CN106018575B - A kind of method of separating and assaying of PET imaging agent precursors TsOP- (+)-DTBZ and its optical isomer - Google Patents
A kind of method of separating and assaying of PET imaging agent precursors TsOP- (+)-DTBZ and its optical isomer Download PDFInfo
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- CN106018575B CN106018575B CN201610296354.4A CN201610296354A CN106018575B CN 106018575 B CN106018575 B CN 106018575B CN 201610296354 A CN201610296354 A CN 201610296354A CN 106018575 B CN106018575 B CN 106018575B
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The invention discloses a kind of PET imaging agent precursors TsOP (+) DTBZ and its method of separating and assaying of optical isomer, belong to analytical chemistry field.The method of separating and assaying of the present invention is to be detached by the normal phase chromatography of mobile phase of positive mixed solvent using Pirkle type chiral stationary phase chromatography columns.Method using the present invention, energy is simple, quickly and accurately separation detection goes out such PET imaging agent precursors and its optical isomer, effectively controls the quality of precursor TsOP (+) DTBZ.
Description
Technical field
The present invention relates to analytical chemistry fields, and in particular to a kind of PET imaging agent precursors TsOP- (+)-DTBZ and its optics
The method of separating and assaying of isomers.
Background technology
Parkinson's disease (PD) is a kind of common central nervous system degenerative disorders, and the elderly is common, and symptom is main
It shows as：It trembles, shake, splinting, gait aphasis, failure of memory etc. seriously affects normal work and the life of people
It is living, it since people are unfamiliar with early symptom, has missed the treatment best opportunity, therefore has early diagnosed and early treatment pole until making a definite diagnosis
Its is important.The pathogenesis of PD is still unclear at present, and the denaturation of nigrostriatal dopamine serotonergic neuron is that the main pathology of PD is special
Sign.Research thinks that it is that the important of PD morbidities is determined that maincenter vesicular monoamine transporter (VMAT2) caused by gene or environmental factor, which is reduced,
Determine factor, therefore utilize molecular imaging technology, monitors the positron emission tomography (PET) and list of intracerebral VMAT2 levels
The development of photon transmitting computer tomography (SPECT) developer is more popular and forward position field in PD researchs.
18F-FP-(+)-DTBZ(18F-AV133 it is) a kind of excellent18The PET developers of F labels, in brain tissue
VMAT2 is specifically bound, and it is horizontal intuitively to weigh intracerebral VMAT2, has good compatibility, higher with VMAT2 in brain
Brain just absorbs, faster brain is removed, higher target/non-target ratio, is expected to become the PET for early diagnosing and monitoring its process for PD
Imaging medicament, currently, the U.S. is carrying out clinical research.
(chemical name is (+) -2- hydroxyl -3- isobutyl groups -9- (3- (tolysulfonyl oxygroup) fluorine third to TsOP- (+)-DTBZ
Oxygroup) -10- methoxyl groups -1,2,3,4,6,7- hexahydro -11bH- benzos [a] quinolizines, chemical structural formula sees below formula) it is to prepare18F-
The labelled precursor of AV133.Due to18F half-life period is only 110min, is clinically used18F-AV133 must be by precursor compound
TsOP- (+)-DTBZ is prepared in situ.Therefore, the purity concerns of TsOP- (+)-DTBZ arrive18The yield and purity of F-AV133, to
The safety and efficacy for influencing clinical application, for that purpose it is necessary to strictly control the optics of its labelled precursor TsOP- (+)-DTBZ
The content of isomer impurities, to obtain labelled precursor TsOP- (+)-DTBZ of high-purity.
Labelled precursor TsOP- (+)-DTBZ has 3 chiral centres, theoretically there are 8 optical isomers, but combine it
Synthetic method and reaction mechanism analyze most possibly optical isomer impurity, as TsOP- (-)-DTBZ there are one existing,
The impurity can be reacted by succeeding marker, remain in PET developers18In F-AV133, drug quality is influenced.Therefore, it controls
The content of optical isomer impurity in TsOP- (+)-DTBZ, to improving18The quality of F-AV133 ensures the peace of many patients medication
Complete and validity is of great significance.
Realize the matter of labelled precursor TsOP- (+)-DTBZ and its optical isomer efficiently separated in its bulk pharmaceutical chemicals and preparation
Have great importance in amount control, in order to effectively control the quality of this labelled precursor, need to invent it is a kind of can be by TsOP- (+)-
The high-efficient liquid phase determining method that DTBZ is efficiently separated with its optical isomer.
There has been no the reports of labelled precursor TsOP- (+)-DTBZ and its optical isomer method for separating and detecting at present.
Invention content
Therefore, the technical problem to be solved in the present invention is to overcome in the prior art that there has been no labelled precursor TsOP- (+)-
The defect of DTBZ and its optical isomer method for separating and detecting, to provide a kind of PET imaging agent precursors TsOP- (+)-DTBZ and
The method of separating and assaying of its optical isomer, and then realize the separation determination of precursor and its optical isomer.
Technical scheme is as follows：
The method of separating and assaying of a kind of PET imaging agent precursors TsOP- (+)-DTBZ and its optical isomer, to use
Pirkle type chiral stationary phase chromatography columns, using positive mixed solvent as the normal phase chromatography of mobile phase；The two technical characteristics
In conjunction with the separation determination that can effectively realize PET imaging agent precursor TsOP- (+)-DTBZ and its optical isomer.
The Pirkle types chiral stationary phase chromatography column is Chirex chiral chromatographic columns.The chromatographic column can obtain preferably
Analyze ＆ separate effect.
The positive mixed solvent be n-hexane, 1,2- dichloroethanes, the mixed solvent of absolute ethyl alcohol or n-hexane,
1,2- dichloroethanes, absolute ethyl alcohol mixed solvent again in trifluoroacetic acid and triethylamine it is one or two kinds of mixed it is molten
Agent.Absolute ethyl alcohol is other than it can adjust mobile phase polarity in these selected mobile phases in the present invention, due to its stronger proton
It gives and ability to accept, strong Hyarogen-bonding can be formed with solute and stationary phase, thus the change of ethanol content is to separating degree
It is affected.And after different amounts of acid or/and alkalinity additive is added, peak symmetry is more preferable, and separating degree has larger carry
Height, acid or/and alkalinity additive has played important function to the separation of optical isomer in this patent.
N-hexane in the solvent, 1,2- dichloroethanes, absolute ethyl alcohol, trifluoroacetic acid and triethylamine volume ratio be 50
~80：15~40：2~10：0~0.2：0~0.1.In view of the intersolubility of solvent, TsOP- (+)-DTBZ and its optical siomerism
The separating degree and analyze speed of body, selective flow phase composition range effect are best.
Chromatographic condition is as follows：Flow rate of mobile phase is 0.4~1.2mL/min, and chromatographic column column temperature is 20~40 DEG C, and detector is adopted
With UV detector, Detection wavelength 254-280nm.Increase the flow velocity of mobile phase, the retention time of optical isomer is all apparent
Shorten, but separating degree slightly reduces；Chromatogram column temperature is improved, retention time variation is not fairly obvious, can within the scope of room temperature
To obtain more stable separating resulting.
Chromatographic condition is as follows：Flow rate of mobile phase is 0.8mL/min；Chromatographic column column temperature is 25 DEG C；The detection of UV detector
Wavelength is 280nm.This condition can make optical isomer obtain more effective separation detection, obtain best separating degree.
Above-mentioned method of separating and assaying, is realized according to the following steps：
(1) it with flowing phased soln PET imaging agent precursors TsOP- (+)-DTBZ bulk pharmaceutical chemicals or preparation, is configured to every 1mL and contains
The sample solution of precursor TsOP- (+) 0.5~1.5mg of-DTBZ；
(2) Pirkle type chiral stationary phase chromatography columns are used；
(3) 2~20 μ L injecting chromatographs of sample solution of (1) are taken, chromatogram is recorded.
Flow rate of mobile phase is 0.4~1.2mL/min, and it is 254~280nm, color that detection, which uses UV detector, Detection wavelength,
It is 20~40 DEG C to compose column column temperature.
The Detection wavelength of UV detector is 280nm.
The application of above-mentioned method of separating and assaying.
To ensure that the quality of precursor TsOP- (+)-DTBZ bulk pharmaceutical chemicals and formulation products, the present invention pass through repetition test, most
It finds to use Pirkle type chiral stationary phase chromatography columns eventually, and is eluted using organic solvent appropriate, can be efficiently separated
Precursor TsOP- (+)-DTBZ bulk pharmaceutical chemicals and its optical isomer.
Beneficial effects of the present invention：Method using the present invention, peak symmetry is preferable, can simply, quickly and accurately detach
It detects PET imaging agent precursor TsOP- (+)-DTBZ and its optical isomer, effectively controls the matter of precursor TsOP- (+)-DTBZ
Amount.
Separation of the method for separating and detecting of the present invention to TsOP- (+)-DTBZ and its isomers, separating degree are all higher than
1.5。
Description of the drawings
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art are briefly described, it should be apparent that, in being described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, other drawings may also be obtained based on these drawings.
Fig. 1 is 1 high-efficient liquid phase chromatogram of embodiment；
Fig. 2 is 2 high-efficient liquid phase chromatogram of embodiment；
Fig. 3 is 3 high-efficient liquid phase chromatogram of embodiment；
Fig. 4 is 4 high-efficient liquid phase chromatogram of embodiment；
Fig. 5 is 5 high-efficient liquid phase chromatogram of embodiment；
Fig. 6 is 6 high-efficient liquid phase chromatogram of embodiment；
Fig. 7 is 7 high-efficient liquid phase chromatogram of embodiment；
Wherein, the mobile phase in Fig. 1 is n-hexane -1,2- dichloroethanes-absolute ethyl alcohol-trifluoroacetic acid-triethylamine=65：
33：2：0.01：0.005；Mobile phase in Fig. 2 is n-hexane -1,2- dichloroethanes-absolute ethyl alcohol-trifluoroacetic acid-triethylamine
=64.6：32.3：3.1：0.01：0.005；Mobile phase in Fig. 3 is n-hexane -1,2- dichloroethanes-absolute ethyl alcohol-trifluoro second
Acid-triethylamine=64：32：4：0.01：0.005；Mobile phase in Fig. 4 is n-hexane -1,2- dichloroethanes-absolute ethyl alcohol-three
Fluoroacetic acid-triethylamine=63.33：31.67：5：0.01：0.005；Mobile phase in Fig. 5：N-hexane -1,2- dichloroethanes-nothing
Water-ethanol-trifluoroacetic acid=50：40：10：0.2；Mobile phase in Fig. 6：N-hexane -1,2- dichloroethanes-- three second of absolute ethyl alcohol
Amine=80：15：5：0.1；Mobile phase in Fig. 7：N-hexane -1,2- dichloroethanes-absolute ethyl alcohol=70：20：10.
Specific implementation mode
It is to preferably further understand the present invention to provide following embodiments, it is not limited to the best embodiment party
Formula is not construed as limiting present disclosure and protection domain, anyone under the inspiration of the present invention or by the present invention and its
The feature of his prior art be combined and obtain it is any with the present invention it is same or similar as product, all fall within the present invention
Within protection domain.
Specific experiment step or condition person are not specified in embodiment, according to routine experiment described in document in the art
The operation of step or condition can carry out.Reagents or instruments used without specified manufacturer, being can be by acquisition purchased in market
Conventional reagent product.
Reagent used in the present invention can be bought from the market.
The specification of the instrument and chromatographic column that are used in the present invention is：
1525 type highly effective liquid phase chromatographic systems of U.S. Waters and work station；
Chromatographic column is Chirex chiral chromatographic columns；
The wavelength of ultraviolet detection is 254-280nm.
Although only listing Chirex chiral chromatographic columns in the embodiment of the present invention, it is chiral others Pirkle types are not represented
Stationary phase chromatographic column can not achieve the goal of the invention of the present invention, and the Chirex chiral chromatographic columns in embodiment are not to the present invention's
Content and protection domain are construed as limiting, and inventor also did other Pirkle type chiral stationary phase chromatographies a few days ago in the present patent application
The experiment of column, effect is close with the Chirex chiral chromatographic columns in the embodiment of the present invention, will not enumerate herein.
Embodiment one
Instrument and condition
Mobile phase：N-hexane -1,2- dichloroethanes-absolute ethyl alcohol-trifluoroacetic acid-triethylamine=65：33：2：0.01：
0.005
Flow velocity：0.8mL/min
Column temperature：25℃
Sampling volume：20μL
Ultraviolet detection wavelength 280nm
Experimental procedure：
Precision weighs TsOP- (+)-DTBZ and its each 5mg of isomers respectively, sets in 10mL brown volumetric flasks, adds mobile phase
Scale is dissolved and be diluted to, is shaken up, as test solution.Test solution is taken to carry out high performance liquid chromatography point by above-mentioned condition
Analysis records chromatogram.
As a result see attached drawing 1, it can be seen that TsOP- (+)-DTBZ and its isomers reach baseline separation under this condition, efficiently
Liquid chromatograph shows that separating degree is 2.5.
Embodiment two
Instrument and condition
Mobile phase：N-hexane -1,2- dichloroethanes-absolute ethyl alcohol-trifluoroacetic acid-triethylamine=64.6：32.3：3.1：
0.01：0.005
Flow velocity：0.8mL/min
Column temperature：30℃
Sampling volume：20μL
Ultraviolet detection wavelength 280nm
Experimental procedure：
Precision weighs TsOP- (+)-DTBZ and its each 10mg of isomers respectively, sets in 10mL brown volumetric flasks, adds mobile phase
Scale is dissolved and be diluted to, is shaken up, as test solution.Test solution is taken to carry out high performance liquid chromatography point by above-mentioned condition
Analysis records chromatogram.
As a result see attached drawing 2, show that the method for separating and detecting of the present invention can be TsOP- (+)-DTBZ and its isomers point
It opens, high performance liquid chromatograph shows that separating degree is 2.2.
Embodiment three
Instrument and condition
Mobile phase：N-hexane -1,2- dichloroethanes-absolute ethyl alcohol-trifluoroacetic acid-triethylamine=64：32：4：0.01：
0.005
Flow velocity：0.8mL/min
Column temperature：25℃
Sampling volume：20μL
Ultraviolet detection wavelength 280nm
Experimental procedure：
Precision weighs TsOP- (+)-DTBZ and its each 5mg of isomers respectively, sets in 10mL brown volumetric flasks, adds mobile phase
Scale is dissolved and be diluted to, is shaken up, as test solution 1.Another precision weighs TsOP- (+)-DTBZ bulk pharmaceutical chemicals 10mg, sets
In 10mL brown volumetric flasks, adds flowing phased soln and be diluted to scale, shake up, as test solution 2.
It takes test solution to carry out efficient liquid phase chromatographic analysis by above-mentioned condition, records chromatogram, as a result see attached drawing 3.
Fig. 3 proves that this law can be used for the quality testing of TsOP- (+)-DTBZ bulk pharmaceutical chemicals, and high performance liquid chromatograph is shown
Separating degree is 2.0.
Example IV
Instrument and condition
Mobile phase：N-hexane -1,2- dichloroethanes-absolute ethyl alcohol-trifluoroacetic acid-triethylamine=63.33：31.67：5：
0.01：0.005
Flow velocity：0.8mL/min
Column temperature：25℃
Sampling volume：20μL
Ultraviolet detection wavelength 280nm
Experimental procedure：
Precision weighs TsOP- (+)-DTBZ and its each 5mg of isomers respectively, sets in 10mL brown volumetric flasks, adds mobile phase
Scale is dissolved and be diluted to, is shaken up, as test solution 1.Another precision weighs TsOP- (+)-DTBZ preparation 10mg, sets 10mL
In brown volumetric flask, adds flowing phased soln and be diluted to scale, shake up, as test solution 2.
It takes test solution to carry out efficient liquid phase chromatographic analysis by above-mentioned condition, records chromatogram, as a result see attached drawing 4.
Fig. 4 proves, this law can be used for the quality testing of TsOP- (+)-DTBZ preparations, and high performance liquid chromatograph is shown point
It is 2.4 from degree.
Embodiment five
Instrument and condition
Mobile phase：N-hexane -1,2- dichloroethanes-absolute ethyl alcohol-trifluoroacetic acid=50：40：10：0.2
Flow velocity：1.0mL/min
Column temperature：35℃
Sampling volume：2μL
Ultraviolet detection wavelength 270nm
Experimental procedure：
Precision weighs TsOP- (+)-DTBZ and its each 15mg of isomers respectively, sets in 10mL brown volumetric flasks, adds mobile phase
Scale is dissolved and be diluted to, is shaken up, as test solution.Test solution is taken to carry out high performance liquid chromatography point by above-mentioned condition
Analysis records chromatogram.
As a result see attached drawing 5, show that the method for separating and detecting of the present invention can be TsOP- (+)-DTBZ and its isomers point
It opens, high performance liquid chromatograph shows that separating degree is 1.6.
Embodiment six
Instrument and condition
Mobile phase：N-hexane -1,2- dichloroethanes-absolute ethyl alcohol-triethylamine=80：15：5：0.1
Flow velocity：1.2mL/min
Column temperature：40℃
Sampling volume：15μL
Ultraviolet detection wavelength 260nm
Experimental procedure：
Precision weighs TsOP- (+)-DTBZ and its each 12mg of isomers respectively, sets in 10mL brown volumetric flasks, adds mobile phase
Scale is dissolved and be diluted to, is shaken up, as test solution.Test solution is taken to carry out high performance liquid chromatography point by above-mentioned condition
Analysis records chromatogram.
As a result see attached drawing 6, show that the method for separating and detecting of the present invention can be TsOP- (+)-DTBZ and its isomers point
It opens, high performance liquid chromatograph shows that separating degree is 1.7.
Embodiment seven
Instrument and condition
Mobile phase：N-hexane -1,2- dichloroethanes-absolute ethyl alcohol=70：20：10
Flow velocity：0.4mL/min
Column temperature：20℃
Sampling volume：10μL
Ultraviolet detection wavelength 254nm
Experimental procedure：
Precision weighs TsOP- (+)-DTBZ and its each 8mg of isomers respectively, sets in 10mL brown volumetric flasks, adds mobile phase
Scale is dissolved and be diluted to, is shaken up, as test solution.Test solution is taken to carry out high performance liquid chromatography point by above-mentioned condition
Analysis records chromatogram.
As a result see attached drawing 7, show that the method for separating and detecting of the present invention can be TsOP- (+)-DTBZ and its isomers point
It opens, high performance liquid chromatograph shows that separating degree is 1.8.
Obviously the foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to restrict the invention, although with reference to before
Stating embodiment, invention is explained in detail, for those skilled in the art, still can be to aforementioned each
Technical solution recorded in embodiment is modified or equivalent replacement of some of the technical features.Here it is not necessarily to
All embodiments can not be exhaustive.All within the spirits and principles of the present invention, any modification made by is equally replaced
It changes, improve, should all be included in the protection scope of the present invention.
Claims (3)
1. the method for separating and assaying of a kind of PET imaging agent precursors TsOP- (+)-DTBZ and its optical isomer, which is characterized in that
It realizes according to the following steps：
(1) it with flowing phased soln PET imaging agent precursors TsOP- (+)-DTBZ bulk pharmaceutical chemicals or preparation, is configured to before every 1mL contains
The sample solution of body TsOP- (+) 0.5 ~ 1.5mg of-DTBZ；
(2) use Pirkle type chiral stationary phase chromatography columns, using positive mixed solvent as mobile phase, flow rate of mobile phase be 0.4 ~
1.2mL/min, chromatographic column column temperature are 20 ~ 40 DEG C, and detector uses UV detector, Detection wavelength 254-280nm；
(3) 2 ~ 20 μ L injecting chromatographs of sample solution of step (1) are taken, chromatography detection is carried out, record chromatogram；
Wherein, the Pirkle types chiral stationary phase chromatography column is Chirex chiral chromatographic columns；
The positive mixed solvent is n-hexane, 1,2- dichloroethanes, the mixed solvent of absolute ethyl alcohol or n-hexane, 1,2-
Dichloroethanes, absolute ethyl alcohol mixed solvent again with one or two kinds of solvent mixed in trifluoroacetic acid and triethylamine.
2. method of separating and assaying according to claim 1, which is characterized in that the solvent is n-hexane, 1,2-, bis- chloroethenes
Alkane, absolute ethyl alcohol, trifluoroacetic acid and triethylamine volume ratio be 50 ~ 80：15~40 ：2~10 ：0~0.2 ：0 ~ 0.1 mixing
Solvent.
3. method of separating and assaying according to claim 1 or 2, which is characterized in that chromatographic condition is as follows：
Flow rate of mobile phase is 0.8mL/min；Chromatographic column column temperature is 25 DEG C；The Detection wavelength of UV detector is 280nm.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101985446A (en) * | 2010-06-10 | 2011-03-16 | 江苏省原子医学研究所 | Method for synthesizing (+/-)-9-O-demethyl-alpha-dihydrotetrabenazine |
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| NZ593848A (en) * | 2008-12-31 | 2013-09-27 | Avid Radiopharmaceuticals Inc | Synthesis of 18f-radiolabeled styrylpyridines from tosylate precursors and stable pharmaceutical compositions thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101985446A (en) * | 2010-06-10 | 2011-03-16 | 江苏省原子医学研究所 | Method for synthesizing (+/-)-9-O-demethyl-alpha-dihydrotetrabenazine |
Non-Patent Citations (4)
| Title |
|---|
| An improved radiosynthesis of [18F]AV-133: a PET imaging agent for vesicular monoamine transporter 2;Lin Zhu等;《Nuclear Medicine and Biology》;20101231;第37卷;第133-141页 * |
| Paul E. Harris等.PET quantification of pancreatic VMAT 2 binding using (+) and (−) enantiomers of [18 F]FP-DTBZ in baboons.《Nuclear Medicine and Biology》.2013,第40卷 * |
| Preparative enantiomeric separation of potent AMP-activated protein kinase activator by HPLC on amylose-based chiral stationary phase;Marie-Pierre Vaccher等;《Journal of Pharmaceutical and Biomedical Analysis》;20081231;第46卷;全文 * |
| 反相高效液相色谱法测定18F-FECNT的前体化合物nor-CClT;唐婕等;《理化检验-化学分册》;20100831;第46卷(第8期);全文 * |
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