CN115785117A - Compound, kit and application of compound and kit as photomagnetic bimodal probe - Google Patents
Compound, kit and application of compound and kit as photomagnetic bimodal probe Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 111
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- 230000002902 bimodal effect Effects 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 82
- 238000002360 preparation method Methods 0.000 claims abstract description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 24
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- 229910052692 Dysprosium Inorganic materials 0.000 claims description 9
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- 239000000203 mixture Substances 0.000 claims description 8
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- -1 lanthanide chloride Chemical class 0.000 claims description 6
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
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- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
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Images
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 photo-magnetic bimodal probe
Description
Technical Field
The present invention relates to the field of optical imaging and magnetic resonance imaging. In particular to a magneto-optical bimodal imaging compound Gd-DOTA pNBn -CS-FITC。
Background
In recent researches on magnetic resonance imaging molecular probes, a multimode molecular probe has attracted great attention, and the probe can be used for diagnosis by combining PET, optical or ultrasonic imaging methods on the basis of magnetic resonance imaging, can be used for multiple imaging devices simultaneously, can compensate each other, and can improve the diagnosis precision of diseases (see Jessica W, MG E, aurora R-R, et al. Chemistry of mri constraints [ J ]. Chemical reviews,2019,119 (2)). Mishra et al originally proposed a synthetic route for a magneto-optical bimodal probe Gd-DOTA-EA-FITC (see Mishra A, pfeuffer J, mishra R, et al. A new class of Gd-based do3 a-ethyl-derived targeted conjugates for mr and optical imaging [ J ]. Bioconjugate Chemistry,2006,17 (3): 773-780), followed by researchers using this probe to establish a method of magneto-optical modal imaging and to conduct research studies on substance transport and tissue flow in the extracellular space in bimodal brain tissue [ J ]. Proc., waita, lieLei, et al. Application of magneto bimodal molecular probe Gd-do3a-EA-FITC in brain tissue interstitial imaging [ J ]. Proc. (Beijing edition, 221-50): 2018, 20102 (university). However, the existing photomagnetic bimodal imaging method cannot simultaneously obtain good optical imaging and magnetic imaging effects.
Disclosure of Invention
In order to solve the above problems of the prior art, according to a first aspect of the present invention, there is provided a compound of formula (I):
wherein the content of the first and second substances,
me is 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 the content of the first and second substances,
me is Gd, la and Dy.
According to a second aspect of the invention, the invention also relates to a process for the preparation of a compound of formula (I), said process comprising the steps of:
a) Reacting the compound of formula (1-5) with aminofluorescein in the presence of a solvent under weakly alkaline conditions to obtain a compound of formula (1-6),
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 according to the invention, in step b), the compound comprising a lanthanide is a lanthanide-containing chloride. In a more preferred embodiment of the process of the invention, the compound comprising a lanthanide is a hydrate of the lanthanide chloride. In a more preferred embodiment of the method of the invention, said lanthanide is selected from Gd, la and Dy. In a particularly preferred embodiment of the process according to the invention, the compound comprising a lanthanide is selected from GdCl 3 ·6H 2 O、LaCl 3 ·6H 2 O、DyCl 3 ·6H 2 One or more of O. In a most preferred embodiment of the process according to the invention, the compound comprising a lanthanide is selected from GdCl 3 ·6H 2 O。
In a preferred embodiment of the process of the invention, in step a), the reaction is carried out at a pH = 7.5-9.5. In a more preferred embodiment of the process of the invention, in step a), the reaction is carried out at a pH = 8.0-9.0. In a most preferred embodiment of the process of the invention, in step a), the reaction is carried out at a pH = 8.0-8.5.
In a preferred embodiment of the process of the invention, in step b), the reaction is carried out at a pH = 7.0-9.0. In a more preferred embodiment of the process of the invention, in step b), the reaction is carried out at a pH = 7.0-8.5. In a most preferred embodiment of the process of the invention, in step b) the reaction is carried out at a pH = 7.0-8.0.
In a preferred embodiment of the process of the invention, the reaction in step a) or step b) is carried out at a temperature of from 20 to 60 ℃. In a more preferred embodiment of the process according to the invention, the reaction in step a) or step b) is carried out at a temperature of from 20 to 50 ℃. In a further preferred embodiment of the process according to the invention, the reaction in step a) or step b) is carried out at a temperature of from 20 to 40 ℃. In a most preferred embodiment of the process of the invention, the reaction is carried out at room temperature in step a) or step b).
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 of 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 1 to 10.
In another more preferred embodiment of the process of the present invention, in step b), the solvent is water.
In a preferred embodiment of the process of 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 of 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 of the invention, in step b), the reaction is carried out at room temperature.
The compounds of formula (I) provided herein, as well as the compounds of formula (I) prepared according to the methods of the present application, are useful as probes in fluorescence diffusion imaging and/or magnetic resonance imaging. The research results of the fluorescence imaging, the fluorescence diffusion imaging and the magnetic resonance imaging of the probe show that the application provides and prepares the compound photomagnetic bimodal probe Gd-DOTA of the formula (I) according to the method of the application pNBn the-CS-FITC has good optical and magnetic imaging properties at the same time. This finding is surprising in that the compounds of formula (I) provided herein and prepared according to the methods of the present application have both photoimageable and magnetic imaging moieties, however, the compounds of the present invention which combine photoimageable and magnetic imaging moieties are superior to the prior art magnetic imaging probe Gd-DOTA pNBn And a fluorescent probe Fluorescein Isothiocyanate (FITC) has better optical and magnetic imaging characteristics.
According to a third aspect of the invention, the invention also provides 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 process of the second aspect of the invention; and
instructions for use.
In a preferred embodiment of the kit according to 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 process according to the second aspect of the invention is in a concentration of 0.05-30mM, preferably 0.1-25mM and more preferably 0.1-20mM in water, in particular 5mM in water, 10mM in water. In the present inventionIn a more preferred embodiment of the kit, the aqueous solution is NaCO at a pH of 7 to 8 3 /NaHCO 3 An aqueous solution of (a).
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 process 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 of 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 0.1-20mM, in particular 5mM, 10 mM. In a more preferred embodiment of the test use of the present invention, the aqueous solution is NaCO at a pH of 7 to 8 3 /NaHCO 3 An aqueous solution of (a).
Thus, the compound of formula (I) according to the first aspect of the invention or the compound of formula (I) prepared according to the process of the second aspect of the invention is preferably used in the form of a solution, e.g. an aqueous solution, e.g. a solution having a concentration of 0.05-30mM, preferably 0.1-25mM and more preferably 0.1-20mM, especially a solution of 5mM, a solution of 10 mM. Preferably, the aqueous solution is NaCO with pH 7-8 3 /NaHCO 3 An aqueous solution of (a).
Drawings
The invention is illustrated and explained only by way of example, and not by way of limitation, in the figures of the accompanying drawings and in which:
FIG. 1 shows the results of fluorescence diffusion imaging of the compound of the invention as a photomagnetic bimodal probe with FITC as a control.
FIG. 2 shows compounds of the invention as magneto-optical bimodal probes with Gd-DOTA, gd-DOTA as controls pNBn And Gd-DOTA pNBn EA-FITC magnetic resonance imaging results.
Detailed Description
In order to more clearly understand the technical features, objects, and effects of the present invention, embodiments of the present invention will now be described with reference to the accompanying drawings, in which like reference numerals refer to like parts throughout.
In the application, all reactions are carried out at room temperature and pressure, and the reactants and reagents used are available, unless otherwise specified.
In the present invention, the concentration unit mM has the same meaning as mmol/L unless otherwise specified.
In the present invention, DOTA is generally referred to herein by the English name 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid, and the Chinese name 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid.
The Chinese name of Gd-DOTA is gadolinium-1, 4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex, a commercially available imaging agent.
Gd-DOTA pNBn Under the name gadolinium- [2,2',2"- (10- (4-aminobenzyl) -1,4,7, 10-tetraazacyclododecane-1,4, 7-triyl)]-a metal complex of triacetic acid.
Gd-DOTA pNBn The Chinese name of-EA-FITC is gadolinium- [4, 7-bis-carboxymethyl-10- (2-fluorescein thioureidoethyl) -1,4,7, 10-tetraazacyclododecan-1-yl]-an acetic acid complex.
According to a first aspect of the present invention there is provided a compound of formula (I), a salt thereof or a solvate thereof:
wherein the content of the first and second substances,
me is 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 the content of the first and second substances,
me is Gd, la and Dy.
According to a second aspect of the invention, the invention also relates to a process for the preparation of a compound of formula (I), said process comprising the steps of:
a) Reacting the compound of formula (1-5) with aminofluorescein in the presence of a solvent under weakly alkaline conditions to obtain a compound of formula (1-6),
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 invention, in step b), the compound comprising a lanthanide is a lanthanide-containing chloride. In a more preferred embodiment of the process of the invention, the compound comprising a lanthanide is a hydrate of the lanthanide chloride. In a more preferred embodiment of the method of the invention, said lanthanide is selected from Gd, la and Dy. In a particularly preferred embodiment of the process according to the invention, the compound comprising a lanthanide is selected from GdCl 3 ·6H 2 O、LaCl 3 ·6H 2 O、DyCl 3 ·6H 2 One or more of O. In a most preferred embodiment of the process according to the invention, the compound comprising a lanthanide is selected from GdCl 3 ·6H 2 O。
In the process of the present invention, the compounds of the formulae (1-5) are known compounds, are commercially available, or can be synthesized according to known methods. Known synthetic methods for 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-butoxyarylmethyl) -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, henovont C, et al, optimizing water exchange rates and nutritional mobility for high-hierarchy reception of a novel gd-do3a hierarchical complex coordinated to in-line as a macromolecular con-strant agents for mri [ J ]. Chemistry & Biodiversity,2018,15 (2): e1700487.
In a preferred embodiment of the process of the invention, in step a), the reaction is carried out at a pH = 7.5-9.5. In a more preferred embodiment of the process of the invention, in step a), the reaction is carried out at a pH = 8.0-9.0. In a most preferred embodiment of the process of the invention, in step a), the reaction is carried out at a pH = 8.0-8.5.
In a preferred embodiment of the process of the invention, in step b), the reaction is carried out at a pH = 7.0-9.0. In a more preferred embodiment of the process of the invention, in step b), the reaction is carried out at a pH = 7.0-8.5. In a most preferred embodiment of the process of the invention, in step b), the reaction is carried out at a pH = 7.0-8.0.
In a preferred embodiment of the process of the invention, the reaction in step a) or step b) is carried out at a temperature of from 20 to 60 ℃. In a more preferred embodiment of the process of the invention, the reaction in step a) or step b) is carried out at a temperature of from 20 to 50 ℃. In a further preferred embodiment of the process according to the invention, the reaction in step a) or step b) is carried out at a temperature of from 20 to 40 ℃. In a most preferred embodiment of the process of the invention, the reaction is carried out at room temperature in step a) or step b).
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 of 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 1 to 10.
In another more preferred embodiment of the process of the present invention, in step b), the solvent is water.
In a preferred embodiment of the process of 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 of 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 of the invention, in step b), the reaction is carried out at room temperature.
In one embodiment of the process of the invention, starting from 1,4,7,10-tetraazacyclododecane and aminofluorescein, the compounds of the formulae (1-5) are obtained by nucleophilic addition and are further reacted with compounds comprising lanthanides to give the compounds of the formula (I). In the context of the present application, the compound of formula (I) is a novel magneto-optical bimodal probe compound Gd-DOTA pNBn CS-FITC, therefore, the present application provides a new imaging tool for photomagnetic bimodal imaging.
In one embodiment of the present invention, exemplified by 5-aminofluorescein, an exemplary synthetic route for the compound of formula (I) is as follows:
the compounds of formula (I) provided herein and the compounds of formula (I) prepared according to the methods of the present application, i.e. the compounds Gd-DOTA of formulae (1-7) obtained according to an exemplary synthetic route pNBn CS-FITC, for use as a probe in fluorescence diffusion imaging and/or magnetic resonance imaging. The results of the studies of fluorescence imaging, fluorescence diffusion imaging and magnetic resonance imaging of the probes indicate that the probes provided herein and prepared according to the methods of the present applicationGd-DOTA Compound of formula (I) pNBn the-CS-FITC has good optical and magnetic imaging properties simultaneously when being used as a photomagnetic bimodal probe. This finding is surprising in that the compounds of formula (I) provided herein and prepared according to the methods of the present application have both photoimaging moieties and magnetic imaging moieties, however, the compounds of the present invention which bind the photoimaging moieties and magnetic imaging moieties have better photoimaging properties over a range of concentrations than the prior art fluorescent probes FITC and than the prior art magnetic imaging probes Gd-DOTA and Gd-DOTA pNBn Has better magnetic imaging property.
According to a third aspect of the invention, the invention also provides 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 process of the second aspect of the invention; and
instructions for use.
In a preferred embodiment of the kit according to 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 process according to the second aspect of the invention is in an aqueous solution at 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 NaCO at a pH of 7 to 8 3 /NaHCO 3 An aqueous solution of (a).
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 process 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 NaCO at a pH of 7 to 8 3 /NaHCO 3 An aqueous solution of (a).
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 process according to the second aspect of the invention or the kit according to the third aspect of the invention comprises the compound in the form of an aqueous solution at a concentration of 0.05-30mM, preferably 0.1-25mM and more preferably 0.1-20mM. Preferably, the aqueous solution is NaCO with pH 7-8 3 /NaHCO 3 An aqueous solution of (a).
Examples
Instrumentation and equipment
Mass spectrometer ESI-MS, water Xevo G2Q-TOF.
A nuclear magnetic resonance spectrometer Bruker Avance III 400M, 600M was used to determine the nuclear magnetic resonance hydrogen spectra.
A nuclear magnetic resonance spectrometer, bruker Avance III 100M, 125M, was used to determine the nuclear magnetic resonance carbon spectra.
3.0T superconducting magnetic resonance scanner, magnetom Trio, siemens Medical Solutions, erlangen, germany.
The reagents used were conventional reagents, available from carbofuran reagents.
Test method
The nuclear magnetic spectrum chemical shift is calibrated according to the solvent used during the test: CDCl 3 (delta. 7.26 and 77.0 ppm), D 2 O(δ4.7ppm)、DMSO-d 6 (delta. 2.50 and 39.52 ppm).
Synthesis of compounds
Synthesis of Compounds 1-1:2,2' - (1, 4,7,10-tetraazacyclododecane-1,4, 7-triyl) tri-tert-butyl triacetate
1,4,7,10-tetraazacyclododecane (2g, 11.61mmol) was dissolved in DMAc (70 mL) under argon, and anhydrous sodium acetate (3.14g, 38.31mmol) was added and stirred at room temperature for 1h. Tert-butyl bromoacetate (7.42g, 38.31mmol) 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 f = 0.5), after the reaction is finished, pouring the reaction liquid into water, adding potassium bicarbonate until white solid is generated, filtering and collecting the solid, washing the solid by saturated potassium bicarbonate water solution, and dissolving the solid in CH after suction filtration 3 Extraction with water, combined organic phases dried over anhydrous magnesium sulfate, concentration by rotary evaporation, column chromatography (DCM: meOH = 50.
1 H NMR(400MHz,CDCl 3 )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 C 26 H 50 N 4 O 6 [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-triyl) triacetate
Under the protection of argon, the compound 1-1 (758mg, 1.47mmol) and 4-nitrobenzyl bromide (318mg, 1.47mmol) were dissolved in ultra-dry acetonitrile (15 mL), sodium bicarbonate (618mg, 7.35mmol) was added, and the reaction was stirred at reflux at 100 ℃ for 8h. TCL monitors the reaction (DCM: meOH =20 f = 0.13), after the reaction is finished, the reaction liquid is cooled to the room temperature, after filtration, the filtrate is subjected to rotary evaporation concentration, and the product is separated and purified by column chromatography (DCM: meOH = 20.
1 H NMR(400MHz,CDCl 3 )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 1-3:2,2' - (10- (4-aminobenzyl) -1,4,7, 10-tetraazacyclododecane-1,4, 7-triyl) triacetic acid tri-tert-butyl
Compound 1-2 (500mg, 0.77mmol) was dissolved in MeOH (4 mL) under argon, pd/C (10%, 15 mg) was added and stirred well, then replaced with hydrogen and kept under hydrogen atmosphere with a hydrogen balloon, the reaction was stirred at room temperature for 12h, the reaction was monitored by tlc (DCM: meOH =45 f = 0.1), at the end of the reaction, pd/C was removed by filtration through celite, the filtrate was collected, concentrated and drained to give compound 1-3 as a white solid (472mg, 99%).
1 H NMR(400MHz,CDCl 3 )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 C 33 H 57 N 5 O 6 [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 (472mg, 0.76mmol) 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, methanol is added to remove TFA and methanol by rotary evaporation. Finally dissolving the obtained residue with a small amount of methanol, dropwise adding into 0 deg.C stirring diethyl ether for precipitation, centrifuging, collecting precipitate, washing with diethyl ether for 2-3 times, and draining to obtain white solid, i.e. compound 1-4 (340mg, 99%).
1 H NMR(400MHz,D 2 O)δ7.64(d,J＝8.3Hz,2H),7.47–7.25(m,2H),4.01–2.64(m,24H).LRMS(TOF-ESI):calcd.for C 21 H 33 N 5 O 6 [M+H] + 452.2504,found 452.1507.
Synthesis of Compounds 1-5:2,2',2"- (10- (4-isothiocyanatobenzyl) -1,4,7, 10-tetraazacyclododecane-1,4, 7-triyl) triacetic acid
Compound 1-4 (70mg, 0.16mmol) was dissolved in an aqueous solution prepared with concentrated HCl at pH =2, the pH of the solution was adjusted to about 2, and CSCl was added 2 (22mg, 0.19mmol) of CCl 4 Adding (1 mL) solution into the solution, carrying out closed vigorous stirring reaction for 48h, monitoring the reaction by LRMS, after the reaction is finished, extracting the reaction liquid by DCM and diethyl ether respectively, combining water phases, carrying out rotary evaporation to remove water, dissolving the obtained residue in a small amount of methanol, dropwise adding the mixture into diethyl ether which is stirring at 0 ℃ for precipitation, centrifugally collecting the precipitate, washing the precipitate for 2-3 times by diethyl ether, and carrying out pumping drying to obtain light yellow green solid, namely the compound 1-5 (58mg, 73%).
1 H NMR(400MHz,DMSO-d 6 )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 C 22 H 31 N 5 O 6 S[M+H] + 494.2068,found 494.2154.
Synthesis of Compounds 1-6:2,2',2"- (10- (4- (3- (3', 6 '-dihydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthine ] -5-yl) thioureido) benzyl) -1,4,7, 10-tetraazacyclododecane-1,4, 7-triyl) triacetic acid
Compounds 1-5 (20mg, 0.040mmol) and 5-aminofluorescein (14mg, 0.040mmol) were dissolved in THF/H 2 O (0.4 mL8.5, the reaction was stirred at room temperature for 72h in the dark and monitored by TLC. After the reaction is finished, spin-drying to remove the solvent, adding a small amount of MeOH/MeCN mixed solution, adding a small amount of silica gel, ultrasonically mixing uniformly and spin-drying. Dry loading, column chromatography separation and purification (DCM: meOH = 2.
LRMS(TOF-ESI):calcd.for C 42 H 44 N 6 O 11 S[M+H] + 840.2789,found 841.2935.
Synthesis of Compounds 1-7 (Compounds of formula (I)): gadolinium-2, 2',2"- (10- (4- (3- (3', 6 '-dihydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthine ] -5-yl) thioureido) benzyl) -1,4,7, 10-tetraazacyclododecane-1,4, 7-triyl) triacetic acid metal complex
Compounds 1-6 (24mg, 0.0284mmol) were dissolved in deionized water (2 mL), dissolved with stirring, and GdCl was added 3 ·6H 2 O (10mg, 0.0284mmol), the solution is in an orange-yellow turbid state, the solution is stirred for 30min at room temperature, the pH of the reaction solution is slowly adjusted to 7-8 by using a sodium bicarbonate aqueous solution with the pH of 7-8 and a saturated sodium bicarbonate aqueous solution, and the solution becomes clear in the adjusting process. And continuously stirring and reacting for 30min at room temperature, centrifuging the reaction solution, washing the bottom precipitate with a sodium bicarbonate aqueous solution with the pH value of 7-8, collecting the supernatant, carrying out reduced pressure rotary evaporation, carrying out vacuum drying on phosphorus pentoxide overnight, washing with deionized water, and drying to obtain the compound 1-7 as an orange solid (27mg, 97%).
LRMS(TOF-ESI):calcd.for C 42 H 41 GdN 6 O 11 S[M+H] + 995.1795,found 995.2014.
Performance testing
1. Fluorescence diffusion imaging
The probe Gd-DOTA of the invention is tested by simulating the brain tissue with 0.3 percent agarose gel pNBn Light imaging of CS-FITC, FITC as control. The specific tests are as follows:
agarose powder (0.15 g) was added to physiological saline (50 mL) and the mixture was heated by microwave to slightly boil to give a clear transparent solution which was cooled at room temperature to prepare a 0.3% agarose gel to mimic brain tissue. Using small animalsThe stereotaxic apparatus determines the position of 2mm below the circle center of the surface of a cuvette as a diffusion source, and uses a microsyringe and an automatic sampling pump to carry out Gd-DOTA (Gd-DOTA) detection on a probe pNBn -CS-FITC (10 mmol/L, 1.0. Mu.L, naCO at pH 7-8) 3 NaHCO3 aqueous solution) and FITC (1 mmol/L, 1.0. Mu.L, naCO at pH 7-8 3 Aqueous NaHCO 3) was introduced into a 3% agarose gel at a rate of 0.2. Mu.l/min. Collecting large-visual-field complete image by using laser scanning confocal microscope (TCS-SP 8 DIVE, leica, germany), and dynamically observing Gd-DOTA by adopting a multiplied by 10 dry mirror at 488nm excitation wavelength pNBn Diffusion of CS-FITC and FITC controls at different time points (15min, 30min,60min,90min, 120min) in agarose. The results are shown in FIG. 1.
As shown in FIG. 1, the fluorescence diffusion imaging results show that the probe Gd-DOTA of the invention has the same diffusion time pNBn The imaging profile of-CS-FITC in agarose gel is clearer, i.e. Gd-DOTA pNBn The diffusion rate of-CS-FITC in agarose gel is higher than that of FITC.
2. Magnetic resonance imaging
The prepared probes of the invention with different concentration gradients Gd-DOTA pNBn Placing the solution of CS-FITC in an 8-channel wrist joint coil, scanning with a 3.0T superconducting magnetic resonance scanner, acquiring images with a rapid acquisition gradient echo sequence (MP-RAGE) prepared by T1 magnetization, and acquiring Gd-DOTA and Gd-DOTA in a control group pNBn And Gd-DOTA pNBn -EA-FITC。
The scanning parameters for the 3D MP-RAGE T1WI sequence are specified as follows: echo Time (Echo Time, TE) 3.7ms, repetition Time (TR) 1500ms, flip Angle (FA) 9 °, inversion Time (Inversion Time, TI) 900ms, field of view (FOV) 267ms, matrix (Matrix) 512 × 512, voxel (Voxel) 0.5 × 0.5mm3, bandwidth (Band width) 300Hz/Px, echo spacing (Echo spacing) 8.8ms, number of shots (NEX: average) 2, parallel Acquisition (PAT) OFF, scan Time (Time of acquisition, TA) 290s, phase encoding step number 96. The imaging results are shown in fig. 2.
As shown in FIG. 2, gd-DOTA in magnetic resonance imaging pNBn -CS-FITC、Gd-DOTA and Gd-DOTA pNBn In a concentration of 0.1-20mM (pH 7-8 NaCO) 3 /NaHCO 3 Aqueous solution of (a) with a change of Gd-DOTA pNBn -EA-FITC NaCO at a concentration of 0.2-1mM (pH 7-8) 3 /NaHCO 3 Aqueous solution of (c) Gd-DOTA pNBn -EA-FITC NaCO at pH 7-8 due to its structure 3 /NaHCO 3 The concentration in the aqueous solution of (a) is only 1mM at the maximum. With increasing concentration, the Gd-DOTA probe of the invention at the same concentration increased the magnetic imaging contrast of all probes, although pNBn The magnetic imaging contrast (i.e. the degree of brightness shown from the picture) of the-CS-FITC can reach that of a single magnetic imaging probe Gd-DOTA pNBn Comparable contrast and significantly better contrast than the commercially available imaging agent Gd-DOTA. Under the condition of low concentration, the probe Gd-DOTA of the invention pNBn The imaging intensity of-CS-FITC can also reach the original photomagnetic bimodal probe Gd-DOTA pNBn EA-FITC imaging intensity. And Gd-DOTA pNBn EA-FITC has limited imaging applications due to its limited solubility in aqueous solutions.
Combining the results of FIGS. 1 and 2, the probe Gd-DOTA of the present invention pNBn CS-FITC has a faster diffusion rate and better water solubility in aqueous solution than FITC, i.e., has a wider application range; gd-DOTA probe of the present invention pNBn -CS-FITC with a single magnetic imaging probe Gd-DOTA pNBn Comparable magnetic imaging contrast and single magnetic imaging probe Gd-DOTA pNBn Fluorescence diffusion imaging properties not possessed; higher magnetic imaging contrast than the commercially available imaging agent Gd-DOTA; compared with the original photomagnetic bimodal probe Gd-DOTA pNBn EA-FITC, probe of the invention Gd-DOTA pNBn CS-FITC has better solubility and can play a role in application scenes with higher solubility requirements.
The above-listed detailed description is only a specific description of possible embodiments of the present invention, and they are not intended to limit the scope of the present invention, and equivalent embodiments or modifications made without departing from the technical spirit of the present invention should be included in the scope of the present invention.
Claims (10)
1. A compound of formula (I), a salt thereof, or a solvate thereof:
wherein, the first and the second end of the pipe are connected with each other,
me is Gd, la and Dy.
2. The compound of formula (I), a salt thereof, or a solvate thereof according to claim 1, which is a compound of formula (I-1) or a compound of formula (I-2):
wherein the content of the first and second substances,
me is Gd, la and Dy.
3. A process for the preparation of a compound of formula (I), characterized in that it comprises the following steps:
a) Reacting the compound of formula (1-5) with an aminofluorescein in the presence of a solvent under weakly alkaline conditions to obtain the compound of formula (1-6), preferably, the aminofluorescein is 5-aminofluorescein or 6-aminofluorescein,
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),
4. a process according to claim 3, wherein in step b) the compound comprising a lanthanide is a lanthanide chloride, preferably a hydrate of the lanthanide chloride; preferably the lanthanide is selected from Gd, la and Dy; particularly preferably, the compound comprising a lanthanide is selected from GdCl 3 ·6H 2 O、LaCl 3 ·6H 2 O and DyCl 3 ·6H 2 O。
5. The process according to any one of claims 3-4, wherein in step a) the reaction is carried out at pH =7.5-9.5, preferably at pH =8.0-9.0, more preferably at pH = 8.0-8.5;
preferably, in step b), the reaction is carried out at pH =7.0-9.0, more preferably at pH =7.0-8.5, more preferably at pH = 7.0-8.0.
6. The process according to any one of claims 4-5, wherein in step a) or step b) the reaction is carried out at a temperature of 20-60 ℃, preferably at a temperature of 20-50 ℃, more preferably at a temperature of 20-40 ℃, most preferably at room temperature.
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;
preferably, in step a), the solvent used is a mixture of water and tetrahydrofuran, preferably a mixture of water and tetrahydrofuran in a volume ratio of 1;
also preferably, in step b), the solvent is water.
8. The process according to claim 7, wherein in step b) the reaction is carried out at a temperature of 20-60 ℃, preferably at a temperature of 20-50 ℃, more preferably at a temperature of 20-40 ℃, most preferably at room temperature.
9. A kit, comprising:
a container comprising a compound of formula (I) according to claim 1 or 2 or a compound of formula (I) prepared according to the process of any one of claims 3 to 8, preferably a compound of formula (I) according to claim 1 or 2 or a compound of formula (I) prepared according to the process of any one of claims 3 to 8, in NaCO at a concentration of 0.05-30mM, preferably 0.1-25mM and more preferably 0.1-20mM, pH 7-8 3 /NaHCO 3 An aqueous solution; and
instructions for use.
10. Use of a compound of formula (I) according to claim 1 or 2 or a compound of formula (I) prepared according to the method of any one of claims 3 to 8 or a kit of claim 9 as a magneto-optical bimodal probe, wherein preferably the compound of formula (I) according to claim 1 or 2 or the compound of formula (I) prepared according to the method of any one of claims 3 to 8 or the compound comprised by the kit of claim 9 is NaCO at a concentration of 0.05-30mM, preferably 0.1-25mM and more preferably 0.1-20mM, pH 7-8 3 /NaHCO 3 An aqueous solution.
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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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| 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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| 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）, vol. 50, no. 2, 30 April 2018 (2018-04-30), pages 221 - 225 * |
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