoro- 3- of 2,2- bis-18F- fluoropropionic acid and its synthetic method and application Pending CN110483278A (en)

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