CN113307758A - P2X7 receptor targeting probe precursor labeled by medical radioactive isotope - Google Patents

P2X7 receptor targeting probe precursor labeled by medical radioactive isotope Download PDF

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CN113307758A
CN113307758A CN202110647401.6A CN202110647401A CN113307758A CN 113307758 A CN113307758 A CN 113307758A CN 202110647401 A CN202110647401 A CN 202110647401A CN 113307758 A CN113307758 A CN 113307758A
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receptor
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CN113307758B (en
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韩俊斌
胥波
高新岩
杨仁银
张月颖
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Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Abstract

The invention relates to the field of organic synthesis, in particular to a medical radioisotope-labeled P2X7 receptor targeting probe precursor, which has a structural formula shown in a formula (I):
Figure DDA0003109634250000011
wherein X is selected from substituted or unsubstituted alkyl of C1-C4,
Figure DDA0003109634250000012
R0A substituted or unsubstituted saturated alkyl group selected from a hydrogen atom, a halogen atom, C1-C5; r1Selected from halogen atoms; r2Selected from the group consisting of C1-C5 substituted or unsubstituted saturated alkyl groups, C1-C4 substituted or unsubstituted unsaturated alkyl groups; r3Selected from halogen atoms, substituted or unsubstituted saturated alkyl groups of C1-C5, substituted or unsubstituted 5-7 membered heterocyclic rings, heterocyclic aryl groups; wherein the 5-7 membered heterocyclic ring contains 1-3N, P, O, S heteroatoms.

Description

P2X7 receptor targeting probe precursor labeled by medical radioactive isotope
Technical Field
The invention relates to the field of organic synthesis, in particular to a P2X7 receptor targeting probe precursor labeled by medical radioactive isotopes, a P2X7 receptor targeting molecular probe thereof and a kit for preparing the molecular probe for imaging a P2X7 receptor.
Background
An important subtype of the P2X series of P2X7 receptor purinergic receptors belongs to the Adenosine Triphosphate (ATP) -gated ion channel. It is widely distributed in human body, especially has high expression in immune system and central nervous system. Relevant studies have shown that it plays an important role in both normal humans and diseases.
The P2X7 receptor is widely involved in the processes related to cell metabolism, and has obvious up-regulation expression in immune system diseases, central nervous system diseases, inflammations, cancers and cardiovascular diseases related to metabolic disorders. Therefore, the small molecule inhibitor of the target has become an important research direction of related therapeutic drugs, and a plurality of drugs enter a clinical test stage at present.
The transformation and development of P2X7 receptor small molecule inhibitor core drug scaffolds in Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) will provide highly sensitive molecular imaging probes. The molecular probe can provide an accurate in-vivo analysis tool for related disease analysis and drug research and development.
On the other hand, the P2X7 receptor is highly expressed in microglia in the central nervous system. After the brain is stimulated or damaged, extracellular ATP can be obviously increased, so that high expression of a P2X7 receptor is greatly stimulated, and an NRLP3 inflammatory signal pathway related to microglia is activated. In addition, the obvious increase of the expression is also proved in a brain inflammation model such as mouse LPS. Therefore, the P2X7 receptor is currently considered to be an important visualization tool for neuroinflammation.
Disclosure of Invention
On the basis of the common general knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily without departing from the concept and the protection scope of the invention.
The invention provides a medical radioactive isotope labeled P2X7 receptor targeting probe precursor in a first aspect, which is characterized in that the structural formula of the targeting probe precursor is shown as the formula (I):
Figure BDA0003109634230000011
wherein X is selected from substituted or unsubstituted alkyl of C1-C4,
Figure BDA0003109634230000012
R0A substituted or unsubstituted saturated alkyl group selected from a hydrogen atom, a halogen atom, C1-C5;
R1selected from halogen atoms;
R2selected from the group consisting of C1-C5 substituted or unsubstituted saturated alkyl groups, C1-C4 substituted or unsubstituted unsaturated alkyl groups;
R3selected from halogen atoms, substituted or unsubstituted saturated alkyl groups of C1-C5, substituted or unsubstituted 5-7 membered heterocyclic rings, heterocyclic aryl groups; wherein the 5-7 membered heterocyclic ring contains 1-3N, P, O, S heteroatoms.
As a preferred embodiment, in the present invention, when X is selected from the group consisting of substituted or unsubstituted alkyl groups of C1-C4, R is1Selected from bromine atoms; or said X is selected from
Figure BDA0003109634230000021
When R is1Selected from fluorine atom and bromine atom.
In a preferred embodiment of the present invention, X is selected from the group consisting of methyl, ethyl, n-propyl, and,
Figure BDA0003109634230000022
R0Selected from hydrogen atom, chlorine atom, fluorine atom, bromine atom;
R1selected from fluorine atom, bromine atom;
R2substituted or unsubstituted saturated alkyl selected from C1-C5;
R3selected from halogen atoms, substituted or unsubstituted saturated alkyl groups of C1-C5.
As a preferred embodiment, the P2X7 receptor targeting probe precursor of the present invention has a formula (i) selected from:
Figure BDA0003109634230000023
r in the Compound 14Selected from the group consisting of C1-C3 unsubstituted saturated alkyl;
r in the compound 2 and the compound 32Each independently selected from- (CH)2) n-; and n is 1-5.
The second aspect of the invention provides a P2X7 receptor targeting molecular probe, wherein the P2X7 receptor targeting molecular probe is prepared by radiolabeling a P2X7 receptor targeting probe precursor.
As a preferred technical scheme, the radioisotope used in the radiolabelling process in the invention is18F or125I。
As a preferred technical scheme, the structural formula of the P2X7 receptor targeting molecular probe is shown as the formula (II):
Figure BDA0003109634230000031
wherein, R is5Is selected from18F or F;
the R is6Is selected from H125IC＝CClR2-、R3HC＝C18FR2-。
As a preferred technical scheme, the structural formula of the P2X7 receptor targeting molecular probe in the invention is selected from the following formulas (II):
Figure BDA0003109634230000032
r in the Compound 2-14Selected from the group consisting of C1-C3 unsubstituted saturated alkyl;
r in the Compound 2-22Each independently selected from- (CH)2) n-; and n is 1-5.
The third aspect of the invention provides an application of the P2X7 receptor targeting probe precursor labeled by medical radioactive isotope, which is applied to diagnosing the central nervous degeneration type progressive disease, inflammation and tumor imaging related to the abnormal expression of the P2X7 receptor.
The fourth aspect of the invention provides a kit for preparing a molecular probe for P2X7 receptor imaging, wherein the kit comprises the precursor of the P2X7 receptor targeting probe labeled by the medical radioisotope.
Compared with the prior art, the invention has the following remarkable advantages and effects: the use of the precursor only needs one-step labeling, and the radiation yield is generally higher.
Drawings
FIG. 1 shows the results of example 118F-labeled P2X7 receptor targeting molecular probe separation spectrum.
FIG. 2 is a drawing of example 2125And (3) separating a spectrum of the I-labeled P2X7 receptor targeting molecular probe.
FIG. 3 shows the results of example 318F-labeled P2X7 receptor targeting molecular probe separation spectrum.
Detailed Description
The technical solutions of the present invention are described in detail below with reference to the drawings and the embodiments, but the present invention is not limited to the scope of the embodiments.
In a first aspect of the present invention, there is provided a medical radioisotope labeled P2X7 receptor targeting probe precursor, wherein the structural formula of the targeting probe precursor is shown in formula (i):
Figure BDA0003109634230000041
wherein X is selected from substituted or unsubstituted alkyl of C1-C4,
Figure BDA0003109634230000042
R0A substituted or unsubstituted saturated alkyl group selected from a hydrogen atom, a halogen atom, C1-C5;
R1selected from halogen atoms;
R2selected from the group consisting of C1-C5 substituted or unsubstituted saturated alkyl groups, C1-C4 substituted or unsubstituted unsaturated alkyl groups;
R3selected from halogen atoms, substituted or unsubstituted saturated alkyl groups of C1-C5, substituted or unsubstituted 5-7 membered heterocyclic rings, heterocyclic aryl groups; wherein the 5-7 membered heterocyclic ring contains 1-3N, P, O, S heteroatoms.
In some embodiments, when X is selected from C1-C4 substituted or unsubstituted alkyl, R1 is selected from a bromine atom; or said X is selected from
Figure BDA0003109634230000043
When R1 is selected from a fluorine atom and a bromine atom.
In some embodiments, X is selected from methyl, ethyl, n-propyl, methyl, ethyl, propyl, isopropyl, and isopropyl,
Figure BDA0003109634230000044
R0Selected from hydrogen atom, chlorine atom, fluorine atom, bromine atom;
R1selected from fluorine atom, bromine atom;
R2substituted or unsubstituted saturated alkyl selected from C1-C5;
R3selected from halogen atoms, substituted or unsubstituted saturated alkyl groups of C1-C5.
In some preferred embodiments, the P2X7 receptor targeting probe precursor is of formula (i) selected from the group consisting of:
Figure BDA0003109634230000051
r in the Compound 14Selected from the group consisting of C1-C3 unsubstituted saturated alkyl;
r in the compound 2 and the compound 342Each independently selected from- (CH)2) n-; and n is 1-5.
In some more preferred embodiments, the P2X7 receptor targeting probe precursor is of formula (i) selected from the group consisting of:
Figure BDA0003109634230000052
Figure BDA0003109634230000061
in a second aspect, the present invention provides a P2X7 receptor-targeting molecular probe, wherein the P2X7 receptor-targeting molecular probe is prepared by radiolabeling the P2X7 receptor-targeting probe precursor according to any one of claims 1 to 4.
In some preferred embodiments, the radioisotope used in the radiolabelling process is18F or125I。
In some preferred embodiments, the P2X7 receptor targeting molecular probe has the structural formula shown in formula (ii):
Figure BDA0003109634230000062
wherein, R is5Is selected from18F or F;
the R is6Is selected from H125IC＝CClR2-、R3HC＝C18FR2-。
In some preferred embodiments, the P2X7 receptor targeting molecular probe has a structural formula selected from the group consisting of formula (ii):
Figure BDA0003109634230000063
r4 in the compound 2-1 is selected from unsubstituted saturated alkyl of C1-C3;
r2 in the compound 2-2 is respectively and independently selected from- (CH2) n-; and n is 1-5.
In some preferred embodiments R4 in said compound 2-1 is selected from methyl, ethyl, n-propyl, n-butyl, isopropyl;
r2 in the compound 2-2 and the compound 2-3 is respectively and independently selected from- (CH2) n-; and n is an integer of 1, 2 and 3.
In some preferred embodiments, the P2X7 receptor targeting molecular probe has a structural formula selected from the group consisting of formula (ii):
Figure BDA0003109634230000071
the third aspect of the invention provides an application of the P2X7 receptor targeting probe precursor labeled by medical radioactive isotope, which is applied to diagnosing the central nervous degeneration type progressive disease, inflammation and tumor imaging related to the abnormal expression of the P2X7 receptor.
The fourth aspect of the invention provides a kit for preparing a molecular probe for P2X7 receptor imaging, wherein the kit comprises the precursor of the P2X7 receptor targeting probe labeled by the medical radioisotope.
The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. The reagents and starting materials used in the present invention are commercially available.
Example 1
A medical radioisotope-labeled P2X7 receptor targeting probe precursor, wherein the structural formula of the targeting probe precursor is shown as a compound 1-1:
Figure BDA0003109634230000081
the preparation method of the compound 1-1 comprises the following steps:
firstly, adding methyl dichloride into 2-chloro-3-methylbenzoic acid, reacting for two hours at 100 ℃ by taking 50mL of methylbenzene as a reaction solvent, monitoring by using a gas chromatography-mass spectrometer after the reaction is finished, and obtaining crude acyl chloride by rotary evaporation; then, the acid chloride solution prepared in the previous step was added dropwise to a suspension of potassium tert-butoxide in tetrahydrofuran at 0 ℃ and the resulting mixture was stirred at 0 ℃ to room temperature for 12 hours, extracted with water and methyl tert-butyl ether and the combined organic layers were Na2SO4Drying, filtration and concentration, purification by silica gel column chromatography gave tert-butyl 2-chloro-3-methylbenzoate (yield: 72%). Tert-butyl 2-chloro-3-methylbenzoate was then dissolved in carbon tetrachloride (100mL) at room temperature, and NBS and AIBN were added. The resulting mixture is in N2The reaction was heated to 80 ℃ for 12 hours. After cooling to room temperature, it was filtered and the filtrate was concentrated in vacuo to give the crude 3- (bromomethyl) -2-chlorobenzoic acid tert-butyl ester as a white solid; mixing the crude product with Na2SO3The mixture in acetonitrile was heated at 80 ℃ for 12 hours, and the crude product was purified by silica gel column chromatography to give tert-butyl 2-chloro-3- ((trifluoromethyl) sulfonyl) methyl) benzoate (yield: 30%); a solution of the product of the previous portion in 20ml of LTFA was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was concentrated in vacuo to give the pure product 2-chloro-3- (((trifluoromethyl) sulfonyl) methyl) benzoic acid as a white solid; LiAlH was added to a two-necked flask4And THF the mixture was stirred vigorously at 0 ℃ for 5 minutes, a suspension of 2-chloro-3- ((trifluoromethyl) sulfonyl) methyl) benzamide in THF was added slowly and stirred for 10 minutes, then heated to 60 ℃ for 2 hours. After completion of the reaction monitored by gas chromatography-mass spectrometry, the mixture was cooled to room temperature, quenched with 10mmol of water, 10mmol of a 15% aqueous solution of sodium hydroxide, and anhydrous MgSO was added to the mixture4Mixtures ofStirring at 0 ℃ for 30 min, filtering and washing with diethyl ether gave the pure product (2-chloro-3- ((trifluoromethylsulfonyl) methyl) phenyl) methanamine (yield: 90%) as a pale yellow solid; HATU, 1-methyl-5-oxopyrrolidine-2-carboxylic acid was then added and stirred at 25 ℃ for 1 hour with acetonitril as solvent, and the residue was purified by silica gel column chromatography to give N- (2-chloro-3- (trifluoromethylsulfonyl) methyl) benzyl) -1-methyl-5-oxopyrrolidine-2-carboxamide as a pale yellow solid (yield: 65%); it is mixed with NFSI and K3PO4The mixture of (a) was stirred in dry dimethylformamide at room temperature for 2 hours, and the residue was purified by silica gel column chromatography to give the pure product N- (2-chloro-3- (difluoro ((trifluoromethyl) sulfonyl) methyl) benzyl) -1-methyl-5-oxopyrrolidine-2-carboxamide as a colorless oil. (yield: 74%); finally, the product of the previous step and lithium bromide, as well as anhydrous acetonitrile, were added to a 10 ml schlenk tube. The reaction mixture was heated at 80 ℃ for 12 hours, and the residue was further purified by silica gel column chromatography to give the pure product N- (3- (bromodifluoromethyl) -2-chlorobenzyl) -1-methyl-5-oxopyrrolidine-2-carboxamide (compound 1-1). (yield: 78%)
Data for the P2X7 receptor targeting molecular probe (compound 1-1) are presented below.1HNMR(400MHz，CDCl3)δ7.59–7.40(m,2H),7.28(t,J＝7.8Hz,1H),7.10(s,1H),4.55(qd,J＝15.0,5.9Hz,2H),3.95(dd,J＝9.0,3.9Hz,1H),2.71(s,3H),2.47–2.13(m,2H),2.04–1.90(m,1H).19F NMR(377MHz,CDCl3)δ-45.18(s,1H).8H)，LC/MS(ESI)：Calculated for C14H14BrClF2N2O2(M+H+)394.9968,found 394.9972.
The P2X7 receptor targeting molecular probe is prepared by carrying out the reaction on the P2X7 receptor targeting probe precursor18F is subjected to radiolabeling to prepare a P2X7 receptor targeting molecular probe.
Figure BDA0003109634230000091
The P2X7 receptor targeting molecular probe is prepared by carrying out the reaction on the P2X7 receptor targeting probe precursor18The method for radiolabeling comprises the following steps: in a vial, 2mg of the labeled precursor (Compound 1-1) was mixed with 10mCi anhydrous TBA18F was dissolved in 500. mu.L of acetonitrile solution, and the mixture was reacted at 110 ℃ for 20min under a closed condition.
Then, 200. mu.L of mobile phase, MeCN and 0.1mol/L ammonium formate buffer (35/65), was injected into the reaction system to quench the reaction, and the mixture was separated and collected by HPLC (Dionex UltiMate 3000 Series). The total radiochemical yield is more than 50 percent (n is 5), the radiochemical purity is more than 98 percent, and the total time of the radioactive labeling is about 40 min.
Example 2
A medical radioisotope-labeled P2X7 receptor targeting probe precursor, wherein the structural formula of the targeting probe precursor is shown as a compound 1-2:
Figure BDA0003109634230000101
the preparation method of the compound 1-2 comprises the following steps:
l-2-pyrrolidone-5-carboxylic acid (1.032g,8.0mmol) and 2-chloro-3- (trifluoromethyl) benzylamine (1.672g, 8.0mmol) were combined with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.917g, 10.0mmol) and 1-hydroxybenzotriazole (1.35g, 10.0mmol) in dry dichloromethane (150 mL). The reaction mixture was stirred at room temperature overnight. The resulting mixture was then washed with 2N hydrochloric acid (50 mL. times.3) and saturated aqueous sodium bicarbonate (40 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by separation with silica gel column chromatography to give the product as a white solid (1.5g, 60%).
The product obtained in the above step (960mg, 3mmol) was added to a glass reaction flask containing 15mL of N, N-dimethylformamide at 0 deg.C, bis-trimethylsilyl aminolithium (4.5mL) and 3-bromopropyne (714mg, 6mmol) were added, and the reaction mixture was stirred at room temperature overnight. After the reaction, the mixture was extracted with a saturated sodium chloride solution and an ethyl acetate solution, and the organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain a white solidCompound 1-2(210mg, 20%). Data for the P2X7 receptor targeting molecular probe (compounds 1-2) are presented below.1H NMR(400MHz，CDCl3)δ7.58–7.72(m,2H),7.38(t,J＝7.8Hz,1H),6.57(s,1H),4.72–4.55(m,2H),4.48(dd,J＝17.7,2.6Hz,1H),4.35–4.17(m,1H),3.70(dd,J＝17.7,2.5Hz,1H),2.59–2.46(m,1H),2.45–2.31(m,2H),2.18(t,J＝2.6Hz,1H),2.14–2.00(m,1H).LC/MS(ESI)：Calculated for C16H14ClF3N2O2(M+H+)359.0769.found 359.0770.
The P2X7 receptor targeting molecular probe is prepared by carrying out the reaction on the P2X7 receptor targeting probe precursor125I, preparing a P2X7 receptor targeting molecular probe by radioactive labeling.
Figure BDA0003109634230000102
The P2X7 receptor targeting molecular probe is prepared by carrying out the reaction on the P2X7 receptor targeting probe precursor125The method for radiolabeling comprises the following steps:
in a vial, 2mg of the labeled precursor (Compound 1), 1mg of m-chloroperoxybenzoic acid, 200. mu. Ci Na125I aqueous solution (Cike), 1mg of lithium chloride was dissolved in 300. mu.L of a mixed solution of dichloromethane and acetic acid (4:1), and the mixture was reacted at 80 ℃ under a closed condition for 20 min.
Then, 200. mu.L of mobile phase, MeCN and 0.1mol/L ammonium formate buffer (55/45), was injected into the reaction system to quench the reaction, and the mixture was separated and collected by HPLC (Dionex UltiMate 3000 Series). The total radiochemical yield is more than 50 percent (n is 5), the radiochemical purity is more than 98 percent, and the total time of the radioactive labeling is about 40 min.
Example 3
A medical radioisotope-labeled P2X7 receptor targeting probe precursor, wherein the structural formula of the targeting probe precursor is shown as compounds 1-3:
Figure BDA0003109634230000111
the preparation method of the compounds 1-3 comprises the following steps:
5-oxo-1- (prop-2-yn-1-yl) pyrrolidine-2-carboxylic acid ethyl ester:
to a stirred suspension of powdered potassium hydroxide (924mg, 16.5mmol) and tetra-n-butylammonium bromide (966mg, 3mmol) in 100mL of anhydrous tetrahydrofuran was added a solution of 3-bromopropyne (1.78g, 15mmol) and ethyl D-pyroglutamate (2.35g, 15mmol) in 100mL of anhydrous tetrahydrofuran, followed by stirring at room temperature for one hour, the precipitate was filtered off and the filtrate was evaporated to give an oily residue. Ethyl acetate was added and the precipitated material was filtered off. The filtrate was washed with water and brine, and the organic layer was dried over anhydrous magnesium sulfate and evaporated. The product was isolated and purified by column chromatography as a light brown oil. (2.1g, 72%).
1- (3-bromoprop-2-yn-1-yl) -5-oxopyrrolidine-2-carboxylic acid ethyl ester:
to a reaction glass vial was added acetone (20mL) under the exclusion of light, the product of the previous step (1.95g,10mmol), followed by NBS (2.136g,12mmol) and silver nitrate (170mg, 1 mmol). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, it was filtered through celite, and the filtrate was evaporated. Then 20mL of n-hexane was added, filtered again, and the filtrate was evaporated in vacuo to give an oily liquid (1.5g, 56%).
1- (3-bromoprop-2-yn-1-yl) -5-oxopyrrolidine-2-carboxylic acid:
a dry reaction glass bottle was charged with the product of the above step (1.5g, 5mmol), sodium hydroxide (400mg, 10mmol) and a solution of 50mL of water and ethanol (5mL of water, 45mL of ethanol), and the reaction mixture was stirred at room temperature for 15 min. After completion of the reaction, the mixture was concentrated, washed with dichloromethane, and the water layer was collected, then adjusted to pH 1 with 1M hydrochloric acid, and extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give a white solid (720mg, 59%).
1- (3-bromoprop-2-yn-1-yl) -N- (2-chloro-3- (trifluoromethyl) benzyl) -5-oxopyrrolidine-2-carboxamide:
1- (3-bromoprop-2-yn-1-yl) -5-oxopyrrolidine-2-carboxylic acid (492mg, 2mmol), 2-chloro-3- (trifluoromethyl) benzylamine (420mg, 2mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (480mg, 2.5mmol) and 1-hydroxybenzotriazole (312mg, 2.5mmol) were combined in dry dichloromethane (100 mL). The reaction mixture was stirred at room temperature overnight. The resulting mixture was then washed with 2N hydrochloric acid (50mL x 3) and saturated aqueous sodium bicarbonate solution (40 mL). The organic layer was dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography to give 1-3(393mg, 45%) as a white solid
Data for the P2X7 receptor targeting molecular probe (compounds 1-3) are presented below.1HNMR(400MHz，CDCl3)δ7.58-7.72(m,2H),7.39(t,J＝7.7Hz,1H),6.48(s,1H),4.64(qd,J＝15.0,6.1Hz,2H),4.56(d,J＝8.2,1H),4.25(dd,J＝8.2,4.1Hz,1H),3.71(d,J＝17.6Hz,1H),2.62–2.45(m,1H),2.45–2.30(m,2H),2.15–1.95(m,1H).LC/MS(ESI)：Calculated for C16H13BrClF3N2O2(M+H+)436.9873,found436.9875.
The P2X7 receptor targeting molecular probe is prepared by carrying out the reaction on the P2X7 receptor targeting probe precursor18F is subjected to radiolabeling to prepare a P2X7 receptor targeting molecular probe.
Figure BDA0003109634230000131
The P2X7 receptor targeting molecular probe is prepared by carrying out the reaction on the P2X7 receptor targeting probe precursor18The method for radiolabeling comprises the following steps:
in a vial, 2mg of the labeled precursor (Compound 1), 10mCiAg18F and 1mg of silver acetate were dissolved in 500. mu.L of acetonitrile solution, and the mixture was reacted at 110 ℃ under a closed condition for 20 min.
Then, 200. mu.L of mobile phase, MeCN and 0.1mol/L ammonium formate buffer (55/45), was injected into the reaction system to quench the reaction, and the mixture was separated and collected by HPLC (Dionex UltiMate 3000 Series). The total radiochemical yield is more than 50 percent (n is 5), the radiochemical purity is more than 98 percent, and the total time length of the radioactive label is about 45 min.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (10)

1. A medical radioisotope-labeled P2X7 receptor targeting probe precursor, wherein the structural formula of the targeting probe precursor is shown as formula (I):
Figure FDA0003109634220000011
wherein X is selected from substituted or unsubstituted alkyl of C1-C4,
Figure FDA0003109634220000012
R0A substituted or unsubstituted saturated alkyl group selected from a hydrogen atom, a halogen atom, C1-C5;
R1selected from halogen atoms;
R2selected from the group consisting of C1-C5 substituted or unsubstituted saturated alkyl groups, C1-C4 substituted or unsubstituted unsaturated alkyl groups;
R3selected from halogen atoms, substituted or unsubstituted saturated alkyl groups of C1-C5, substituted or unsubstituted 5-7 membered heterocyclic rings, heterocyclic aryl groups; wherein the 5-7 membered heterocyclic ring contains 1-3N, P, O, S heteroatoms.
2. The P2X7 receptor targeting probe precursor of claim 1, wherein when X is selected from the group consisting of substituted or unsubstituted alkyl groups of C1-C4, R is1Selected from bromine atoms; or said X is selected from
Figure FDA0003109634220000013
When R is1Selected from fluorine atom and bromine atom.
3. The P2X7 receptor targeting probe precursor of claim 1 or 2, wherein X is selected from the group consisting of methyl, ethyl, n-propyl,
Figure FDA0003109634220000014
R0Selected from hydrogen atom, chlorine atom, fluorine atom, bromine atom;
R1selected from fluorine atom, bromine atom;
R2substituted or unsubstituted saturated alkyl selected from C1-C5;
R3selected from halogen atoms, substituted or unsubstituted saturated alkyl groups of C1-C5.
4. The P2X7 receptor targeting probe precursor of claim 1, wherein formula (i) is selected from the group consisting of:
Figure FDA0003109634220000015
Figure FDA0003109634220000021
r in the Compound 14Selected from the group consisting of C1-C3 unsubstituted saturated alkyl;
r in the compound 2-2 and the compound 2-32Each independently selected from- (CH)2) n-; and n is 1-5.
5. A P2X7 receptor-targeting molecular probe, wherein the P2X7 receptor-targeting molecular probe is prepared by radiolabeling the P2X7 receptor-targeting probe precursor of any one of claims 1-4.
6. The P2X7 receptor-targeting molecular probe of claim 5, wherein the probe is used in a radiolabelling procedureThe radioisotope is18F or125I。
7. The P2X7 receptor-targeting molecular probe of claim 5, wherein the P2X7 receptor-targeting molecular probe has the structural formula shown in formula (II):
Figure FDA0003109634220000022
wherein, R is5Is selected from18F or F;
the R is6Is selected from H125IC＝CClR2-、R3BrC＝C18FR2-。
8. The P2X7 receptor-targeting molecule probe of claim 5, wherein the P2X7 receptor-targeting molecule probe has a structural formula selected from the group consisting of formula (II):
Figure FDA0003109634220000023
Figure FDA0003109634220000031
r in the Compound 2-14Selected from the group consisting of C1-C3 unsubstituted saturated alkyl;
r in the Compound 2-22Each independently selected from- (CH)2) n-; and n is 1-5.
9. Use of a radioisotope labelled P2X7 receptor targeting probe precursor for medical use as claimed in any one of claims 1 to 4 for the diagnosis of progressive disease of the CNS degenerative type, inflammation and tumour imaging associated with aberrant expression of the P2X7 receptor.
10. A kit for preparing a molecular probe for P2X7 receptor imaging, comprising a precursor of the P2X7 receptor targeting probe labeled with a medical radioisotope as claimed in any one of claims 1 to 4.
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CN114230505A (en) * 2021-11-15 2022-03-25 中山大学附属第五医院 Preparation of fluorine-18 labeled targeting P2X7 receptor molecular probe and application of molecular probe in animal model PET imaging

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CN114230505A (en) * 2021-11-15 2022-03-25 中山大学附属第五医院 Preparation of fluorine-18 labeled targeting P2X7 receptor molecular probe and application of molecular probe in animal model PET imaging

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