CN109959612A - A kind of optoacoustic probe is preparing the application in NTR photo-acoustic detection reagent - Google Patents

A kind of optoacoustic probe is preparing the application in NTR photo-acoustic detection reagent Download PDF

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CN109959612A
CN109959612A CN201711340754.1A CN201711340754A CN109959612A CN 109959612 A CN109959612 A CN 109959612A CN 201711340754 A CN201711340754 A CN 201711340754A CN 109959612 A CN109959612 A CN 109959612A
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aryl
alkyl
arlydene
alkylidene
substituted alkylene
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蔡林涛
孟晓青
龚萍
张佳丽
周理华
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/1702—Systems in which incident light is modified in accordance with the properties of the material investigated with opto-acoustic detection, e.g. for gases or analysing solids

Abstract

The present invention provides a kind of optoacoustic probes to prepare the application in NTR photo-acoustic detection reagent.Optoacoustic probe provided by the present invention is using 2- (2- nitroimidazole) ethamine as specificly-response group, itself signal is very weak, and after nitro is reduced into amino, photoacoustic signal greatly enhances, thus can successfully realize NTR detection and the first can be realized the probe compound of NTR photo-acoustic detection.Meanwhile optoacoustic probe of the present invention not will receive reducing substances Vc, GSH, Cys common in organism and not interfere；In physiological conditions, pH fluctuation will not the photo-acoustic detection performance to IR1048 MZ have an impact.Further, the excitation wave of optoacoustic probe of the present invention is more advantageous to bio-imaging, organism background influence to be detected is smaller, and tissue penetration depths are deeper near infrared region；And since probe is positively charged, transmembrane movement can be quickly completed under the action of cell membrane negative electricity；Probe toxicity is low simultaneously, bio-compatibility is good, can be used in the imaging analysis of in vivo NTR.

Description

A kind of optoacoustic probe is preparing the application in NTR photo-acoustic detection reagent
Technical field
The present invention relates to lesion detection reagent fields, in particular to a kind of optoacoustic probe in preparation NTR photo-acoustic detection Application in reagent.
Background technique
It is well known that malignant tumour seriously endangers human life and health, wherein entity tumor accounts for clinical malignant tumour 85% More than, and weary oxygen is one of important feature of entity tumor.Tumor hypoxia cell is raw in metabolism, molecular genetics and pathology Reason aspect changes, to play very important effect in the evolution progression of tumour, and leads to chemicotherapy resistance Cause tumor by local recurrence, DISTANT METASTASES IN and prognosis mala.It therefore, is still one very popular to the research of Tumor cell hypoxia Project.Increase it is well known that anoxic will lead to reduction stress, lead to the overexpression of nitroreductase (NTR), NTR level with Tumor hypoxia degree is directly related, it is considered to be indicative tumor markers.Therefore, we can pass through the inspection of NTR level It surveys to evaluate the weary oxygen degree of tumour.
Currently, more and more probes evaluate tumor hypoxia degree by detection NTR based on this principle, however, mesh Preceding probe compound used is fluorescence probe, although its qualitative detection analysis for being able to carry out tumour, fluorescence probe Resolution ratio is lower, this is unfavorable for the accurate imaging analysis of NTR.
Photoacoustic imaging technology is an emerging imaging in biological tissues technology.It inherits optical imagery and ultrasonic imaging Feature, high contrast, the high-resolution ability of ultrasonic imaging with optical imagery.Thus, provide it is a kind of it is novel, can be used in The probe of NTR photoacoustic imaging detection is just at a technical problem to be solved urgently.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of optoacoustic probe and is preparing the application in NTR photo-acoustic detection reagent, this Optoacoustic probe compound toxicity provided by inventing is low, bio-compatibility is good, can be with the in vivo NTR's with high s/n ratio Imaging analysis.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
A kind of optoacoustic probe is preparing the application in NTR photo-acoustic detection reagent, and the optoacoustic probe structure is as follows:
NO2-R1-R2-X1-R3(I),
In compound (I), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub- Alkylaryl, arlydene alkyl or substituted alkylene aryl；
R3For two area's luminescent dye molecule base of near-infrared；
X1For alkyl, imino group, amide groups, hydroxyl or ester group；
Preferably, two area's luminescent dye molecule of near-infrared are as follows: IR1048 and its derivative, IR1050 and its derivative, or One of person I R1061 and its derivative.
Preferably, optoacoustic probe of the present invention is in preparing the application in NTR photo-acoustic detection reagent, R3For IR1048 And its derivative molecular base.
Preferably, optoacoustic probe of the present invention in preparing the application in NTR photo-acoustic detection reagent, visit by the optoacoustic Needle construction is as follows:
In compound (II) or (II'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace sub- virtue Base, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；
X1For imino group, amide groups or ester group；
R4、R5Independently it is the alkylidene of C0-C30, substituted alkylene, alkenylene, replaces alkenylene, arlydene, takes For arlydene, alkylidene aryl, alkenylene aryl, substituted alkylene aryl, replace alkenylene aryl, arlydene alkyl, sub- virtue Base alkenyl replaces arlydene alkyl, or replaces arlydene alkenyl；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
X2For halogen or tetrafluoroborate.
Preferably, optoacoustic probe of the present invention is in preparing the application in NTR photo-acoustic detection reagent, the compound (II) or in (II'),
R2For the alkylidene or substituted alkylene of C1~C30；X1For imino group, amide groups or ester group；R4For C0-C30 Alkylidene or substituted alkylene；R5For C2-C30 alkenylene or replace alkenylene；R6For the alkylidene or substitution time alkane of C2-C30 Base；R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl Aryl replaces alkylaryl, aryl alkyl or substituted aryl alkyl；R12、R18It is independently fluorine, chlorine, bromine or iodine；X2For Halogen or tetrafluoroborate.
Preferably, optoacoustic probe of the present invention in preparing the application in NTR photo-acoustic detection reagent, visit by the optoacoustic Needle construction is as follows:
Preferably, optoacoustic probe of the present invention in preparing the application in NTR photo-acoustic detection reagent, visit by the optoacoustic The preparation step of needle is as follows:
By NO2-R1-R2-Y1(i) and R3-Y2(ii) hybrid reaction is to get the optoacoustic probe；
Wherein, in compound (i), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces sub- heteroaryl Base；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub- Alkylaryl, arlydene alkyl or substituted alkylene aryl；
Y1For amino, carboxyl or hydroxyl；
In compound (ii), R3For two area's luminescent dye molecule base of near-infrared,
Y2For amino, halogen, hydroxyl or carboxyl；
Preferably, two area's luminescent dye molecule of near-infrared are as follows: IR1048 and its derivative, IR1050 and its derivative, or One of person IR1061 and its derivative.
Preferably, optoacoustic probe of the present invention is in preparing the application in NTR photo-acoustic detection reagent, compound (i) Structure are as follows:
Wherein, in compound (iii) or (iii'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or take For arlydene, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；
Y1For amino, carboxyl or hydroxyl；
R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
And/or the structure of compound (ii) are as follows:
Wherein, in compound (iv), R4、R5Independently it is the alkylidene of C0-C30, substituted alkylene, alkenylene, takes For alkenylene, arlydene, replace arlydene, alkylidene aryl, alkenylene aryl, substituted alkylene aryl, substitution alkenylene virtue Base arlydene alkyl, arlydene alkenyl, replaces arlydene alkyl, or replaces arlydene alkenyl；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R20It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
Y2For amino, halogen, hydroxyl or carboxyl；
X2For halogen or tetrafluoroborate.
Preferably, optoacoustic probe of the present invention is in preparing the application in NTR photo-acoustic detection reagent, the compound (iii) or (iii') respectively by
With X3- R2-Y3(vi) it is made by condensation and deprotection；
Wherein, in compound (v) or (v'), R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkane Base, substituted aryl, alkylaryl, replaces alkylaryl, aryl alkyl or substituted aryl alkyl at aryl；
In compound (vi), X3For halogen；R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace sub- virtue Base, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；Y3For with after protection group reaction Amino, carboxyl perhaps hydroxyl and by hydrolysis to obtain corresponding amino, carboxyl or hydroxyl.
Preferably, optoacoustic probe of the present invention is in preparing the application in NTR photo-acoustic detection reagent, the compound (iii) or in (iii'): R2For the alkylidene or substituted alkylene of C1~C30；X1For imino group, amide groups or ester group； R21、R22Independently it is hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, replaces alkyl virtue Base, aryl alkyl or substituted aryl alkyl；Y1For amino, hydroxyl or carboxyl；
And/or in compound (iv), R4For the alkylidene or substituted alkylene of C0-C30；R5For C2-C30 alkenylene or take For alkenylene；R6For the alkylidene or substitution alkylidene of C2-C30；R7-R11、R13-R18、R19-R22It is independently hydrogen, C1- The alkyl of C30 replaces alkyl, aryl, substituted aryl, alkylaryl, replaces alkylaryl, aryl alkyl or substituted aryl alkane Base；R12、R18It is independently fluorine, chlorine, bromine or iodine；Y2For amino, halogen, hydroxyl or carboxyl；X2For halogen or tetrafluoro Borate.
Preferably, optoacoustic probe of the present invention is in preparing the application in NTR photo-acoustic detection reagent, compound (iii) structure are as follows:The structure of compound (iii') are as follows:
And/or the structure of compound (iv) are as follows:
Compared with prior art, the invention has the benefit that
(1) optoacoustic probe I R1048-MZ provided by the present invention is rung using 2- (2- nitroimidazole) ethamine as specificity Group is answered, and using two area dyestuff R-1048 of near-infrared as precursor structure, the optoacoustic probe signals are very weak, and nitro is reduced ammonification After base (i.e. I R1048-MZ is reduced to I R1048-MZH), photoacoustic signal is greatly enhanced, it is thus possible to successfully realize NTR's It detects and the first can be realized the probe compound of NTR photo-acoustic detection；
(2) optoacoustic probe of the present invention not will receive reducing substances Vc, GSH, Cys common in organism and not interfere；
Meanwhile in physiological conditions, pH fluctuation will not the photo-acoustic detection performance to I R1048MZ have an impact；
(3) from scratch, it is an example that photoacoustic signal changes clearly to photoacoustic signal before and after optoacoustic probe response of the present invention " OFF-ON " (on/off) type optoacoustic probe；
(4) excitation wave of optoacoustic probe is more advantageous to bio-imaging, organism background influence to be detected is more near infrared region It is small, and tissue penetration depths are deeper；
(5) since probe is positively charged, transmembrane movement can be quickly completed under the action of cell membrane negative electricity；Probe toxicity simultaneously It is low, bio-compatibility is good, can be used in the imaging analysis of in vivo NTR.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below There is attached drawing needed in technical description to be briefly described.
Fig. 1 is that 1 product MZ-BOC nuclear-magnetism of the embodiment of the present invention tests map；
Fig. 2 is 1 product MZ-BOC mass spectrometric measurement map of the embodiment of the present invention；
Fig. 3 is that 1 product MZ nuclear-magnetism of the embodiment of the present invention tests map；
Fig. 4 is 1 product MZ mass spectrometric measurement map of the embodiment of the present invention；
Fig. 5 is 1 product photosensitizer molecule I R1048-MZ nuclear-magnetism test chart of the embodiment of the present invention；
Fig. 6 is 1 product photosensitizer molecule I R1048-MZ mass spectrometric measurement figure of the embodiment of the present invention；
Fig. 7 is the reacting flow chart of the embodiment of the present invention 1；
Fig. 8 is photoacoustic signal value of the various concentration embodiment 1I R1048-MZ solution under 808nm excitation；
Fig. 9 is photo-acoustic detection result of the embodiment 1I R1048-MZ for negative tumor mouse.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is The conventional products that can be obtained by commercially available purchase.
It is fluorescence probe in view of the probe compound detected currently used for NTR, more accurate biology can not be provided The technical problems such as internal NTR horizontal checkout result and noise are larger, the present invention provides a kind of novel optoacoustic probe chemical combination Object, optoacoustic probe itself photoacoustic signal of the present invention is weaker, and (NTR is a kind of containing flavo-enzyme, is with NADH after being restored by NTR Nitro compound is reduced to corresponding amine by electron donor, it can is visited optoacoustic of the present invention by the effect of NTR and NADH Nitro on needle is reduced to corresponding amino), photoacoustic signal greatly enhances, and can be realized the accurate inspection of in vivo NTR level It surveys, the in vivo NTR imaging analysis result with high s/n ratio is provided.
Specifically, optoacoustic probe structure provided by the present invention is as follows:
NO2-Rx-R2-X1-R3(I),
In compound (I), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；It is excellent Choosing, R1For the arlydene of C5~C15, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；It is further preferred that R1For The inferior heteroaryl of C5~C15 replaces inferior heteroaryl, wherein inferior heteroaryl replaces the hetero atom in inferior heteroaryl to be One of nitrogen, oxygen, sulphur are a variety of, and contained heteroatomic quantity is one in each inferior heteroaryl or substitution inferior heteroaryl Or it is multiple；Such as R1It can be, but be not limited to: furans, thiophene, pyrroles, imidazoles, thiazole, pyrazoles, pyrans, pyridine, pyrimidine, quinoline Quinoline or purine etc.；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub- Alkylaryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For the alkylidene of the linear chain or branched chain of C0~C30, C0 The substituted alkylene of the linear chain or branched chain of~C30；It is furthermore preferred that R2For the alkylidene of the linear chain or branched chain of C1~C12, C1~ The substituted alkylene of the linear chain or branched chain of C12；It is further preferred that R2For the alkylidene of the linear chain or branched chain of C1~C6, C1~ The substituted alkylene of the linear chain or branched chain of C6, such as can be, but be not limited to methylene, ethylidene, propylidene, isopropylidene, Butylidene, isobutylidene, pentylidene, isoamylidene, sub- neopentyl, hexylidene etc.；
R3For two area's luminescent dye molecule base of near-infrared, it is preferred that two area's luminescent dye molecule of near-infrared are as follows: IR1048 and Its derivative, IR1050 and its derivative or one of IR1061 and its derivative；
Wherein, I R1048 structure is as follows:(tetrafluoro boric acid 1- Butyl -2- [2- [3- [(1- butyl -6- chlorobenzene [cd] indoles -2 (1H)-subunit) ethylidene] the chloro- 1- cyclohexene -1- base of -2-] second Alkenyl] -6- chlorobenzene [cd] indoles, CAS 155613-98-2)；
Wherein, IR1050 structure is as follows:(1-Butyl-2-[2-[3- [(1-butyl-6-chlorobenz[cd]indol-2(1H)-ylidene)ethylidene]-2-chloro-5-methyl- 1-cyclohexen-1-yl] ethenyl] -6-chlorobenz [cd] indoliumtetrafluoroborate, No. CAS: 155614-00-9)；
Wherein, IR1061 structure is as follows:(tetrafluoro boric acid 4- [2- [the chloro- 3- of 2- [(2,6- diphenyl -4H- thiapyran -4- subunit) ethylidene] -1- cyclohexene -1- base] vinyl] -2,6- hexichol Base thio-pyrylium, No. CAS: 155614-01-0)；
And optoacoustic probe NO as described above2-R1-R2-X1-R3(I) in, R3It can be the near-infrared two of structure as above Area's luminescent dye molecule base, or two area's luminescent dye molecule derivative base of near-infrared for structure as above；
It is furthermore preferred that R3For IR1048 molecule base or R3For IR1048 derivative molecular base；
X1For imino group, amide groupsOr ester group
Preferably, optoacoustic probe structure provided by the present invention is as follows:
That is, invention further provides one kind using nitroimidazole as specificly-response group, it is with IR-1048 derivative Two area's luminescent dye molecule of near-infrared is the optoacoustic probe of precursor structure.
And the optoacoustic probe of the preferred structure, in normal physiological context, photoacoustic signal is weaker, and weary in tumour cell In oxygen environment, increases since anoxic will lead to reduction stress, lead to the overexpression of nitroreductase (NTR), thus, in tumour In weary oxygen environment, which can be restored by NTR, and nitryl group therein can be reduced to amino, and after restoring The photoacoustic signal of product greatly enhances, and can carry out photoacoustic imaging detection, and this but also optoacoustic probe of the present invention have it is good NTR and cancer target detection effect.
Further, in compound (II) or (II'), R2Alkylidene or substituted alkylene, sub- virtue for C0~C30 Base replaces arlydene, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For the alkylidene or substituted alkylene of C1~C30；It is furthermore preferred that R2For the alkylidene of the linear chain or branched chain of C1~C12, C1~ The substituted alkylene of the linear chain or branched chain of C12；It is further preferred that R2For the alkylidene of the linear chain or branched chain of C1~C6, C1~ The substituted alkylene of the linear chain or branched chain of C6, such as can be, but be not limited to methylene, ethylidene, propylidene, isopropylidene, Butylidene, isobutylidene, pentylidene, isoamylidene, sub- neopentyl, hexylidene etc.；
X1For imino group, amide groupsOr ester group
R4For the alkylidene of C0-C30, substituted alkylene, alkenylene, replace alkenylene, arlydene, substitution arlydene, Asia Alkylaryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkenyl, replaces alkenylene aryl Arlydene alkyl, or replace arlydene alkenyl；Preferably, R4For the alkylidene or substituted alkylene of C0-C30；It is furthermore preferred that R4For the straight chain or the alkylidene of straight chain of C0-C12, the substituted alkylene of C0~C12；It is further preferred that R4For the straight of C0~C6 The alkylidene of chain or branch, the substituted alkylene of the linear chain or branched chain of C0~C6, such as R4It can be chemical bond (i.e. cyclohexenyl group With X1Be connected directly), methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene, Sub- neopentyl, hexylidene etc.；
R5For the alkylidene of C0-C30, substituted alkylene, alkenylene, replace alkenylene, arlydene, substitution arlydene, Asia Alkylaryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkenyl, replaces alkenylene aryl Arlydene alkyl, or replace arlydene alkenyl；Preferably, R5For C2-C30 alkenylene or replace alkenylene；It is furthermore preferred that R5 For the straight chain of C2~C12 or alkenylene, the straight chain of C2~C12 or the substitution alkenylene of straight chain of straight chain；It is further preferred that R5 For the straight chain of C2-C6 or alkenylene, the straight chain of C2~C6 or the substitution alkenylene of straight chain of straight chain, for example, R5It can be sub- second Alkenyl, allylidene, sub- isopropenyl, butenylidene, sub- isobutenyl, inferior pentenyl, sub- hexenyl etc.；
R6For the alkylidene or substitution alkylidene of C2-C30；Preferably, R6For the alkylidene of the linear chain or branched chain of C2~C12, The substituted alkylene of the linear chain or branched chain of C1~C12；It is further preferred that R6For the alkylidene of the linear chain or branched chain of C2~C6, The substitution alkylidene of the linear chain or branched chain of C2~C6, such as can be, but be not limited to ethylidine, propylidyne, secondary isopropyl, secondary fourth Base, secondary isobutyl group, pentamethylene, secondary isopentyl, secondary neopentyl, hexylidyne etc.；
R7-R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
Preferably, R7-R11、R13-R18、R19-R22Independently it is hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, takes For aryl, alkylaryl, replace alkylaryl, aryl alkyl or substituted aryl alkyl；It is furthermore preferred that R7-R11、R13-R18、 R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl；It is further preferred that R7-R11、R13-R18、R19-R22Point It is not independently the substitution alkyl of the linear chain or branched chain of hydrogen, the alkyl of the linear chain or branched chain of C1-C12, C1-C12；It is further excellent Choosing, R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of the linear chain or branched chain of C1-C6, the straight chain of C1-C6 or branch The substitution alkyl of chain, such as R7-R11、R13-R18、R19-R22Independently be hydrogen, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl group, amyl, isopentyl, neopentyl, hexyl etc.；
Preferably, R12、R18It is independently fluorine, chlorine, bromine or iodine；
X2For halogen or tetrafluoroborate.
It is furthermore preferred that optoacoustic probe structure provided by the present invention is as follows:
And the preparation method of optoacoustic probe of the present invention as above can refer to it is as follows: by NO2-R1-R2-Y1(i) and R3-Y2(ii) Target light sonic probe compound can be obtained in hybrid reaction, and preparation method is more convenient and operation is relatively simple, is suitable for big rule The expanding production of mould；
Wherein, in compound (i), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces sub- heteroaryl Base；Preferably, R1For the arlydene of C5~C15, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；Further preferably , R1For the inferior heteroaryl or substitution inferior heteroaryl of C5~C15, wherein inferior heteroaryl replaces miscellaneous in inferior heteroaryl Atom be one of nitrogen, oxygen, sulphur or a variety of, and each inferior heteroaryl or replace inferior heteroaryl in contained heteroatomic quantity For one or more；Such as R1It can be, but be not limited to: is furans, thiophene, pyrroles, imidazoles, thiazole, pyrazoles, pyrans, pyridine, phonetic Pyridine, quinoline or purine etc.；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub- Alkylaryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For the alkylidene or substituted alkylene of C1~C30；More Preferably, R2For the alkylidene of the linear chain or branched chain of C1~C12, the substituted alkylene of the linear chain or branched chain of C1~C12；Further Preferably, R2For the alkylidene of the linear chain or branched chain of C1~C6, the substituted alkylene of the linear chain or branched chain of C1~C6, such as can be with For, but it is not limited to methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene, Asia newly Amyl, hexylidene etc.；
Y1For amino, carboxyl or hydroxyl；
In compound (ii), R3For two area's luminescent dye molecule base of near-infrared, it is preferred that two area's fluorescent dye of near-infrared point Son are as follows: IR1048 and its derivative, IR1050 and its derivative or one of IR1061 and its derivative；
Y2For amino, halogen, hydroxyl or carboxyl.
It is further preferred that raw materials used structure is as follows in preparation method of the present invention:
Wherein, in compound (iii) or (iii'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or take For arlydene, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For C1 The alkylidene or substituted alkylene of~C30；It is furthermore preferred that R2For the alkylidene of the linear chain or branched chain of C1~C12, C1~C12's The substituted alkylene of linear chain or branched chain；It is further preferred that R2For the alkylidene of the linear chain or branched chain of C1~C6, C1~C6's is straight The substituted alkylene of chain or branch, such as can be, but be not limited to methylene, ethylidene, propylidene, isopropylidene, butylidene, Isobutylidene, pentylidene, isoamylidene, sub- neopentyl, hexylidene etc.；
Y1For amino, carboxyl or hydroxyl；
R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；Preferably, R21、R22It is independently hydrogen, C1-C30 Alkyl replaces alkyl；It is further preferred that R21、R22It is independently hydrogen, the alkyl of the linear chain or branched chain of C1-C12, C1- The substitution alkyl of the linear chain or branched chain of C12；Still more preferably, R21、R22It is independently hydrogen, the straight chain of C1-C6 or branch The substitution alkyl of the alkyl of chain, the linear chain or branched chain of C1-C6, such as R21、R22Independently be hydrogen, methyl, ethyl, propyl, Isopropyl, butyl, isobutyl group, amyl, isopentyl, neopentyl, hexyl etc.；
And:
Wherein, in compound (iv),
R4For the alkylidene of C0-C30, substituted alkylene, alkenylene, replace alkenylene, arlydene, substitution arlydene, Asia Alkylaryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkenyl, replaces alkenylene aryl Arlydene alkyl, or replace arlydene alkenyl；Preferably, R4For the alkylidene or substituted alkylene of C0-C30；It is furthermore preferred that R4For the straight chain or the alkylidene of straight chain of C0-C12, the substituted alkylene of C0~C12；It is further preferred that R4For the straight of C0~C6 The alkylidene of chain or branch, the substituted alkylene of the linear chain or branched chain of C0~C6, such as R4It can be chemical bond (i.e. cyclohexenyl group With X1Be connected directly), methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene, Sub- neopentyl, hexylidene etc.；
R5For the alkylidene of C0-C30, substituted alkylene, alkenylene, replace alkenylene, arlydene, substitution arlydene, Asia Alkylaryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkenyl, replaces alkenylene aryl Arlydene alkyl, or replace arlydene alkenyl；Preferably, R5For C2-C30 alkenylene or replace alkenylene；It is furthermore preferred that R5 For the straight chain of C2~C12 or alkenylene, the straight chain of C2~C12 or the substitution alkenylene of straight chain of straight chain；It is further preferred that R5 For the straight chain of C2-C6 or alkenylene, the straight chain of C2~C6 or the substitution alkenylene of straight chain of straight chain, for example, R5It can be sub- second Alkenyl, allylidene, sub- isopropenyl, butenylidene, sub- isobutenyl, inferior pentenyl, sub- hexenyl etc.；
R6For the alkylidene or substitution alkylidene of C2-C30；Preferably, R6For the alkylidene of the linear chain or branched chain of C2~C12, The substituted alkylene of the linear chain or branched chain of C1~C12；It is further preferred that R6For the alkylidene of the linear chain or branched chain of C2~C6, The substitution alkylidene of the linear chain or branched chain of C2~C6, such as can be, but be not limited to ethylidine, propylidyne, secondary isopropyl, secondary fourth Base, secondary isobutyl group, pentamethylene, secondary isopentyl, secondary neopentyl, hexylidyne etc.；
R7-R20It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
Preferably, R7-R11、R13-R18、R19-R22Independently it is hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, takes For aryl, alkylaryl, replace alkylaryl, aryl alkyl or substituted aryl alkyl；It is furthermore preferred that R7-R11、R13-R18、 R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl；It is further preferred that R7-R11、R13-R18、R19-R22Point It is not independently the substitution alkyl of the linear chain or branched chain of hydrogen, the alkyl of the linear chain or branched chain of C1-C12, C1-C12；It is further excellent Choosing, R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of the linear chain or branched chain of C1-C6, the straight chain of C1-C6 or branch The substitution alkyl of chain, such as R7-R11、R13-R18、R19-R22Independently be hydrogen, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl group, amyl, isopentyl, neopentyl, hexyl etc.；
Preferably, R12、R18It is independently fluorine, chlorine, bromine or iodine；
Y2For amino, halogen, hydroxyl or carboxyl；
X2For halogen or tetrafluoroborate.
Further, raw material as described above
It can be by With X3-R2-Y3(vi) it is made by condensation and deprotection reaction；
I.e., it is possible to which used compound (v) or (v') and compound (vi) pass through substitution-hydrolysis (deprotection) two-step reaction system , and the Y in compound (vi)3Substituent group is then Y1Product structure after being reacted with protective agent, and pass through second remove-insurance Step is protected, it can be by Y3Reaction obtains Y1；
Wherein, in compound (v) or (v'), R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkane Base, substituted aryl, alkylaryl, replaces alkylaryl, aryl alkyl or substituted aryl alkyl at aryl；Preferably, R21、R22 It is independently hydrogen, the alkyl of C1-C30, substitution alkyl；It is further preferred that R21、R22It is independently hydrogen, C1-C12 The alkyl of linear chain or branched chain, C1-C12 linear chain or branched chain substitution alkyl；Still more preferably, R21、R22Independently It is the substitution alkyl of the linear chain or branched chain of hydrogen, the alkyl of the linear chain or branched chain of C1-C6, C1-C6, such as R21、R22Independently It is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl, isopentyl, neopentyl, hexyl etc.；
In compound (vi), X3For halogen；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub- Alkylaryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For the alkylidene or substituted alkylene of C1~C30；More Preferably, R2For the alkylidene of the linear chain or branched chain of C1~C12, the substituted alkylene of the linear chain or branched chain of C1~C12；Further Preferably, R2For the alkylidene of the linear chain or branched chain of C1~C6, the substituted alkylene of the linear chain or branched chain of C1~C6, such as can be with For, but it is not limited to methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene, Asia newly Amyl, hexylidene etc.；
Y3For with amino, carboxyl or the hydroxyl after protection group reaction, and by hydrolysis to obtain corresponding amino, carboxylic Base or hydroxyl；
For example, Y3It can be acyl group, ether, carbonyl amino, carboxyl or hydroxyl that perhaps ester group is protected.
Still more preferably, in preparation method of the present invention, raw materials used compound are as follows:
And(I R-1048)。
Further, with compound(MZ) for, to the preparation method of the raw material into one Step explanation, which can refer to as follows:
Embodiment 1
(1) preparation of MZ-BOC molecule:
By 2- nitroimidazole (0.5g, 4.42mmo l) with 2mL DMF dissolution, then it is added portionwise under agitation K2CO3(0.915g, 6.63mmo l) and N-Boc- bromine ethamine (0.99g, 4.42mmol) reacts overnight under nitrogen protection；
Then, revolving removes solvent, and vacuum drying after obtained solid is dissolved in water, is extracted with ethyl acetate, collects organic Phase, revolving remove solvent, and crude product re-crystallizing in ethyl acetate obtains dark yellow solid product MZ-BOC (0.10g, 89%).
Referring to Fig. 1 and Fig. 2, atlas analysis is as follows for product MZ-BOC nuclear-magnetism and mass spectrometric measurement map difference:
MZ-BOC:1H NMR(400MHz,DMSO-d6) δ 7.46 (s, 1H), 7.14 (s, 1H), 4.43 (t, J=5.6Hz, 2H), 3.36 (q, J=5.9Hz, 2H), 1.31 (s, 9H)；
HRMS(ESI+):m/z calcd for C10H16N4O4:279.1064[M+Na+],found 279.1060。
(2) preparation of MZ molecule
MZ-BOC (0.85g, 3.3mmol) is dissolved in methanol (2mL), then under agitation, is added 1.25M HCl's Methanol solution (2mL), reacts 5h at room temperature；
Then, revolving removes solvent, and obtained solid is washed with methanol, collects washing lotion, rotates and removes solvent, vacuum drying, Obtained solid crude product recrystallizing methanol obtains faint yellow solid product MZ (0.64g, 89%).
Respectively referring to Fig. 3 and Fig. 4, atlas analysis is as follows for product MZ nuclear-magnetism and mass spectrometric measurement map:
MZ:1HNMR(400MHz,CD3OD): δ 7.48 (d, J=1.0Hz, 1H), 7.14 (d, J=1.1Hz, 1H), 4.50 (t, J=6.3Hz, 2H), 3.07 (t, J=6.3Hz, 2H)；
HRMS(ESI+):m/z calcd for C5H8N4O2:157.0720[M+H+],found 157.0725； 179.0539[M+Na+],found179.0537。
(3) preparation of optoacoustic probe molecule IR1048-MZ:
IR-1048 (37mg, 0.05mmol) is dissolved in anhydrous DMF (10mL), then into solution be added MZ (112.6mg, 0.5mmol), quickly stirring, and a period of time is reacted under 40 DEG C of nitrogen protections；
Then, revolving removes solvent, and silicagel column is crossed in vacuum drying, and methylene chloride: methanol makees eluent, and gradient elution removes Solvent is removed, obtains solid product, IR1048-MZ,(6.44mg23%).
Referring to figs. 5 and 6, atlas analysis is as follows for product nuclear-magnetism and mass spectrometric measurement map difference:
IR1048-MZ:1HNMR (400MHz, Methanol-d4): δ 8.63 (d, J=7.5Hz, 1H), 8.17 (d, J= 7.6Hz, 1H), 8.11 (d, J=8.2Hz, 1H), 8.01 (d, J=12.8Hz, 1H), 7.96-7.84 (m, 5H), 7.72 (s, 1H), 7.51 (d, J=7.8Hz, 1H), 7.14 (s, 1H), 7.10 (d, J=8.4Hz, 1H), 7.06 (s, 1H), 6.90 (d, J= 7.8Hz, 1H), 6.15 (d, J=12.9Hz, 1H), 4.29-4.23 (m, 2H), 2.63-2.51 (m, 2H), 1.82-1.77 (m, 2H), 1.47 (td, J=15.3,14.4,7.8Hz, 4H), 1.12 (dq, J=14.5,7.7Hz, 4H), 1.01 (t, J=7.4Hz, 4H), 0.92 (dt, J=18.6,7.2Hz, 6H), 0.76-0.70 (m, 1H), 0.59 (t, J=7.2Hz, 3H)；
HRMS(ESI+):m/zcalcdforC45H45BCl2F4N6O2:771.2976[M-BF4 -]；found771.2975..
The reaction process of embodiment 1 is referring to Fig. 7.
Embodiment 2
(1) preparation of MZ-BOC molecule:
2- nitroimidazole (1.0g, 8.84mmol) is dissolved with 4mLDMF, K is then added portionwise under agitation2CO3 (1.83g, 13.26mmol) and N-Boc- bromine ethamine (1.98g, 8.84mmol) reacts overnight under nitrogen protection.
Revolving removes solvent, and vacuum drying, obtained solid is soluble in water, is then extracted with ethyl acetate, collects organic phase, Revolving removes solvent.Gained crude product obtains dark yellow solid product MZ-BOC (0.19g, 83%) with re-crystallizing in ethyl acetate.
Product MZ-BOC nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
(2) preparation of MZ molecule
MZ-BOC (1.7g, 6.6mmol) is dissolved in methanol (4mL), the methanol that 1.25M HCl is added under stirring condition is molten Liquid (4mL), reacts 8h at room temperature；
Revolving removes solvent, and obtained solid is washed with methanol, collects washing lotion, and revolving removes solvent, vacuum drying.Obtained solid Crude product recrystallizing methanol obtains faint yellow solid product MZ (1.16g, 81%).
Product MZ nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
(3) preparation of optoacoustic probe molecule IR1048-MZ:
IR-1048 (74mg, 0.1mmol) is dissolved in anhydrous DMF (15mL), then be added MZ (225.2mg, 1.0mmol), it quickly stirs, is reacted under 40 DEG C of nitrogen protections；
Revolving removes solvent, and vacuum drying crosses silicagel column, methylene chloride: methanol makees eluent, and gradient elution removes molten Agent obtains solid product IR1048-MZ (10.08mg18%).
Product IR1048-MZ nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
Embodiment 3
(1) preparation of MZ-BOC molecule:
2- nitroimidazole (1.5g, 13.26mmol) is dissolved with 6mLDMF, then, under agitation, is added portionwise K2CO3(2.745g, 19.89mmol) and N-Boc- bromine ethamine (2.97g, 13.26mmol) reacts overnight under nitrogen protection.
Revolving removes solvent, and vacuum drying, obtained solid is soluble in water, is then extracted with ethyl acetate, collects organic phase, Revolving removes solvent.Crude product obtains dark yellow solid product MZ-BOC (0.26g, 78%) with re-crystallizing in ethyl acetate.
Product MZ-BOC nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
(2) preparation of MZ molecule
MZ-BOC (2.55g, 9.9mmol) is dissolved in methanol (6mL), is then added 1.25MHCl's under agitation Methanol solution (6mL), reaction is stayed overnight at room temperature；
Revolving removes solvent, and obtained solid is washed with methanol, collects washing lotion, and revolving removes solvent, vacuum drying；Obtained solid Crude product recrystallizing methanol obtains faint yellow solid product MZ (1.60g, 74%)；
Product MZ nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
(3) preparation of optoacoustic probe molecule IR1048-MZ:
IR-1048 (111mg, 0.15mmol) is dissolved in anhydrous DMF (25mL), then be added MZ (337.8mg, 1.5mmol), it quickly stirs, reacts 10h under 50 DEG C of nitrogen protections；
Revolving removes solvent, and vacuum drying crosses silicagel column, methylene chloride: methanol makees eluent, and gradient elution removes molten Agent obtains solid product IR1048-MZ (15.96mg, 19%).
Product IR1048-MZ nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
Embodiment 4
(1) preparation of MZ-BOC molecule:
2- nitroimidazole (5g, 44.2mmol) is dissolved with 20mLDMF, and K is added portionwise under stirring2CO3(9.15g, 66.3mmol) and N-Boc- bromine ethamine (9.9g, 44.2mmol), 18h is reacted under nitrogen protection.
Revolving removes solvent, and vacuum drying, obtained solid is soluble in water, is then extracted with ethyl acetate, collects organic phase, Revolving removes solvent.Crude product re-crystallizing in ethyl acetate obtains dark yellow solid product MZ-BOC (0.81g, 72%)；
Product nuclear-magnetism and mass spectrometry results are in the same manner as in Example 1.
(2) preparation of MZ molecule
MZ-BOC (8.5g, 33mmol) is dissolved in methanol (20mL), the methanol solution of 1.25MHCl is added with stirring (20mL), reacts 18h at room temperature；
Revolving removes solvent, and obtained solid is washed with methanol, collects washing lotion, and solvent is removed in rotation, is dried in vacuo.Obtained solid is thick Product recrystallizing methanol obtains faint yellow solid product MZ (5.11g, 71%).
Product nuclear-magnetism and mass spectrometry results are in the same manner as in Example 1.
(3) preparation of probe molecule IR1048-MZ:
IR-1048 (370mg, 0.1mmol) is dissolved in anhydrous DMF (50mL), MZ (1.126g, 5mmol) then is added, It quickly stirs, is reacted for 24 hours under 60 DEG C of nitrogen protections；
Revolving removes solvent, and vacuum drying crosses silicagel column, methylene chloride: methanol makees eluent, and gradient elution removes molten Agent obtains solid product IR1048-MZ (44.8mg16%).
Experimental example 1
Using IR1048-MZ prepared in embodiment 1 as experimental material, tested as follows:
(1) NTR solution (the NTR final concentration difference of various concentration is added into the IR1048-MZ solution that concentration is 5 μ g/mL Are as follows: 0,1,2,3,4,5,6,7,8,9,10 μ g/mL), using 808nm as exciting light, solution is detected with photoacoustic imager, is tied Fruit is as shown in Figure 8.
Testing result as shown in Figure 8 it is found that under the conditions of 808nm is exciting light, believe by the optoacoustic of IR1048-MZ of the present invention Number value is gradually increased with the increase of NTR concentration, and is in good linear relationship with NTR concentration.
It can be seen that optoacoustic probe of the present invention after being restored by NTR, has good optoacoustic performance, can be used in NTR water Flat effective detection.
(2) by 200 μ LIR1048-MZ solution (by tail bone be injected intravenously injection mouse body in (dosage 0.2mg/kg), Mouse is imaged with toy photoacoustic imager, as a result as shown in Figure 9.
After 14h, there is apparent photoacoustic signal in tumor locus, and dotted line indicates tumor boundaries, and it is longitudinal deep to measure tumour Degree is 14.6 millimeters.
It can be seen that optoacoustic probe of the present invention can be realized effective NTR photo-acoustic detection, and then realize the optoacoustic inspection of tumour Survey imaging；Meanwhile optoacoustic probe penetration into tissue of the present invention is strong, deep tissues can be carried out effective photo-acoustic detection at Picture.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims Including belonging to all such changes and modifications in the scope of the invention.

Claims (10)

1. a kind of optoacoustic probe is preparing the application in NTR photo-acoustic detection reagent, which is characterized in that the optoacoustic probe structure is such as Under:
NO2-R1-R2-X1-R3(I),
In compound (I), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene, alkylidene aryl or substituted alkylene Aryl, arlydene alkyl or substituted alkylene aryl；
R3For two area's luminescent dye molecule base of near-infrared；
X1For alkyl, imino group, amide groups, hydroxyl or ester group；
Preferably, two area's luminescent dye molecule of near-infrared are as follows: IR1048 and its derivative, IR1050 and its derivative, or One of IR1061 and its derivative.
2. optoacoustic probe according to claim 1 is preparing the application in NTR photo-acoustic detection reagent, which is characterized in that R3For IR1048 and its derivative molecular base.
3. optoacoustic probe according to claim 1 is preparing the application in NTR photo-acoustic detection reagent, which is characterized in that institute It is as follows to state optoacoustic probe structure:
Or
In compound (II) or (II'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene, Asia Alkylaryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；
X1For imino group, amide groups or ester group；
R4、R5Independently it is the alkylidene of C0-C30, substituted alkylene, alkenylene, replaces alkenylene, arlydene, replaces Asia Aryl, alkenylene aryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkene at alkylidene aryl Base replaces arlydene alkyl, or replaces arlydene alkenyl；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R22Independently it is hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, takes Haloalkylaryl, aryl alkyl or substituted aryl alkyl；
X2For halogen or tetrafluoroborate.
4. optoacoustic probe according to claim 3 is preparing the application in NTR photo-acoustic detection reagent, which is characterized in that institute It states in compound (II) or (II'),
R2For the alkylidene or substituted alkylene of C1~C30；
X1For imino group, amide groups or ester group；
R4For the alkylidene or substituted alkylene of C0-C30；
R5For C2-C30 alkenylene or replace alkenylene；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl Aryl replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
R12、R18It is independently fluorine, chlorine, bromine or iodine；
X2For halogen or tetrafluoroborate.
5. optoacoustic probe according to claim 4 is preparing the application in NTR photo-acoustic detection reagent, which is characterized in that institute It is as follows to state optoacoustic probe structure:
Or
6. optoacoustic probe of any of claims 1-5 exists preparing the application in NTR photo-acoustic detection reagent, feature In the preparation step of the optoacoustic probe is as follows:
By NO2-R1-R2-Y1(i) and R3-Y2(ii) hybrid reaction is to get the optoacoustic probe；
Wherein, in compound (i), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene, alkylidene aryl or substituted alkylene Aryl, arlydene alkyl or substituted alkylene aryl；
Y1For amino, carboxyl or hydroxyl；
In compound (ii), R3For two area's luminescent dye molecule base of near-infrared,
Y2For amino, halogen, hydroxyl or carboxyl；
Preferably, two area's luminescent dye molecule of near-infrared are as follows: IR1048 and its derivative, IR1050 and its derivative, or One of IR1061 and its derivative.
7. preparing the application in NTR photo-acoustic detection reagent according to claim 6 optoacoustic probe, which is characterized in that compound (i) Structure are as follows:
Or
Wherein, in compound (iii) or (iii'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace sub- Aryl, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；
Y1For amino, carboxyl or hydroxyl；
R21、R22Independently it is hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, takes Haloalkylaryl, aryl alkyl or substituted aryl alkyl；
And/or the structure of compound (ii) are as follows:
Wherein, in compound (iv), R4、R5Independently it is the alkylidene of C0-C30, substituted alkylene, alkenylene, replaces Asia Alkenyl, arlydene replace arlydene, alkylidene aryl, alkenylene aryl, substituted alkylene aryl, replace alkenylene aryl, Asia Aryl alkyl, arlydene alkenyl replace arlydene alkyl, or replace arlydene alkenyl；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R20Independently it is hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, takes Haloalkylaryl, aryl alkyl or substituted aryl alkyl；
Y2For amino, halogen, hydroxyl or carboxyl；
X2For halogen or tetrafluoroborate.
8. optoacoustic probe according to claim 7 is preparing the application in NTR photo-acoustic detection reagent, which is characterized in that institute State compound (iii) or (iii') respectively by
With X3-R2-Y3(vi) pass through contracting It closes and deprotection is made；
Wherein, in compound (v) or (v'), R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, virtue Base, alkylaryl, replaces alkylaryl, aryl alkyl or substituted aryl alkyl at substituted aryl；
In compound (vi), X3For halogen；R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene, Alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；Y3For with the ammonia after protection group reaction Base, carboxyl perhaps hydroxyl and by hydrolysis to obtain corresponding amino, carboxyl or hydroxyl.
9. optoacoustic probe according to claim 7 is preparing the application in NTR photo-acoustic detection reagent, which is characterized in that institute It states in compound (iii) or (iii'):
R2For the alkylidene or substituted alkylene of C1~C30；
X1For imino group, amide groups or ester group；
R21、R22Independently it is hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, replaces alkyl Aryl, aryl alkyl or substituted aryl alkyl；
Y1For amino, hydroxyl or carboxyl；
And/or in compound (iv), R4For the alkylidene or substituted alkylene of C0-C30；
R5For C2-C30 alkenylene or replace alkenylene；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl Aryl replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
R12、R18It is independently fluorine, chlorine, bromine or iodine；
Y2For amino, halogen, hydroxyl or carboxyl；
X2For halogen or tetrafluoroborate.
10. optoacoustic probe according to claim 9 is preparing the application in NTR photo-acoustic detection reagent, which is characterized in that change Close the structure of object (iii) are as follows:
The structure of compound (iii') are as follows:
And/or the structure of compound (iv) are as follows:
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CN113552099A (en) * 2020-04-24 2021-10-26 中国科学院宁波工业技术研究院慈溪生物医学工程研究所 Fluorescent diagnosis kit and application thereof
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CN112694431B (en) * 2019-10-23 2022-09-16 中国医学科学院药物研究所 Nitroreductase in hypersensitive fluorescent probe detection bacteria and application in bacterial infection
CN113552099A (en) * 2020-04-24 2021-10-26 中国科学院宁波工业技术研究院慈溪生物医学工程研究所 Fluorescent diagnosis kit and application thereof
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