CN104178132A - Fluorescent compound and application thereof in medicine - Google Patents
Fluorescent compound and application thereof in medicine Download PDFInfo
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- CN104178132A CN104178132A CN201410368979.8A CN201410368979A CN104178132A CN 104178132 A CN104178132 A CN 104178132A CN 201410368979 A CN201410368979 A CN 201410368979A CN 104178132 A CN104178132 A CN 104178132A
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- 239000007850 fluorescent dye Substances 0.000 title abstract description 11
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to a fluorescent compound with A beta plaque affinity and a composition which contains the derivative, namely the fluorescent compound. The fluorescent compound is as shown in a general formula (I), wherein a substituent group in the general formula (I) is as shown in the specification. The invention also relates to a preparation method of the fluorescent compound and an application of the fluorescent compound in a method for developing A beta plaques.
Description
Technical field
The present invention relates to specific molecular identifying and diagnosing reagent field, more particularly, relate to a kind of fluorescent chemicals with amyloid plaques avidity, and the application of this compounds in the method for imaging amyloid plaques.
Background technology
Alzheimer's disease (Alzheimer's Disease, AD) is a kind of lethality nerve degenerative diseases that carries out sexual development.China enters aging society in advance at present, and nearly 6,000,000 people suffer from AD, and quantity occupies first of countries in the world, and number of patients is with annual more than 300,000 speed increase.China's over-65s prevalence reaches 7.2%, and AD patient is to rejuvenation trend development.AD has become the fourth-largest killer who causes old man's death who is only second to heart trouble, cancer, apoplexy.AD not only has a strong impact on middle-aged and old qualities of life, and brings heavy economical load to patient family and society.Due to AD cause of disease complexity, definite pathogeny is still unclear at present, mainly diagnoses by the cerebral damage of evaluate patient clinically, and how patient diagnosed has entered the middle and advanced stage of the course of disease and incured loss through delay treatment.Lack effective detection means, become the major obstacles of AD early diagnosis and treatment.
In AD patient's brain, the amyloid plaques (A beta plaque) taking amyloid-beta (A β) as main component is one of the most significant pathologic mark of AD.A beta plaque has started to occur at the premorbid many decades of AD, AD nervous tissue degeneration mark and important pathological characteristics the earliest, the formation that amyloid cascade hypothesis proposes neurocyte outer fiber shape A beta plaque is the critical event that development occurs AD pathology, and finally cause cognition dysfunction (Hardy J, et al. Science
.2002,297 (5580), 353 – 356).In recent years, the prevention that A beta plaque forms and reverse become one of target for the treatment of AD, suppress the generation of A beta plaque in brain and the medicine of accumulating and therapy and have obtained broad research.
Except AD, A beta plaque is also present in other diseases, as cerebral amyloid angiopathy, amyloid cardiomyopathy, amyloid polyneuropathy, systemic old amyloidosis with hereditary cerebral hemorrhage of amyloidosis etc.Therefore it is noticeable that, research and development have the part (A beta molecule probe) of specific binding A beta plaque.Utilize A beta molecule probe and molecular imaging technology to carry out the video picture of A beta plaque, can realize without spike and detection in the body of wound, real-time A beta plaque, and then provide very big facility for the research of early diagnosis, curative effect monitoring and the medicine of the diseases such as AD etc.
Between the several years in past, existing more radioactivity A beta molecule probe enters clinical experimental stage, as [
11c] PIB (Klunk WE, et al. Ann. Neurol. 2004,55 (3), 306 – 319), [
18f] GE-067(Koole M, et al. J. Nucl. Med. 2009,50 (5), 818-822), [
18f] BAY-94-9172(Rowe CC, et al.Lancet. Neurol. 2008,7 (2), 129-135), [
18f] AV-45(Wong DF, et al. J. Nucl. Med.2010,51 (6), 913-920) etc.But the application of radiological imaging agent is also subject to some effects limit, the ray sending such as radiological imaging agent has certain radiation injury, needs the supporting magnetic resonance acceleator that has production radionuclide of medical institutions etc. human body.
In comparison, optical imagery has that safety is "dead", data acquisition time is short and the many advantages such as with low cost, and the application in medical diagnosis etc. is in widespread attention in recent years; Especially emerging near-infrared fluorescence imaging technology, in its spectral range, the autofluorescence of biological tissue disturbs less, and background tissue fluorescent signal is very low, and penetrate tissue distance can be up to several centimetres.Therefore, research and development have the fluorescent imaging agent (molecular probe) of A beta plaque avidity, will have very important scientific meaning and actual value.But on the general study of A β fluorescent molecular probe, make little progress at present.Based on above-mentioned technical background, be necessary to propose a kind of new compound, be applied to the research of early diagnosis, curative effect monitoring and the medicine of the diseases such as AD with the fluorescent imaging agent as A beta plaque.
In addition, according to the feature of nuclear medicine, use the isotope labeling technique of standard, the same A beta molecule of radio-labeling probe, can carry out the checking of optical imagery, improves the accuracy of A beta plaque imaging in brain.
Summary of the invention
The technical problem to be solved in the present invention is, the fluorophore of existing fluorescent imaging (radiography) agent often has larger molecular structure and with electric charge, thereby is not suitable for being applied to the developer of A beta plaque in brain.The invention provides a kind of small molecules fluorescent chemicals, electron donating group in its structure and drawing electron group, the conjugated structure of push away-La of formation electronic action, and increase the conjugated system of π-π * transition by carbon-carbon double bond, the fluorescence that compound molecule is produced moves to near-infrared region, and its structural entity of while has met again the avidity with A beta plaque.
The object of the present invention is to provide fluorescent chemicals and the application thereof with A beta plaque avidity.
In order to realize the object of the invention, the fluorescent chemicals with A beta plaque avidity of the present invention, is referred to as " PAD compounds ", its structure as shown in the formula (I):
Wherein, n gets 1,2,3 or 4; X gets CH or N; R gets Br, I, OCH
3, OH, NH
2, NH (CH
3), N (CH
3)
2, (OCH
2cH
2) F, (OCH
2cH
2)
2f, (OCH
2cH
2)
3f, (OCH
2cH
2)
4f or (OCH
2cH
2)
5f.
The present invention also provides the preparation method of the compound of described formula (I), comprises the following steps:
Respectively get
with
0.5 mmol, is dissolved in 10 mL n-propyl alcohols, then adds 200 μ L piperidines, stirs lower backflow 3-10 hour; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Crude product separates through column chromatography (eluent is ethyl acetate: normal hexane), obtains the described fluorescent chemicals with A beta plaque avidity; Wherein m gets 0,1,2 or 3; X gets CH or N; R gets Br, I, OCH
3, OH, NH
2, NH (CH
3), N (CH
3)
2, (OCH
2cH
2) F, (OCH
2cH
2)
2f, (OCH
2cH
2)
3f, (OCH
2cH
2)
4f or (OCH
2cH
2)
5f.
Described preparation process is as follows:
Wherein, m gets 0,1,2 or 3; N gets 1,2,3 or 4; X gets CH or N; R gets Br, I, OCH
3, OH, NH
2, NH (CH
3), N (CH
3)
2, (OCH
2cH
2) F, (OCH
2cH
2)
2f, (OCH
2cH
2)
3f, (OCH
2cH
2)
4f or (OCH
2cH
2)
5f.
The compound that described preparation process is used
for commercial compound,
for existing compound, can make by the process shown in following formula:
Wherein, p gets 0,1 or 2; M gets 1,2 or 3; X gets CH or N; R gets Br, I, OCH
3, OH, NH
2, NH (CH
3), N (CH
3)
2, (OCH
2cH
2) F, (OCH
2cH
2)
2f, (OCH
2cH
2)
3f, (OCH
2cH
2)
4f or (OCH
2cH
2)
5f.
The present invention also provides the application of described compound in preparation A beta plaque developer.
Described application is that the compound radionuclide of formula of the present invention (I) is passed through, after ordinary method mark, to be prepared into A beta plaque developer.
Described radionuclide can be
123i,
125i,
131i,
18f or
11c.
The present invention also provides a kind of diagnosis composition, and described composition comprises the preparation that the compound shown in formula (I) and pharmaceutically acceptable carrier are made." pharmaceutically acceptable carrier " comprises various vehicle and thinner.Of the present invention combination of traditional Chinese medicine learn on acceptable carrier can comprise liquid, as water, physiological saline, glycerine and ethanol.
The present invention also provides a kind of diagnosis composition, and described composition comprises the preparation that the compound through radioisotope labeling shown in formula (I) and pharmaceutically acceptable carrier are made." pharmaceutically acceptable carrier " comprises various vehicle and thinner.Of the present invention combination of traditional Chinese medicine learn on acceptable carrier can comprise liquid, as water, physiological saline, glycerine and ethanol.
The present invention further provides the method for video picture A beta plaque.In the first step of this developing method, the compound shown in can the formula (I) of detection limit is introduced in tissue or patient.Compound normally diagnosis composition part and by well known to a person skilled in the art that method is administered to tissue or patient.In a preferred embodiment of the invention, introduce patient and being enough to make compound with after time that A beta plaque is combined with the compound shown in can the formula (I) of detection limit, atraumatic detection compound.In another embodiment of the present invention, compound shown in formula (I) is introduced to patient, so that compound is combined with A beta plaque, get tissue sample from patient through the enough time, and depart from patient and detect the compound in tissue.In the 3rd embodiment of the present invention, get tissue sample and the compound shown in formula (I) is introduced to this tissue sample from patient.Being enough to make after this compound is bonded to the time of A beta plaque, detection compound.
Can be by entirety or local route of administration by the compound administration shown in formula (I) to patient.For example, can be by compound administration to patient so that it is delivered to whole body.Alternatively, can be by compound administration to specific organ or the tissue paid close attention to.For example, in order to diagnose or follow the trail of the process of patient's AD, need the amyloid plaques in location and quantitative brain.
Term " tissue " refers to a part for patient body.The example of tissue comprises brain, the heart, lung, liver,kidney,spleen, pancreas, stomach, intestines, blood vessel, artery.It can detection limit be the amount of the required compound of detection method by selecting.Those skilled in the art can easily determine in order to provide detection need to introduce the amount of patient's compound.The amount of the compound that for example, can increase to patient is until compound detected by the method for selecting.
Term " patient " refers to the mankind and other animals.Those skilled in the art also know how to confirm is enough to make compound and time that A beta plaque is combined.Introduce patient by the compound shown in can the formula (I) of detection limit, then the place's detection compound of each time after administration, can easily measure the required time.
Term " combination " refers to the chemical interaction between compound and A beta plaque.In conjunction with example comprise covalent linkage, ionic linkage, hydrophilic-aqueous favoring mutual effect, hydrophobic-hydrophobic interaction and complex compound.
Video picture means of the present invention are optics video picture, nuclear magnetic resonance or nuclear medicine image.Wherein the nuclear medicine image method of atraumatic comprises positron emission tomography (PET) and single photon emission computerized tomography (SPECT).
The invention provides the application of the compound shown in formula (I) in diagnosis and the medicine research of amyloid deposition relative disease.Described amyloid deposition relative disease is alzheimer's disease or cerebral amyloid angiopathy.
The invention provides the purposes of a kind of fluorescent chemicals in A beta plaque radiography.The structure of fluorescent chemicals suc as formula (
) shown in:
Wherein, n gets 1,2,3 or 4; R gets Br, I, OCH
3, OH, NH
2, NH (CH
3), N (CH
3)
2, (OCH
2cH
2) F, (OCH
2cH
2)
2f, (OCH
2cH
2)
3f, (OCH
2cH
2)
4f or (OCH
2cH
2)
5f.
The invention provides a kind of diagnosis composition, described composition comprise formula (
) shown in compound and the preparation made of pharmaceutically acceptable carrier." pharmaceutically acceptable carrier " comprises various vehicle and thinner.Of the present invention combination of traditional Chinese medicine learn on acceptable carrier can comprise liquid, as water, physiological saline, glycerine and ethanol.
The present invention further provides the method for radiography A beta plaque.In the first step of this angiographic method, formula that can detection limit (
) shown in compound introduce tissue or patient in.Compound normally diagnosis composition part and by well known to a person skilled in the art that method is administered to tissue or patient.In a preferred embodiment of the invention, with formula that can detection limit (
) shown in compound introduce patient and being enough to make compound with after time that A beta plaque is combined, atraumatic detection compound.In another embodiment of the present invention, by formula (
) shown in compound introduce patient, so that compound is combined with A beta plaque, get tissue sample from patient through the enough time, and depart from patient and detect the compound in tissue.In the 3rd embodiment of the present invention, from patient get tissue sample and by formula (
) shown in compound introduce this tissue sample.Being enough to make after this compound is bonded to the time of A beta plaque, detection compound.
Can by entirety or local route of administration by formula (
) shown in compound administration to patient.For example, can be by compound administration to patient so that it is delivered to whole body.Alternatively, can be by compound administration to specific organ or the tissue paid close attention to.For example, in order to diagnose or follow the trail of the process of patient's AD, need the amyloid plaques in location and quantitative brain.
Term " tissue " refers to a part for patient body.The example of tissue comprises brain, the heart, lung, liver,kidney,spleen, pancreas, stomach, intestines, blood vessel, artery.It can detection limit be the amount of the required compound of detection method by selecting.Those skilled in the art can easily determine in order to provide detection need to introduce the amount of patient's compound.The amount of the compound that for example, can increase to patient is until compound detected by the method for selecting.
Term " patient " refers to the mankind and other animals.Those skilled in the art also know how to confirm is enough to make compound and time that A beta plaque is combined.Formula by can detection limit (
) shown in compound introduce patient, then the place's detection compound of the each time after administration, can easily measure the required time.
Term " combination " refers to the chemical interaction between compound and A beta plaque.In conjunction with example comprise covalent linkage, ionic linkage, hydrophilic-aqueous favoring mutual effect, hydrophobic-hydrophobic interaction and complex compound.
Brain in vivo one of the crucial prerequisite of developer is the ability having through complete hemato encephalic barrier.Normal mouse living imaging is tested and is shown, the fluorescent chemicals in the present invention can pass hemato encephalic barrier effectively, and has the advantage such as good brain capture amount and the interior clearance rate of brain.
In addition, the compound in the present invention all has good photoluminescent property, and the fluorescent emission wavelength of part of compounds reaches near-infrared region; External fluorescent dye experiment show this compounds can selective binding and fluorescent mark AD Transgenic Mice Brain in A beta plaque, be expected to become a kind of novel fluorescence developer that detects A beta plaque for spike in body.
Compound in the present invention can be by being applied to the nuclear medicine image of A beta plaque after radioisotope labeling.
Brief description of the drawings
Fig. 1 is the chemical structural formula of the fluorescent chemicals of the A of having beta plaque avidity of the present invention.
Fig. 2 is the compound (PAD-1) and A β of embodiment mono-
1-42fluorescence emission spectrum before and after aggregate mixes.
Fig. 3 is the compound (PAD-1) of the embodiment mono-fluorescent dye mark to AD transgenic mice brain section.
Fig. 4 is the compound (PAD-2) of the embodiment mono-fluorescent dye mark to AD transgenic mice brain section.
Fig. 5 is the compound (PAD-8) of the embodiment mono-fluorescent dye mark to AD transgenic mice brain section.
Fig. 6 is the radioautograph to AD transgenic mice brain section of the compound (PAD-6) of embodiment bis-.
Fig. 7 is the radioautograph to AD transgenic mice brain section of the compound (PAD-8) of embodiment bis-.
Fig. 8 is the fluorescent signal that compound (PAD-1, PAD-2 and PAD-8) the tail vein of embodiment mono-injects each time point brain after normal mouse.
Embodiment
Illustrate in greater detail by the following examples the present invention, but the invention is not restricted to described embodiment.Other suitable modifications common and apparent various condition and parameter to those skilled in the art and changing within the spirit and scope of the present invention.If do not specialize, the conventional means that in embodiment, technique means used is known well for those skilled in the art, the raw materials used commercial goods that is.
Embodiment
Embodiment mono-: PAD compounds synthetic
PAD compounds of the present invention is synthetic by following synthesis path:
。
synthetic PAD-1:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and paradimethy laminobenzaldehyde (75.0 mg, 0.50 mmol), be dissolved in 10 mL n-propyl alcohols, then add 200 μ L piperidines, stir lower backflow 10 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=2: 1) separate, obtain 86.1 mg PAD-1, structure is as follows, and productive rate is 57.0%.MS:?m/z?304(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.38?(s,?3H),?3.06?(s,?6H),?6.47?(d,?2H,?
J?=?16.0?Hz),?6.59?(s,?1H),?6.70?(d,?2H,?
J?=?8.8?Hz),?7.38?(d,?1H,?
J?=?16.0?Hz),?7.43?(d,?2H,?
J?=?8.8?Hz)。
。
synthetic PAD-2:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and to dimethylamino phenylacrolein (88.0 mg, 0.50 mmol), be dissolved in 10 mL n-propyl alcohols, then add 200 μ L piperidines, stir lower backflow 3 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=7: 3) separate, obtain 99.1 mg PAD-2, structure is as follows, and productive rate is 60.1%.MS:?m/z?330(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.20?(s,?3H),?2.86?(s,?6H),?5.51?(s,?1H),?5.91?(s,?1H),?6.47?(d,?2H,?
J?=?16.0?Hz),?6.59?(s,?1H),?6.70?(d,?2H,?
J?=?8.8?Hz),?6.85?(s,?1H),?7.13?(d,?2H,?
J?=?8.8?Hz)。
。
synthetic PAD-3:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and p-Aminobenzaldehyde (61.0 mg, 0.50 mmol), be dissolved in 10 mL n-propyl alcohols, then add 200 μ L piperidines, stir lower backflow 3 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=4: 1) separate, obtain 27.5 mg PAD-3, structure is as follows, and productive rate is 20.0%.MS:?m/z?276(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.28?(s,?3H),?4.10(s,?2H),?6.41?(d,?2H,?
J?=?16.0?Hz),?6.59?(s,?1H),?6.70?(d,?2H,?
J?=?8.8?Hz),?6.77?(d,?1H,?
J?=?16.0?Hz),?7.09?(d,?2H,?
J?=?8.8?Hz)。
。
synthetic PAD-4:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and p-Hydroxybenzaldehyde (61.0 mg, 0.50 mmol), be dissolved in 10 mL n-propyl alcohols, then add 200 μ L piperidines, stir lower backflow 3 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=4: 1) separate, obtain 43.0 mg PAD-4, structure is as follows, and productive rate is 31.2%.MS:?m/z?277(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.38?(s,?3H),?6.57?(d,?2H,?
J?=?16.0?Hz),?6.69?(s,?1H),?6.85?(d,?2H,?
J?=?8.8?Hz),?7.08?(d,?1H,?
J?=?16.0?Hz),?7.33?(d,?2H,?
J?=?8.8?Hz)。
。
synthetic PAD-5:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and 4-methoxybenzaldehyde (116.0 mg, 0.50 mmol), be dissolved in 10 mL n-propyl alcohols, then add 200 μ L piperidines, stir lower backflow 3 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=4: 1) separate, obtain 25.6 mg PAD-5, structure is as follows, and productive rate is 50.2%.MS:?m/z?291(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.38?(s,?3H),?3.86?(s,?3H),?6.47?(d,?2H,?
J?=?16.0?Hz),?6.59?(s,?1H),?6.70?(d,?2H,?
J?=?8.8?Hz),?7.38?(d,?1H,?
J?=?16.0?Hz),?7.53?(d,?2H,?
J?=?8.8?Hz)。
。
synthetic PAD-6:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and 4-benzaldehyde iodine (116.0 mg, 0.50 mmol), be dissolved in 10 mL n-propyl alcohols, then add 200 μ L piperidines, stir lower backflow 3 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=4: 1) separate, obtain 97.6 mg PAD-6, structure is as follows, and productive rate is 50.2%.MS:?m/z?387(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.18?(s,?3H),?6.47?(d,?2H,?
J?=?16.0?Hz),?6.59?(s,?1H),?7.08?(d,?1H,?
J?=?16.0?Hz),?7.17?(d,?2H,?
J?=?8.8?Hz),?7.63?(d,?2H,?
J?=?8.8?Hz)。
。
synthetic PAD-7:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and 4-bromobenzaldehyde (93.0 mg, 0.50 mmol), be dissolved in 10 mL n-propyl alcohols, then add 200 μ L piperidines, stir lower backflow 3 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=4: 1) separate, obtain 38.8 mg PAD-7, structure is as follows, and productive rate is 23.2%.MS:?m/z?339(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.16?(s,?3H),?6.47?(d,?2H,?
J?=?16.0?Hz),?6.59?(s,?1H),?6.88?(d,?1H,?
J?=?16.0?Hz),?7.07?(d,?2H,?
J?=?8.8?Hz),?7.53?(d,?2H,?
J?=?8.8?Hz)。
。
synthetic PAD-8:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and
(84.0 mg, 0.50 mmol), is dissolved in 10 mL n-propyl alcohols, then adds 200 μ L piperidines, stirs lower backflow 10 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=1: 1) separate, obtain 32.1 mg PAD-8, structure is as follows, and productive rate is 20.0%.MS:?m/z?323?(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.38?(s,?3H),?4.44?(s,?2H),?4.94?(s,?2H),?6.59?(s,?1H),?6.67?(d,?2H,?
J?=?16.0?Hz),?6.70?(d,?2H,?
J?=?8.8?Hz),?7.38?(d,?1H,?
J?=?16.0?Hz),?7.53?(d,?2H,?
J?=?8.8?Hz)。
。
synthetic PAD-9:
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and
(68.0 mg, 0.50 mmol), is dissolved in 10 mL n-propyl alcohols, then adds 200 μ L piperidines, stirs lower backflow 10 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=3: 7) separate, obtain 81.0 mg PAD-9, structure is as follows, and productive rate is 56.0%.MS:?m/z?290?(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.38?(s,?3H),?2.96?(s,?3H),?6.47?(d,?2H,?
J?=?16.0?Hz),?6.59?(s,?1H),?6.70?(d,?2H,?
J?=?8.8?Hz),?7.38?(d,?1H,?
J?=?16.0?Hz),?7.23?(d,?2H,?
J?=?8.8?Hz)。
。
Embodiment bis-: the radio-labeled of PAD compounds
radioiodination compound PAD-6:
。
Take 169.0 mg PAD-7 and 800.0 mg tributyl tins are dissolved in 20mL toluene, add 120 mg triphenylphosphine palladiums, stir lower backflow 20 hours; Pressure reducing and steaming toluene, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=1: 3) separate, obtain 27.0 mg midbody compounds
1, productive rate is 11.0%.MS:?m/z?551?(M
++H)。
Take midbody compound prepared by 1 mg above-mentioned steps
1, add 1 mL dissolve with ethanol.Adding successively hydrogen peroxide, the 3 μ L activity of 100 μ L3% is the Na of 0.15 mCi
125the hydrochloric acid 150 μ L of I solution and 1 mol/L.Shake up, confined reaction 6 minutes, adds saturated NaHSO
3100 μ L cancellation reactions, the NaOH solution of 1 mol/L regulates pH to neutral.HPLC post separates (moving phase: acetonitrile/water is 70/30), obtains the compound PAD-6 that radiochemicsl purity is greater than 98%, and mark rate is 60%.
compound labeled with radioactive fluorine PAD-8:
。
Take 2,6-dimethyl-4-pyrans subunit propane dinitrile (86.0 mg, 0.50 mmol) and
(83.0 mg, 0.50 mmol), is dissolved in 10 mL n-propyl alcohols, then adds 200 μ L piperidines, stirs lower backflow 10 hours; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=2: 1) separate, obtain 96.0 mg intermediates
1, productive rate is 60.0%.MS:?m/z?321?(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.38?(s,?3H),?4.04?(s,?2H),?4.33?(s,?2H),?6.59?(s,?1H),?6.67?(d,?2H,?
J?=?16.0?Hz),?6.70?(d,?2H,?
J?=?8.8?Hz),?7.38?(d,?1H,?
J?=?16.0?Hz),?7.53?(d,?2H,?
J?=?8.8?Hz)。
Intermediate
1(
, 96 mg, 0.3 mmol) and be dissolved in 5 mL pyridines, add 4-toluene sulfonyl chloride (233 mg, 1.22 mmol), under room temperature, react 3 hours.Resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product.Through column chromatography, (eluent is ethyl acetate to crude product: normal hexane=1: 1) separate, obtain 113.0 mg intermediates
2, productive rate is 80.0%.MS:?m/z?475?(M
++H)。
1H?NMR?(400?MHz,?CDCl
3):
δ2.36?(s,?3H),?3.04?(s,?3H),?4.04?(s,?2H),?4.33?(s,?2H),?6.59?(s,?1H),?6.67?(d,?2H,?
J?=?16.0?Hz),?6.70?(d,?2H,?
J?=?8.8?Hz),?7.38?(d,?1H,?
J?=?16.0?Hz),?7.53?(d,?2H,?
J?=?8.8?Hz)，?7.60?(d,?2H,?
J?=?8.0?Hz),?8.30?(d,?2H,?
J?=?8.0?Hz)。
Take 9.5 mg Kryptofix 222 and 1.7 mg salt of wormwood, be dissolved in acetonitrile/water (96/ 4) 1.0 mL, obtain Kryptofix 222/K
2cO
3solution.Magnetic resonance acceleator is generated
18f
-by the enrichment of QMA post, with 1.0 mL Kryptofix 222/K
2cO
3on eluant solution post
18f
-, collect elutriant and be placed in taper confined reaction bottle, under 120 C argon gas stream, volatilize solvent.In bottle, residue dissolves and volatilize to remove completely moisture under 120 C argon gas stream with 1.0 mL acetonitriles.In reaction flask, add successively midbody compound
2(
), acetonitrile 200 μ L, vortex vibration is also reacted 5 min at 110 C.Ethyl acetate (1.0 mL × 2) extractive reaction liquid also volatilizes solvent under argon gas stream, obtains crude product.Separate and purifying HPLC post separation (moving phase: acetonitrile/water is 70/30) by HPLC, obtain the compound PAD-8 that radiochemicsl purity is greater than 98%, mark rate is 45%.
Embodiment tri-: the mensuration of fluorescence exciting wavelength and fluorescent emission wavelength
Compound in the present invention has good photoluminescent property.In order to investigate the photoluminescent property of the compound in the present invention, concrete implementation step is: it is appropriate that precision takes compound in the present invention, is dissolved in methyl alcohol, and is diluted to 1 μ molL with methyl alcohol
-1.Application spectrophotofluorometer carries out fluoroscopic examination.Fixing excitation/emission wavelength 400-750 nm continuous sweep transmitting/excitation wavelength, draw the capable image of ripple.The maximum excitation wavelength of the part of compounds in the embodiment of the present invention and maximum emission wavelength are in table 1.
Maximum fluorescence excitation wavelength and the maximum emission wavelength of the part of compounds in table 1 embodiment.
| ? | PAD-1 | PAD-2 | PAD-4 |
| λ ex(nm) | 480 | 496 | 465 |
| λ em (nm) | 603 | 654 | 579 |
Embodiment tetra-: A β
1-42the mixed compound fluorescence spectrum of aggregate
Compound in the present invention has the character that fluorescence strengthens after being combined with A beta peptide aggregation body.In order to investigate compound in the present invention and the variation of the mixed fluorescence spectrum behavior of A β, concrete implementation step is: it is appropriate that precision takes compound in the present invention, is dissolved in ethanol, and is diluted to 1 μ molL with PBS
-1.Application spectrophotofluorometer carries out fluoroscopic examination.Fixing excitation/emission wavelength 400-750 nm continuous sweep transmitting/excitation wavelength, draw the capable image of ripple.Select A β
1-42albumen is cultivated A beta peptide aggregation body in 37 DEG C of water-baths, for simulating the A beta peptide aggregation body in human brain.By compound (1 μ molL
-1) and A β
1-42aggregate (2.75 μ molL
-1) mix, application spectrophotofluorometer carries out fluoroscopic examination.Fixing excitation/emission wavelength 400-750 nm continuous sweep transmitting/excitation wavelength, draw the capable image of ripple.Compound in the present invention has the character that fluorescence strengthens after being combined with A beta peptide aggregation body.Wherein, the compound PAD-1 in the embodiment of the present invention and A β
1-42fig. 2 is shown in fluorescence spectrum behavior before and after aggregate mixes.PAD-1 and A β
1-42the mixed fluorescence intensity of aggregate significantly strengthens, and is 7 times of compound autofluorescence intensity.
Embodiment five: fluorescent dye experiment
Compound in the present invention can selective binding A beta plaque, and fluorescent mark A beta plaque effectively.In order to investigate the marked capacity to A beta plaque, concrete implementation step is: compound concentration is 1 μ molL
-1the present invention in compound, drip respectively and cover AD transgenic mice brain section (10 μ m), cultivate 10 minutes by room temperature; Section is carried out rinsing by the order of 40% ethanol (2 minutes), 40% ethanol (2 minutes), pure water (30 seconds), air-dry rear application fluorescence microscope.Compound in the present invention can selective binding A beta plaque, and fluorescent mark A beta plaque effectively.Wherein, the coloration result of compound PAD-1, the PAD-2 in the embodiment of the present invention, PAD-8 is respectively as Fig. 3, Fig. 4, Fig. 5.
Embodiment six: radioautograph experiment
The compound of the radioisotope labeling in the present invention can selective binding A beta plaque, and radio-labeling A beta plaque effectively.Concrete implementation step is: the compound (5 μ Ci) of getting the radioisotope labeling in the present invention covers AD transgenic mice brain section, and (10 μ m), cultivate under room temperature 30 minutes; Section is carried out rinsing by the order of 40% saturated ethanol of Quilonum Retard (2 minutes), 40% ethanol (2 minutes), pure water (30 seconds), air-dry after, preservative film wrap up and is placed in phosphorus screen and descends to expose and spend the night; Phosphorus screen is analyzed with radioautograph instrument.The compound of the radioisotope labeling in the present invention can selective binding A beta plaque, and radio-labeled A beta plaque effectively.Wherein, the radioautograph result of the compound PAD-6 in the embodiment of the present invention and PAD-8 is respectively as Fig. 6, Fig. 7.
Embodiment seven: mouse living imaging experiment
Compound in the present invention can pass hemato encephalic barrier effectively, and has the initial intake of good brain and clearance rate.In order to investigate hemato encephalic barrier handling capacity, and investigate release rate in hemato encephalic barrier handling capacity and brain simultaneously, concrete implementation step is: get compound (2.0 mg/kg in the present invention, containing 20% methyl-sulphoxide, 10% polysorbate, 70% physiological saline), in tail vein injection enters normal nude mice (n=3) body, utilize optical imaging system to carry out mouse living imaging.Determine that whole brain is area-of-interest (ROI) and calculates fluorescent signal.Regulating blank brain signal is 0(sum=0).Taking maximum fluorescence signal value as 1, calculate the relative signal value of each time point, and draw the fluorescent signal curve of each time point brain.Compound in the present invention can enter in brain through hemato encephalic barrier effectively, and has the initial intake of good brain and clearance rate.Wherein, the result of compound PAD-1, the PAD-2 in the embodiment of the present invention and PAD-8 as shown in Figure 8.Compound injects the rapid fluorescent signal that shows in normal mouse hindbrain; Along with time lengthening, fluorescence intensity weakens gradually, when 60 min fluorescent signal basically eliminate go out outside brain.
Although, above with a general description of the specific embodiments the present invention is described in detail, on basis of the present invention, can make some amendments or improvement to it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (22)
1. a fluorescent chemicals with A beta plaque avidity, is characterized in that: its structure as shown in the formula (I):
Wherein,
N gets 1,2,3 or 4;
X gets CH or N;
R gets Br, I, OCH
3, OH, NH
2, NH (CH
3), N (CH
3)
2, (OCH
2cH
2) F, (OCH
2cH
2)
2f, (OCH
2cH
2)
3f, (OCH
2cH
2)
4f or (OCH
2cH
2)
5f.
2. the preparation method of compound claimed in claim 1, comprises the following steps: respectively get
with
0.5 mmol, is dissolved in 10 mL n-propyl alcohols, then adds 200 μ L piperidines, stirs lower backflow 3-10 hour; Boil off n-propyl alcohol, resistates washes with water, then is extracted with ethyl acetate, and anhydrous magnesium sulfate drying spends the night; Ethyl acetate layer revolves and steams to obtain crude product; Crude product separates through column chromatography (eluent is ethyl acetate: normal hexane), obtains described and A beta plaque and have the compound of avidity; Wherein m gets 0,1,2 or 3; X gets CH or N; R gets Br, I, OCH
3, OH, NH
2, NH (CH
3), N (CH
3)
2, (OCH
2cH
2) F, (OCH
2cH
2)
2f, (OCH
2cH
2)
3f, (OCH
2cH
2)
4f or (OCH
2cH
2)
5f.
3. the application of compound claimed in claim 1 in preparation A beta plaque developer.
4. the application described in claim 3, is characterized in that: by compound claimed in claim 1 with being prepared into A beta plaque developer after radioisotope labeling.
5. radioisotope labeling claimed in claim 4, is characterized in that: described radionuclide is
123i,
125i,
131i,
18f or
11c.
6. radioisotope labeling claimed in claim 4, is characterized in that: described radionuclide is
123i,
125i,
131i or
18f.
7. for the diagnosis composition of video picture A beta plaque, it comprises the preparation that compound claimed in claim 1 and pharmaceutically acceptable carrier are made.
8. for the diagnosis composition of video picture A beta plaque, it comprises the preparation made from compound claimed in claim 1 and the pharmaceutically acceptable carrier of radioisotope labeling.
9. radioisotope labeling claimed in claim 8, is characterized in that: described radionuclide is
123i,
125i,
131i,
18f or
11c.
10. the method for video picture A beta plaque, comprising:
A. can detection limit introduce tissue or patient as claim 7 or diagnosis composition claimed in claim 8;
B. through the enough time so that compound be combined with A beta plaque; With
C. detect the compound of being combined with one or more A beta plaques.
11. video pictures claimed in claim 10, is characterized in that: video picture means are optical imagery, nuclear magnetic resonance or nuclear medicine.
The application of 12. compounds claimed in claim 1 in diagnosis and the medicine research of amyloid deposition relative disease.
Amyloid deposition relative disease described in 13. claims 12, is characterized in that: amyloid deposition relative disease is alzheimer's disease or cerebral amyloid angiopathy.
The application of 14. diagnosis compositions claimed in claim 7 in diagnosis and the medicine research of amyloid deposition relative disease.
Amyloid deposition relative disease described in 15. claims 14, is characterized in that: amyloid deposition relative disease is alzheimer's disease or cerebral amyloid angiopathy.
The application of 16. diagnosis compositions claimed in claim 8 in diagnosis and the medicine research of amyloid deposition relative disease.
Amyloid deposition relative disease described in 17. claims 16, is characterized in that: amyloid deposition relative disease is alzheimer's disease or cerebral amyloid angiopathy.
The purposes of 18. compounds claimed in claim 1 in A beta plaque radiography.
The purposes of 19. compounds according to claim 18 in A beta plaque radiography, is characterized in that, as shown in the formula (I), wherein, n gets 1,2,3 or 4 to its compound structure; X gets CH; R gets Br, I, (OCH
2cH
2) F, (OCH
2cH
2)
2f, (OCH
2cH
2)
3f, (OCH
2cH
2)
4f or (OCH
2cH
2)
5f.
20. diagnosis compositions for A beta plaque radiography, it comprises the preparation that compound described in claim 19 and pharmaceutically acceptable carrier are made.
The method of 21. radiography A beta plaques, comprising:
A. diagnosis composition as claimed in claim 20 that can detection limit is introduced tissue or patient;
B. through the enough time so that compound be combined with A beta plaque; With
C. detect the compound of being combined with one or more A beta plaques.
The application of diagnosis composition described in 22. claims 20 in diagnosis and the medicine research of amyloid deposition relative disease, is characterized in that: described amyloid deposition relative disease is alzheimer's disease or cerebral amyloid angiopathy.
Priority Applications (1)
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