CN115785117B - Compound, kit and application of compound serving as photomagnetic bimodal probe - Google Patents
Compound, kit and application of compound serving as photomagnetic bimodal probe Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 106
- 239000000523 sample Substances 0.000 title claims abstract description 34
- 230000002902 bimodal effect Effects 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 77
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 51
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 32
- 239000007864 aqueous solution Substances 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 22
- 150000002602 lanthanoids Chemical class 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 7
- GZAJOEGTZDUSKS-UHFFFAOYSA-N 5-aminofluorescein Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C21OC(=O)C1=CC(N)=CC=C21 GZAJOEGTZDUSKS-UHFFFAOYSA-N 0.000 claims description 5
- YOAWSYSKQHLFPM-UHFFFAOYSA-N 5-amino-3',6'-dihydroxyspiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C11OC(=O)C2=CC=C(N)C=C21 YOAWSYSKQHLFPM-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- SOHCYNFHNYKSTM-UHFFFAOYSA-N methylsulfinylmethane;oxolane Chemical compound CS(C)=O.C1CCOC1 SOHCYNFHNYKSTM-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 description 37
- 238000003384 imaging method Methods 0.000 description 37
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Abstract
The present application relates to a compound of formula (I), to a process for the preparation of a compound of formula (I), to a kit comprising a compound of formula (I), and to the use as a photomagnetic bimodal probe
Description
Technical Field
The present invention relates to the field of optical imaging and magnetic resonance imaging. In particular to a photo-magnetic bimodal imaging compound Gd-DOTA pNBn -CS-FITC.
Background
In recent years, research on magnetic resonance imaging molecular probes has been greatly focused on multi-mode molecular probes, and the probes can be simultaneously used for diagnosis of various imaging devices by combining PET, optical or ultrasonic imaging methods based on magnetic resonance imaging, so that the diagnosis precision of diseases is improved (see Jessica W,M G E,Aurora R-R,et al.Chemistry of mri contrast agents:Current challenges and new frontiers.[J].Chemical reviews,2019,119(2)).Mishra and the like which firstly propose a synthetic route of a photo-magnetic dual-mode probe Gd-DOTA-EA-FITC (see Mishra A,Pfeuffer J,Mishra R,et al.A new class of gd-based do3a-ethylamine-derived targeted contrast agents for mr and optical imaging[J].Bioconjugate Chemistry,2006,17(3):773-780),) and research and exploration are carried out on material transport and tissue flow in extracellular space in brain tissues (Liqian, containing aloe, liang Lei, and the like), however, the existing photo-magnetic dual-mode molecular probe Gd-do3a-EA-FITC can not simultaneously obtain good photo-imaging and magnetic imaging effects by using the photo-magnetic dual-mode probe Gd-do3a-EA-FITC in brain tissue space imaging analysis [ J ]. Beijing university (medical edition) and 2018,50 (02): 221-225).
Disclosure of Invention
In order to solve the above-mentioned problems occurring in the prior art, according to a first aspect of the present invention, there is provided a compound of formula (I):
Wherein,
Me is selected from Gd, la and Dy.
In a preferred embodiment of the compounds of the invention, the compounds of formula (I) are in particular compounds of formula (I-1) or formula (I-2):
Wherein,
Me is selected from Gd, la and Dy.
According to a second aspect of the present invention, the present invention also relates to a process for the preparation of a compound of formula (I), said process comprising the steps of:
a) Reacting a compound of formula (1-5) with an aminofluorescein in the presence of a solvent under weakly alkaline conditions to give a compound of formula (1-6),
And
B) Reacting the compound of formula (1-6) obtained in step a) with a compound comprising a lanthanide in the presence of a solvent and a catalyst under weakly basic conditions to obtain a compound of formula (I),
In a preferred embodiment of the method of the invention, the aminofluorescein is 5-aminofluorescein or 6-aminofluorescein.
In another preferred embodiment of the process of the present invention, in step b), the compound comprising a lanthanide is a lanthanide-containing chloride. In a more preferred embodiment of the process of the present invention, the compound comprising a lanthanide is a hydrate of the lanthanide chloride. In a more preferred embodiment of the process of the present invention, the lanthanoid is selected from Gd, la and Dy. In a particularly preferred embodiment of the process of the invention, the lanthanide-containing compound is selected from one or more of GdCl 3·6H2O、LaCl3·6H2O、DyCl3·6H2 O. In a most preferred embodiment of the process of the invention, the lanthanide-containing compound is selected from GdCl 3·6H2 O.
In a preferred embodiment of the process according to the invention, in step a), the reaction is carried out at a ph=7.5 to 9.5. In a more preferred embodiment of the process according to the invention, in step a), the reaction is carried out at a ph=8.0 to 9.0. In a most preferred embodiment of the process according to the invention, in step a), the reaction is carried out at a ph=8.0 to 8.5.
In a preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a ph=7.0 to 9.0. In a more preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a ph=7.0 to 8.5. In a most preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a ph=7.0 to 8.0.
In a preferred embodiment of the process according to the invention, in step a) or step b), the reaction is carried out at a temperature of from 20 to 60 ℃. In a more preferred embodiment of the process according to the invention, in step a) or step b), the reaction is carried out at a temperature of from 20 to 50 ℃. In a further preferred embodiment of the process according to the invention, in step a) or step b), the reaction is carried out at a temperature of from 20 to 40 ℃. In a most preferred embodiment of the process according to the invention, in step a) or step b), the reaction is carried out at room temperature.
In a preferred embodiment of the process according to the invention, in step a) or step b), the solvent used is selected from one or more of water, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide.
In a more preferred embodiment of the process according to the invention, in step a) the solvent used is a mixture of water and tetrahydrofuran, for example a mixture of water and tetrahydrofuran in a volume ratio of from 1:10 to 10:1, preferably a mixture of water and tetrahydrofuran in a volume ratio of from 1:8 to 8:1, more preferably a mixture of water and tetrahydrofuran in a volume ratio of from 1:6 to 6:1.
In another more preferred embodiment of the process of the invention, in step b), the solvent is water.
In a preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a temperature of from 20 to 60 ℃. In a more preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a temperature of from 20 to 50 ℃. In a further preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a temperature of from 20 to 40 ℃. In a most preferred embodiment of the process according to the invention, in step b), the reaction is carried out at room temperature.
The compounds of formula (I) provided by the application and the compounds of formula (I) prepared by the method of the application are used as probes in fluorescence diffusion imaging and/or magnetic resonance imaging. Research results of fluorescent imaging, fluorescent diffusion imaging and magnetic resonance imaging of the probe show that the compound of the formula (I) provided by the application and prepared by the method have good photo-magnetic imaging properties at the same time. This finding is surprising in that the present application provides and the compounds of formula (I) prepared according to the method of the present application have a photoimaging moiety and a magnetic imaging moiety, however, the compounds of the present application which combine the photoimaging moiety and the magnetic imaging moiety have better photoimaging properties than the prior art magnetic imaging probe Gd-DOTA pNBn and the fluorescent probe fluorescein isothiocyanate (Fluorescein Isothiocyanate, FITC).
According to a third aspect of the invention, there is also provided a kit comprising:
A container comprising a compound of formula (I) according to the first aspect of the invention or a compound of formula (I) prepared according to the method of the second aspect of the invention; and
Instructions for use.
In a preferred embodiment of the kit of the invention, the compound of formula (I) according to the first aspect of the invention or the compound of formula (I) prepared according to the method of the second aspect of the invention is in an aqueous solution, in particular in an aqueous solution of 5mM, in an aqueous solution of 10mM, at a concentration of 0.05 to 30mM, preferably 0.1 to 25mM and more preferably 0.1 to 20 mM. In a more preferred embodiment of the kit of the invention, the aqueous solution is an aqueous solution of NaCO 3/NaHCO3 having a pH of 7 to 8.
According to a fourth aspect of the invention there is provided the use of a compound of formula (I) according to the first aspect of the invention or a compound of formula (I) prepared according to the method of the second aspect of the invention or a kit according to the third aspect of the invention as a magneto-optical bimodal probe.
In a preferred embodiment of the use according to the invention, wherein preferably the compound of formula (I) according to the first aspect of the invention or the compound of formula (I) prepared according to the method according to the second aspect of the invention or the kit according to the third aspect of the invention comprises the compound in an aqueous solution, in particular in an aqueous solution of 5mM, in an aqueous solution of 10mM, at a concentration of 0.05 to 30mM, preferably 0.1 to 25mM and more preferably 0.1 to 20 mM. In a more preferred embodiment of the test use according to the invention, the aqueous solution is an aqueous solution of NaCO 3/NaHCO3 having a pH of 7 to 8.
Thus, when the compound of formula (I) according to the first aspect of the invention or the compound of formula (I) prepared according to the method of the second aspect of the invention is used, it is preferably used in the form of a solution, for example an aqueous solution, for example a solution having a concentration of 0.05 to 30mM, preferably 0.1 to 25mM and more preferably 0.1 to 20mM, in particular a 5mM solution, a 10mM solution. Preferably, the aqueous solution is an aqueous solution of NaCO 3/NaHCO3 having a pH of 7 to 8.
Drawings
The following drawings are only illustrative and explanatory of the invention, and are not restrictive of the scope of the invention, wherein:
FIG. 1 shows the fluorescence diffusion imaging results of the compounds of the present invention as magneto-optical bimodal probes with FITC as control.
FIG. 2 shows the magnetic resonance imaging results of the compounds of the present invention as magneto-optical bimodal probes with Gd-DOTA, gd-DOTA pNBn and Gd-DOTA pNBn -EA-FITC as controls.
Detailed Description
For a clearer understanding of the technical features, objects and effects of the present invention, embodiments of the present invention will now be described with reference to the drawings, in which like reference numerals refer to like parts throughout the various views.
In the present application, unless otherwise indicated, all reactions were carried out at room temperature and pressure and all reagents and reagents used were obtained.
In the present invention, the concentration unit mM and mmol/L have the same meaning unless otherwise specified.
In the invention, DOTA English is fully called 1,4,7,10-Tetraazacyclododecane-1,4,7,10-TETRAACETIC ACID, and Chinese name is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.
Gd-DOTA has the Chinese name gadolinium-1, 4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid complex, and is a commercial imaging agent.
The chinese name of Gd-DOTA pNBn is gadolinium- [2,2',2"- (10- (4-aminobenzyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) ] -triacetic acid metal complex.
Gd-DOTA pNBn -EA-FITC, chinese name gadolinium- [4, 7-bis-carboxymethyl-10- (2-fluorescein thiourea ethyl) -1,4,7, 10-tetraazacyclododecane-1-yl ] -acetic acid complex.
According to a first aspect of the present invention there is provided a compound of formula (I):
Wherein,
Me is selected from Gd, la and Dy.
In a preferred embodiment of the compounds of the invention, the compounds of formula (I) are in particular compounds of formula (I-1) or formula (I-2):
Wherein,
Me is selected from Gd, la and Dy.
According to a second aspect of the present invention, the present invention also relates to a process for the preparation of a compound of formula (I), said process comprising the steps of:
a) Reacting a compound of formula (1-5) with an aminofluorescein in the presence of a solvent under weakly alkaline conditions to give a compound of formula (1-6),
And
B) Reacting the compound of formula (1-6) obtained in step a) with a compound comprising a lanthanide in the presence of a solvent and a catalyst under weakly basic conditions to obtain a compound of formula (I),
In a preferred embodiment of the method of the invention, the aminofluorescein is 5-aminofluorescein or 6-aminofluorescein.
In another preferred embodiment of the process of the present invention, in step b), the compound comprising a lanthanide is a lanthanide-containing chloride. In a more preferred embodiment of the process of the present invention, the compound comprising a lanthanide is a hydrate of the lanthanide chloride. In a more preferred embodiment of the process of the present invention, the lanthanoid is selected from Gd, la and Dy. In a particularly preferred embodiment of the process of the invention, the lanthanide-containing compound is selected from one or more of GdCl 3·6H2O、LaCl3·6H2O、DyCl3·6H2 O. In a most preferred embodiment of the process of the invention, the lanthanide-containing compound is selected from GdCl 3·6H2 O.
In the process of the present invention, the compounds of formula (1-5) are known compounds, commercially available, or may be synthesized according to known methods. Known synthetic methods of the compounds of the formulae (1-5) are, for example, the methods described in the following documents ：[4]Jagadish B,Brickert-Albrecht G L,Nichol G S,et al.On the synthesis of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane[J].Tetrahedron Lett,2011,52(17):2058-2061;Mizukami S,Tonai K,Kaneko M,et al.Lanthanide-based protease activity sensors for time-resolved fluorescence measurements[J].Journal of the American Chemical Society,2008,130(44):14376-14377;Granato L,Vander Elst L,Henoumont C,et al.Optimizing water exchange rates and rotational mobility for high-relaxivity of a novel gd-do3a derivative complex conjugated to inulin as macromolecular contrast agents for mri[J].Chemistry&Biodiversity,2018,15(2):e1700487.
In a preferred embodiment of the process according to the invention, in step a), the reaction is carried out at a ph=7.5 to 9.5. In a more preferred embodiment of the process according to the invention, in step a), the reaction is carried out at a ph=8.0 to 9.0. In a most preferred embodiment of the process according to the invention, in step a), the reaction is carried out at a ph=8.0 to 8.5.
In a preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a ph=7.0 to 9.0. In a more preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a ph=7.0 to 8.5. In a most preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a ph=7.0 to 8.0.
In a preferred embodiment of the process according to the invention, in step a) or step b), the reaction is carried out at a temperature of from 20 to 60 ℃. In a more preferred embodiment of the process according to the invention, in step a) or step b), the reaction is carried out at a temperature of from 20 to 50 ℃. In a further preferred embodiment of the process according to the invention, in step a) or step b), the reaction is carried out at a temperature of from 20 to 40 ℃. In a most preferred embodiment of the process according to the invention, in step a) or step b), the reaction is carried out at room temperature.
In a preferred embodiment of the process according to the invention, in step a) or step b), the solvent used is selected from one or more of water, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide.
In a more preferred embodiment of the process according to the invention, in step a) the solvent used is a mixture of water and tetrahydrofuran, for example a mixture of water and tetrahydrofuran in a volume ratio of from 1:10 to 10:1, preferably a mixture of water and tetrahydrofuran in a volume ratio of from 1:8 to 8:1, more preferably a mixture of water and tetrahydrofuran in a volume ratio of from 1:6 to 6:1.
In another more preferred embodiment of the process of the invention, in step b), the solvent is water.
In a preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a temperature of from 20 to 60 ℃. In a more preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a temperature of from 20 to 50 ℃. In a further preferred embodiment of the process according to the invention, in step b), the reaction is carried out at a temperature of from 20 to 40 ℃. In a most preferred embodiment of the process according to the invention, in step b), the reaction is carried out at room temperature.
In a specific embodiment of the process of the present application, the compound of formula (1-5) is obtained by nucleophilic addition reaction starting from 1,4,7, 10-tetraazacyclododecane and aminofluorescein, and is further reacted with a compound comprising a lanthanide to obtain the compound of formula (I). In the context of the present application, the compound of formula (I) is a novel opto-magnetic bimodal probe compound Gd-DOTA pNBn -CS-FITC, and therefore the present application provides a novel imaging tool for opto-magnetic bimodal imaging.
In a specific embodiment of the present invention, using 5-aminofluorescein as an example, an exemplary synthetic route for the compounds of formula (I) is as follows:
The compound of the formula (I) and the compound of the formula (I) prepared by the method provided by the application, namely the compound Gd-DOTA pNBn -CS-FITC of the formula (1-7) obtained according to an exemplary synthetic route, are used as probes in fluorescence diffusion imaging and/or magnetic resonance imaging. The research results of fluorescence imaging, fluorescence diffusion imaging and magnetic resonance imaging of the probe show that the compound Gd-DOTA pNBn -CS-FITC of the formula (I) prepared by the method provided by the application has good optical and magnetic imaging properties when being used as an optical magnetic bimodal probe. This finding is surprising in that the present application provides and the compounds of formula (I) prepared according to the process of the present application have a photoimaging moiety and a magnetic imaging moiety, however, the compounds of the present application combining the photoimaging moiety and the magnetic imaging moiety have better photoimaging properties over a range of concentrations than the prior art fluorescent probe FITC and better magnetic imaging properties than the prior art magnetic imaging probes Gd-DOTA and Gd-DOTA pNBn.
According to a third aspect of the invention, there is also provided a kit comprising:
A container comprising a compound of formula (I) according to the first aspect of the invention or a compound of formula (I) prepared according to the method of the second aspect of the invention; and
Instructions for use.
In a preferred embodiment of the kit of the invention, the compound of formula (I) according to the first aspect of the invention or the compound of formula (I) prepared according to the method of the second aspect of the invention is in an aqueous solution having a concentration of 0.05-30mM, preferably 0.1-25mM and more preferably 0.1-20 mM. In a more preferred embodiment of the kit of the invention, the aqueous solution is an aqueous solution of NaCO 3/NaHCO3 having a pH of 7 to 8.
According to a fourth aspect of the invention there is provided the use of a compound of formula (I) according to the first aspect of the invention or a compound of formula (I) prepared according to the method of the second aspect of the invention or a kit according to the third aspect of the invention as a magneto-optical bimodal probe. In a more preferred embodiment of the use according to the invention, the aqueous solution is an aqueous solution of NaCO 3/NaHCO3 having a pH of 7 to 8.
In a preferred embodiment of the use according to the invention, wherein preferably the compound of formula (I) according to the first aspect of the invention or the compound of formula (I) prepared according to the method according to the second aspect of the invention or the kit according to the third aspect of the invention comprises the compound in an aqueous solution at a concentration of 0.05-30mM, preferably 0.1-25mM and more preferably 0.1-20 mM. Preferably, the aqueous solution is an aqueous solution of NaCO 3/NaHCO3 having a pH of 7 to 8.
Examples
Instrument and equipment
Mass spectrometer ESI-MS, water Xevo G2Q-TOF.
The nuclear magnetic resonance spectrometer BrukerAvance III M and 600M is used for measuring nuclear magnetic resonance hydrogen spectra.
Nuclear magnetic resonance spectrometer BrukerAvance III M, 125M for measuring nuclear magnetic resonance carbon spectrum.
3.0T superconducting magnetic resonance scanner, magnetom Trio, SIEMENS MEDICAL Solutions, erlangen, germany.
The reagents used were conventional reagents, purchased from carbofuran reagent company.
Test method
The nuclear magnetic pattern chemical shift is calibrated according to the solvent used in the test: CDCl 3 (δ7.26 and 77.0 ppm), D 2O(δ4.7ppm)、DMSO-d6 (δ2.50 and 39.52 ppm).
Synthesis of Compounds
Synthesis of Compound 1-1: tri-tert-butyl 2,2' - (1, 4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetate
1,4,7, 10-Tetraazacyclododecane (2 g,11.61 mmol) was dissolved in DMAc (70 mL) under argon atmosphere, and anhydrous sodium acetate (3.14 g,38.31 mmol) was added thereto and stirred at room temperature for 1h. Tert-butyl bromoacetate (7.42 g,38.31 mmol) was slowly added dropwise to the above solution at-20℃and the reaction was stirred at room temperature for 48h. TLC monitored the reaction (DCM: meoh=20:1, r f =0.5), after completion of the reaction, the reaction solution was poured into water, potassium bicarbonate was added to give a white solid, the solid was collected by filtration, washed with saturated aqueous potassium bicarbonate solution, the solid after suction filtration was dissolved in CH 3, extracted with water, the combined organic phases were dried over anhydrous magnesium sulfate, concentrated by rotary evaporation, column chromatography (DCM: meoh=50:1→20:1), concentrated and suction dried to give compound 1-1 (3.83 g, 64%) as a white hygroscopic solid.
1H NMR(400MHz,CDCl3)δ9.99(s,1H),3.36(s,4H),3.27(s,2H),3.08(t,J＝5.0Hz,4H),3.01-2.60(m,12H),1.44(d,J＝2.8Hz,27H).LRMS(TOF-ESI):calcd.for C26H50N4O6[M+H]+515.3803,found 515.3854.
Synthesis of Compounds 1-2: tri-tert-butyl 2,2' - (10- (4-nitrobenzyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-tri-yl) triacetate
Compound 1-1 (758 mg,1.47 mmol) and 4-nitrobenzyl bromide (318 mg,1.47 mmol) were dissolved in ultra-dry acetonitrile (15 mL) under argon, sodium bicarbonate (618 mg,7.35 mmol) was added, and the mixture was heated to 100deg.C under reflux with stirring for 8h. TCL was monitored (DCM: meoh=20:1, r f =0.13), after completion of the reaction, the reaction was cooled to room temperature, the filtrate was concentrated by rotary evaporation, and purified by column chromatography (DCM: meoh=20:1), concentrated and dried to give compound 1-2 (897 mg, 94%) as a pale yellow foam solid.
1H NMR(400MHz,CDCl3)δ7.30(d,J＝8.2Hz,1H),7.24–7.17(m,1H),7.04–6.51(m,2H),4.79–2.26(m,24H),1.72–1.01(m,27H).
Synthesis of Compounds 1-3: tri-tert-butyl 2,2' - (10- (4-aminobenzyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetate
MeOH (4 mL) under argon protection dissolved compound 1-2 (500 mg,0.77 mmol), pd/C (10%, 15 mg) was added and stirred well, hydrogen was replaced and kept in hydrogen atmosphere with hydrogen balloon, stirring was performed at room temperature for 12h, TLC monitored reaction (DCM: meOH=45:1, R f =0.1), after completion of reaction, celite was filtered to remove Pd/C, and the filtrate was collected and concentrated and pumped to give compound 1-3 (472 mg, 99%) as a white solid.
1H NMR(400MHz,CDCl3)δ8.33–7.99(m,2H),7.94–7.57(m,2H),4.52–2.08(m,24H),1.46(s,27H).LRMS(TOF-ESI):calcd.for C33H57N5O6[M+H]+620.4382,found 620.4394.
Synthesis of Compounds 1-4:2,2' - (10- (4-aminobenzyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
Compounds 1-3 (470 mg,0.76 mmol) were dissolved in TFA (7.50 mL) at room temperature, stirred at room temperature for 48h, and the reaction monitored by LRMS. After the reaction was completed, methanol was added thereto and TFA and methanol were removed by rotary evaporation. Finally, the obtained residue is dissolved by a small amount of methanol, and is added dropwise into diethyl ether which is stirred at 0 ℃ to precipitate out, the precipitate is collected by centrifugation, washed for 2-3 times by diethyl ether, and a white solid which is the compound 1-4 (340 mg, 99%) is obtained after pumping.
1H NMR(400MHz,D2O)δ7.64(d,J＝8.3Hz,2H),7.47–7.25(m,2H),4.01–2.64(m,24H).LRMS(TOF-ESI):calcd.for C21H33N5O6[M+H]+452.2504,found 452.1507.
Synthesis of Compounds 1-5:2,2' - (10- (4-benzyl isothiocyanate) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
An aqueous solution with ph=2 was prepared with concentrated HCl to dissolve compounds 1 to 4 (70 mg,0.16 mmol), the pH of the solution was adjusted to keep it around 2, CSCl 2 (22 mg,0.19 mmol) of CCl 4 (1 mL) was added to the above solution, the reaction was vigorously stirred in a closed manner for 48h, lrms monitored the reaction, after the reaction was completed, the reaction solution was extracted with DCM and diethyl ether, the aqueous phase was combined, water was distilled off in a small amount of methanol, the resulting residue was added dropwise to 0 ℃ in stirring diethyl ether to precipitate out, the precipitate was collected by centrifugation, washed 2 to 3 times with diethyl ether, and a pale yellow green solid was obtained after suction drying as compound 1 to 5 (58 mg, 73%).
1H NMR(400MHz,DMSO-d6)δ7.62(d,J＝8.0Hz,2H),7.44(d,J＝8.0Hz,2H),5.02–3.36(m,24H).LRMS(TOF-ESI):calcd.for C22H31N5O6S[M+H]+494.2068,found 494.2154.
Synthesis of Compounds 1-6:2, 2'- (10- (4- (3- (3', 6 '-dihydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthine ] -5-yl) thiourea) benzyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-tri-yl) triacetic acid
Compounds 1 to 5 (20 mg,0.040 mmol) and 5-aminofluorescein (14 mg,0.040 mmol) were dissolved in a mixed solution of THF/H 2 O (0.4 mL:0.1 mL), the pH of the above solution was adjusted with saturated aqueous sodium bicarbonate to maintain 8-8.5, the reaction was stirred at room temperature in the absence of light for 72H, and TLC monitored. After the reaction, the solvent was removed by spin-drying, a small amount of MeOH/MeCN mixed solution was added, a small amount of silica gel was added, and the mixture was spun-dried by ultrasonic mixing. Dry loading, column chromatography separation and purification (DCM: meoh=2:1→1:1→1:2) and spin drying gave compounds 1-6 (24 mg, 71%).
LRMS(TOF-ESI):calcd.for C42H44N6O11S[M+H]+840.2789,found 841.2935.
Synthesis of Compounds 1-7 (Compounds of formula (I)): gadolinium-2, 2 '- (10- (4- (3- (3', 6 '-dihydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthine ] -5-yl) thiourea) benzyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-tri-yl) triacetic acid metal complex
Compound 1-6 (24 mg,0.0284 mmol) was dissolved in deionized water (2 mL), stirred and dissolved, gdCl 3·6H2 O (10 mg,0.0284 mmol) was added, the solution was in an orange-yellow cloudy state, stirred at room temperature for 30min, and the pH of the reaction solution was slowly adjusted to 7-8 using aqueous sodium bicarbonate solution and saturated aqueous sodium bicarbonate solution at pH 7-8, and the solution became clear during the adjustment. Stirring reaction is continued for 30min at room temperature, the reaction solution is centrifuged, the bottom precipitate is washed by sodium bicarbonate aqueous solution with pH of 7-8, supernatant is collected and distilled under reduced pressure, phosphorus pentoxide is dried overnight in vacuum, and the compound 1-7 is obtained as orange solid (27 mg, 97%) after washing with deionized water.
LRMS(TOF-ESI):calcd.for C42H41GdN6O11S[M+H]+995.1795,found 995.2014.
Performance testing
1. Fluorescence diffusion imaging
Brain tissue was simulated by using 0.3% agarose gel, and photoimaging of the probe Gd-DOTA pNBn -CS-FITC of the invention was tested, with FITC as a control group. The specific test is as follows:
Agarose powder (0.15 g) was added to physiological saline (50 mL), and the mixture was heated to slight boiling by microwave to give a clear transparent solution, which was cooled at room temperature to prepare 0.3% agarose gel for use in simulating brain tissue. The method comprises the steps of adopting a small animal stereotactic instrument to determine that a position, with the center of a circle of a small dish facing downwards by 2mm, is used as a diffusion source, and using a microsyringe and an autosampler pump to introduce a probe Gd-DOTA pNBn -CS-FITC (10 mmol/L,1.0 mu L, aqueous solution of NaCO 3/NaHCO 3 with pH of 7-8) and FITC (1 mmol/L,1.0 mu L, aqueous solution of NaCO 3/NaHCO 3 with pH of 7-8) into 3% agarose gel at a rate of 0.2 mu L/min. A laser scanning confocal microscope (TCS-SP 8 DIVE, leica, germany) was used to collect complete images of a large field of view, and the diffusion of Gd-DOTA pNBn -CS-FITC and FITC control groups in agarose at different time points (15 min,30min,60min,90min,120 min) was dynamically observed using a X10 dry mirror, excitation wavelength of 488 nm. The results are shown in FIG. 1.
As shown in FIG. 1, the fluorescence diffusion imaging result shows that the imaging profile of the probe Gd-DOTA pNBn -CS-FITC in the agarose gel is clearer under the same diffusion time, namely the diffusion rate of Gd-DOTA pNBn -CS-FITC in the agarose gel is higher than that of FITC.
2. Magnetic resonance imaging
The prepared solution of the probe Gd-DOTA pNBn -CS-FITC with different concentration gradients is placed in an 8-channel wrist joint coil, a 3.0T superconducting magnetic resonance scanner is adopted for scanning, a rapid acquisition gradient echo sequence (MP-RAGE) prepared by T1 magnetization is adopted for acquiring images, and a contrast group adopts Gd-DOTA, gd-DOTA pNBn and Gd-DOTA pNBn -EA-FITC.
The scanning parameters for the 3D MP-RAGE T1WI sequence are specifically as follows: echo Time (TE) 3.7ms, repetition Time (TR) 1500ms, flip angle (FLIP ANGLE, FA) 9 degrees, inversion time (reverse time, TI) 900ms, field of view (FOV) 267ms, matrix (Matrix) 512 x 512, voxel (Voxel) 0.5 x 0.5mm3, bandwidth (Band width) 300Hz/Px, echo spacing (Echo spacing) 8.8ms, excitation number (NEX: average) 2, parallel Acquisition (PAT) OFF, scan time (Time of acquiration, TA) 290s, phase encoding step number 96. The imaging results are shown in fig. 2.
As shown in FIG. 2, in the magnetic resonance imaging, the concentration of Gd-DOTA pNBn -CS-FITC, gd-DOTA and Gd-DOTA pNBn was varied between 0.1 and 20mM (aqueous solution of NaCO 3/NaHCO3 at pH7 to 8), the concentration of Gd-DOTA pNBn -EA-FITC was varied between 0.2 and 1mM (aqueous solution of NaCO 3/NaHCO3 at pH7 to 8), and the concentration of Gd-DOTA pNBn -EA-FITC in aqueous solution of NaCO 3/NaHCO3 at pH7 to 8 was only 1mM at maximum due to the structure itself. With increasing concentration, although the magnetic imaging contrast of all probes is increased, the magnetic imaging contrast (i.e. the brightness degree displayed from a photo) of the Gd-DOTA pNBn -CS-FITC probe of the invention can reach the contrast equivalent to that of the Gd-DOTA pNBn single magnetic imaging probe at the same concentration, and is obviously superior to that of a commercial imaging agent Gd-DOTA. Under the condition of low concentration, the imaging intensity of the Gd-DOTA pNBn -CS-FITC of the probe can also reach the imaging intensity of the original photo-magnetic bimodal probe Gd-DOTA pNBn -EA-FITC. Gd-DOTA pNBn -EA-FITC, however, has limited imaging applications due to limited solubility in aqueous solutions.
By combining the results of fig. 1 and 2, the probe Gd-DOTA pNBn -CS-FITC of the invention has faster diffusion rate and better water solubility in aqueous solution than FITC, i.e. has wider application range; the probe Gd-DOTA pNBn -CS-FITC has the magnetic imaging contrast equivalent to that of the single magnetic imaging probe Gd-DOTA pNBn and fluorescence diffusion imaging characteristics which are not possessed by the single magnetic imaging probe Gd-DOTA pNBn; the magnetic imaging contrast is higher than that of a commercial imaging agent Gd-DOTA; compared with the original photo-magnetic bimodal probe Gd-DOTA pNBn -EA-FITC, the probe Gd-DOTA pNBn -CS-FITC provided by the invention has better solubility and can play a role in application scenes under higher solubility requirements.
The above list of detailed descriptions is only specific to practical embodiments of the present invention, and they are not intended to limit the scope of the present invention, and all equivalent embodiments or modifications that do not depart from the spirit of the present invention should be included in the scope of the present invention.
Claims (10)
1. A compound of formula (I):
Wherein,
Me is Gd.
2. The compound of formula (I) or a salt thereof according to claim 1, which is a compound of formula (I-1) or a compound of formula (I-2):
Wherein,
Me is Gd.
3. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that it comprises the steps of:
a) Reacting a compound of formula (1-5) with an aminofluorescein, which is 5-aminofluorescein or 6-aminofluorescein, in the presence of a solvent under weakly alkaline conditions to obtain a compound of formula (1-6),
And
B) Reacting the compound of formula (1-6) obtained in step a) with a compound comprising a lanthanide, which lanthanide is Gd, in the presence of a solvent and a catalyst under weakly basic conditions to obtain a compound of formula (I),
4. The method of claim 3, wherein in step b), the lanthanide-containing compound is a lanthanide-containing chloride.
5. The process according to any one of claims 3 to 4, wherein in step a) the reaction is carried out at a pH = 7.5-9.5;
wherein in step b), the reaction is carried out at a ph=7.0-9.0.
6. The process according to any one of claims 4 to 5, wherein in step a) or step b), the reaction is carried out at a temperature of 20 to 60 ℃.
7. The process according to any one of claims 5 to 6, wherein in step a) or step b) the solvent used is selected from one or more of water, tetrahydrofuran dimethyl sulfoxide, N-dimethylformamide.
8. The process according to claim 7, wherein in step a) the solvent used is a mixture of water and tetrahydrofuran;
In step b), the solvent is water.
9. A kit, comprising:
a container comprising a compound of formula (I) according to claim 1 or 2, wherein the compound of formula (I) according to claim 1 or 2 is in an aqueous solution of NaCO 3/NaHCO3 at a concentration of 0.05-30mM at a pH of 7-8; and
Instructions for use.
10. Use of a compound of formula (I) according to claim 1 or 2 for the preparation of a magneto-optical bimodal probe, wherein the compound of formula (I) according to claim 1 or 2 is in aqueous solution of NaCO 3/NaHCO3 at a concentration of 0.05-30mM at a pH of 7-8.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102284067A (en) * | 2011-08-08 | 2011-12-21 | 中国科学院化学研究所 | Fluorescent molecular image probe and magnetic/fluorescent bimodal molecular image probe and preparation method thereof |
| CN107101987A (en) * | 2017-07-05 | 2017-08-29 | 辽宁科技大学 | Magnetic resonance/fluorescent dual module state probe and its application |
| CN110551141A (en) * | 2018-06-26 | 2019-12-10 | 韩鸿宾 | process for the preparation of compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102284067A (en) * | 2011-08-08 | 2011-12-21 | 中国科学院化学研究所 | Fluorescent molecular image probe and magnetic/fluorescent bimodal molecular image probe and preparation method thereof |
| CN107101987A (en) * | 2017-07-05 | 2017-08-29 | 辽宁科技大学 | Magnetic resonance/fluorescent dual module state probe and its application |
| CN110551141A (en) * | 2018-06-26 | 2019-12-10 | 韩鸿宾 | process for the preparation of compounds |
Non-Patent Citations (2)
| Title |
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| Anurag Mishra.A New Class of Gd-Based DO3A-Ethylamine-Derived Targeted Contrast Agents for MR and Optical Imaging.Bioconjugate Chem..2006,第17卷(第3期),773–780. * |
| 李昀倩.光磁双模态分子探针Gd-DO3A-EA-FITC在脑组织间隙成像分析中的应用.北京大学学报（医学版）.2018,第50卷(第2期),221-225. * |
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