CN117362192A - PET radioactive tracer for imaging glycine transporter Glyt2 - Google Patents

PET radioactive tracer for imaging glycine transporter Glyt2 Download PDF

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CN117362192A
CN117362192A CN202210775862.6A CN202210775862A CN117362192A CN 117362192 A CN117362192 A CN 117362192A CN 202210775862 A CN202210775862 A CN 202210775862A CN 117362192 A CN117362192 A CN 117362192A
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fluoropropyl
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田海滨
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Zhejiang Yihe Medical Technology Co ltd
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Abstract

The invention discloses a PET radioactive tracer for imaging glycine transporter Glyt2, which uses a fluorine propyl substituted benzamide analogue as a potential PETGlyT2 radioactive tracer, wherein the method of radiolabelling the analogue is to replace one methoxy group with fluoroalkyl ether and then reduce the methoxy group with aluminum hydride generated in situ to obtain diamine. Alkylation was performed by heating 3- [18F ] fluoropropyl ester at 1408C in the presence of NaH for 30min, HPLC analysis of the reaction mixture showing two radioactive peaks corresponding to retention times of 3- [18F ] fluoropropyl mesylate and [18F ]3, respectively; sampling at the intermediate time points indicated an initial rapid rate of alkylation followed by a slow increase to 30min. The PET radioactive tracer [18F ]3 is synthesized by alkylation of a precursor 2 and 3- [18F ] fluoropropyl ester, and the radioactive ligand has high specific activity, high radiochemical purity and sufficient radiochemical yield and can be used for PET research of animals.

Description

PET radioactive tracer for imaging glycine transporter Glyt2
Technical Field
The invention relates to the technical field of radioactive tracers, in particular to a PET radioactive tracer for imaging glycine transporter Glyt 2.
Background
Recent clinical studies have demonstrated the efficacy of exogenous glycine in the treatment of psychotic negative symptoms. Since extracellular glycine is regulated by high affinity glycine transporters, pharmacological inhibition of this transporter represents a new mechanism for increasing glycine content in the brain. 1 clinical study of high dose glycine treatment can improve prognosis in schizophrenic patients with negative symptoms, supporting the insight that increasing NMDA transmission by increasing glycine levels can be beneficial to psychotic patients. The 2-glycine transporter has been cloned and can now be divided into two distinct gene families, glycine transporter 1 (GlyT 1) and glycine transporter 2 (GlyT 2). These genes have now been further divided into three subtypes of GlyT-1 (a, b and c) and two splice variant versions of GlyT2 (a and b). 3-5 immunocytochemistry studies have shown that GlyT1 transporter is widely distributed throughout the Central Nervous System (CNS), whereas GlyT2 transporter distribution is similar to that of the shinine-sensitive glycine receptor (ssGlyR), limited to the spinal cord and brainstem. Allebratid et al 8 report a new class of GlyT1 inhibitors. However, these molecules lack activity on the GlyT2 subtype.
To this end we propose a PET radiotracer for imaging the glycine transporter Glyt 2.
Disclosure of Invention
(one) solving the technical problems
In view of the shortcomings of the prior art, the invention provides a PET radioactive tracer for imaging glycine transporter Glyt2, the PET radioactive tracer [18F ]3 of the invention is synthesized by alkylation of precursor 2 and 3- [18F ] fluoropropyl ester, and the radioactive ligand has higher specific activity and radiochemical purity and sufficient radiochemical yield and can be used for PET research of animals.
(II) technical scheme
In order to achieve the above purpose, the invention is realized by the following technical scheme: a PET radiotracer for imaging the glycine transporter Glyt2 comprising
Using a fluoropropyl substituted benzamide analogue as a potential petgyt 2 radiotracer, radiolabelling the analogue by substituting one of the methoxy groups with a fluoroalkyl ether;
the saponification reaction of methyl ester is utilized to obtain asymmetric substituted acid, the latter half of the polymerization synthesis is condensed by using potassium cyanide and dimethylamine through the direct sequence of cyclopentanone to obtain aminobutyronitrile 4, and then the aminobutyronitrile is reduced by using aluminum hydride generated in situ to obtain diamine. The final assembly of the ligand is an ester 14 completed by the Williamson reaction between phenol and 3-fluoropropyl ester (by reaction of 3-chloro-1-propanol with potassium fluoride in ethylene glycol followed by esterification with p-toluenesulfonyl chloride pyridine), the methyl ester is hydrolyzed (acid 15), then converted to acid chloride ion and reacted with diamine to give the target ligand, acid 10 is converted to acid chloride with thionyl chloride 11 for the synthesis of phenolic precursors and reacted with diamine 5 in THF at room temperature;
the preparation method comprises the steps of synthesizing the 3- [18f ] fluoropropyl mesylate [18f ] serving as a marked intermediate by a two-step one-pot method, reacting the 3- [18f ] fluoropropyl mesylate [18f ] with 1, 3-propanediol in the presence of potassium carbonate and potassium carbonate-222 to obtain the 3- [18f ] fluoropropyl tosylate, wherein the marked radioactive intermediate is not separated, but directly undergoes alkylation reaction in the same pot after acetonitrile is evaporated.
As a preferred embodiment of the invention, the alkylation is carried out by heating 3- [18F ] fluoropropyl ester at 1408C in the presence of NaH for 30min, and HPLC analysis of the reaction mixture shows two radioactive peaks corresponding to retention times of 3- [18F ] fluoropropyl mesylate and [18F ]3, respectively; sampling at the intermediate time points indicated an initial rapid rate of alkylation followed by a slow increase to 30min.
As a preferred embodiment of the invention, for SPE, the reaction mixture is added to water and the aqueous mixture is passed through a cartridge, the nine bases are washed with water and the radioactive product is eluted with methanol.
As a preferred embodiment of the present invention, the recovery rate of ethyl acetate for extracting [18f ]3 from the aqueous reaction mixture is 40%; after evaporation of ethyl acetate, the residue was dissolved in methanol and the crude product was purified by semi-preparative HPLC with a total radiochemical yield of [18f ]3 of 14-16% and a total synthesis time of about 128min, and by HPLC UV analysis, [18F ]3 had a radiochemical purity of >98% and a specific activity of 1462342GBq/mmol; stability tests showed that it was stable at 60 min.
(III) beneficial effects
The present invention provides a PET radiotracer for imaging the glycine transporter Glyt 2. The beneficial effects are as follows:
the PET radioactive tracer [18F ]3 is synthesized by alkylation of a precursor 2 and 3- [18F ] fluoropropyl ester, and the radioactive ligand has high specific activity, high radiochemical purity and sufficient radiochemical yield and can be used for PET research of animals.
Drawings
FIG. 1 is a schematic representation of the synthesis of 3-methyl-5-methoxybenzamide ([ 18F ] 3) of the present invention by the reaction of a monodemethyl phenol precursor;
FIG. 2 shows the polymerization synthesis of [18F ]3 with diamine in THF at room temperature according to the present invention;
FIG. 3 is a synthesis formula of radiosynthesis [18F ]3 of the invention;
FIG. 4 shows the radioactive liquid chromatography of the reaction mixtures of [18f ] fluoropropyl methanesulfonic acid (a) and [18f ]3 (b) of the present invention;
FIG. 5 shows the alkylation rates of 3-18F fluoropropyl groups of precursor 2 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to fig. 1-5, the embodiment of the present invention provides a technical solution: a PET radiotracer for imaging the glycine transporter Glyt2 comprising
Using a fluoropropyl substituted benzamide analogue as a potential petgyt 2 radiotracer, radiolabelling the analogue by substituting one of the methoxy groups with a fluoroalkyl ether;
the saponification reaction of methyl ester is utilized to obtain asymmetric substituted acid, the latter half of the polymerization synthesis is condensed by using potassium cyanide and dimethylamine through the direct sequence of cyclopentanone to obtain aminobutyronitrile 4, and then the aminobutyronitrile is reduced by using aluminum hydride generated in situ to obtain diamine. The final assembly of the ligand is an ester 14 completed by the Williamson reaction between phenol and 3-fluoropropyl ester (by reaction of 3-chloro-1-propanol with potassium fluoride in ethylene glycol followed by esterification with p-toluenesulfonyl chloride pyridine), the methyl ester is hydrolyzed (acid 15), then converted to acid chloride ion and reacted with diamine to give the target ligand, acid 10 is converted to acid chloride with thionyl chloride 11 for the synthesis of phenolic precursors and reacted with diamine 5 in THF at room temperature;
example 1
The preparation method comprises the steps of synthesizing the 3- [18f ] fluoropropyl mesylate [18f ] serving as a marked intermediate by a two-step one-pot method, reacting the 3- [18f ] fluoropropyl mesylate [18f ] with 1, 3-propanediol in the presence of potassium carbonate and potassium carbonate-222 to obtain the 3- [18f ] fluoropropyl tosylate, wherein the marked radioactive intermediate is not separated, but directly undergoes alkylation reaction in the same pot after acetonitrile is evaporated.
As a preferred embodiment of the invention, the alkylation is carried out by heating 3- [18F ] fluoropropyl ester at 1408C in the presence of NaH for 30min, and HPLC analysis of the reaction mixture shows two radioactive peaks corresponding to retention times of 3- [18F ] fluoropropyl mesylate and [18F ]3, respectively; sampling at the intermediate time points indicated an initial rapid rate of alkylation followed by a slow increase to 30min.
As a preferred embodiment of the invention, for SPE, the reaction mixture is added to water and the aqueous mixture is passed through a cartridge, the nine bases are washed with water and the radioactive product is eluted with methanol.
As a preferred embodiment of the present invention, the recovery rate of ethyl acetate for extracting [18f ]3 from the aqueous reaction mixture is 40%; after evaporation of ethyl acetate, the residue was dissolved in methanol and the crude product was purified by semi-preparative HPLC with a total radiochemical yield of [18f ]3 of 14-16% and a total synthesis time of about 128min, and by HPLC UV analysis, [18F ]3 had a radiochemical purity of >98% and a specific activity of 1462342GBq/mmol; stability tests showed that it was stable at 60 min.
Example 2
A solution of potassium cyanide (6.5 g,0.1 mol) in 50ml of water was added to a stirred cooled suspension of HNMe2 hydrochloric acid (8.15 g,0.1 mol) and cyclopentanone (8.4 g,0.1 mol). The mixture was stirred at room temperature overnight and extracted with Et2 o. The organic layer was washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give colorless oil 4 (7.15 g,52%, ignition.87%). 161HNMR (CDCl 3) d:2.27 (s, 6H, CH 32), 2.1 (m, 2H), 1.8-1.6 (m, 6H); 13CNMR (CDCl 3) d:119.6 (CN), 69.4 (C1), 41.9 (CH 32), 38.4 (C2 and C5), 23.2 (C3 and C4)
Aminomethyl-1-dicarboxamide-cyclopentane (5): to a stirred suspension of lithium aluminum hydride (12.4 g,0.32 mol) in 200ml of dry THF, cooled to 08C under N2, a solution of sulfuric acid (8.2 ml,0.16 mol) in dry THF (30 ml) was added dropwise. The mixture was stirred for 2 hours and then allowed to rest overnight at room temperature. To this suspension, a solution of 4 (13.8 g,0.10 mol) was added dropwise at 08℃and 80ml of THF was added. The mixture was heated at 40-508C for 3 hours, then cooled with water and quenched. The mixture was filtered and the filtrate was concentrated under reduced pressure. The oil residue was purified by distillation between bulbs to give 5 (6.31 g,45%, ignition.56%); 161HNMR (CDCl 3) d:2.6 (s, 2H, NCH 2), 2.2 (s, 6H, methyl x 2), 1.8-1.3 (m, 8H, cyclopentyl); 13CNMR (CDClC 3) d:70.1 (C1), 48.6 (CNH 2), 39.6 (methyl 2), 30.1 (C2), 30.9 (C5), 25.9 (C3 and C4).
Methyl 3,4, 5-triacetoxybenzoate (6): the methyl 3,4, 5-triacetoxybenzoate was prepared as described above for 12, with only minor modifications. A mixture of methyl gallate (5.00 g,27.15 mmol) and acetic anhydride (9.98 g,97.7 mmol) with pyridine (25 ml) was stirred at 08C for 2 hours to room temperature. The reaction mixture was then poured into 1.2M hydrochloric acid and extracted with ethyl acetate (375 ml). The combined ethyl acetate extracts were washed with aqueous sodium bicarbonate until the wash was basic, washed with brine (50 ml), dried (magnesium sulfate) and evaporated in vacuo. Recrystallization (EtOH) gave 7.90g (93%) of 6 as a white solid, m.p.119-1218C (illumination temperature 126.5-1288C) 17.
Methyl 3, 5-diacetyl toxin-4-benzyl benzoate (7): a mixture of methyl 3,4, 5-triethylbenzoate 6 (4.00 g, 12.90 mmol), potassium carbonate (5.40 g, 38.70 mol), KI (0.330 g, 2.0 mmol) and chlorobenzyl (3.26 g, 25.80 mmol) was refluxed in acetone (200 ml) for 18 hours. The reaction mixture was then cooled, poured into water (300 ml) and extracted with Et2o (3100 ml). The combined Et2o extracts were washed with brine (3100 ml), dried (magnesium sulfate) and evaporated in vacuo. Recrystallization (EtOH) gives 3.98g (72%) of 7, m.p.104-1068C (lit94-968C). 171HNMR (CDCl 3) d:7.7 (s, 2H), 7.4 (m, 5H), 5.1 (s, 2H), 3.8 (s (3H), 2.1 (6H), 1HNMR (CDCl 3) d, 7.69 (2H, s, H2, H6), 7.36 (5H, s, CH2Ph, arH), 5.05 (2H, s, methylene), 3.89 (3H, s, CO2 Me), 2.20 (6H, s, 3-OAc, 5 OAc).
Methyl 4-benzylmethoxy-3, 5-dihydroxybenzoate (8): to a solution of 7 (1.60 g,4.46 mmol) in methanol (80 ml) was added a solution of potassium carbonate (2.80 g) in water (40 ml), 08℃for 10min. After stirring at room temperature for 20min, the solvent was evaporated, acidified with 1mHC (ph=2) and then extracted with EtOAc (3100 ml). The glycolic acid extract was combined, washed with brine (2100 ml) and water (1100 ml), dried (magnesium sulfate) and evaporated in vacuo. The recrystallized (CHC 13/n-hexane) content was 1.06g (90%) of 8, m.p.127-1298C (lit.m.p.: 133-1348℃) 171H NMR (CDCl 3) d:7.3 (m, 5H), 7.2 (s, 2H), 5.6 (s, 1H), 5.1 (s, 2H), 3.8 (s, 3H).
Methyl 4-benzyl 3-hydroxy 5-methoxybenzoate (9): methyl 4-benzylmethoxy-3, 5-dihydroxybenzoate (8) (2.02 g;7.4 mmol) and 1.96g potassium carbonate were suspended in 10ml DMF. Then, 0.994g (7.00 mmol) of CH3I was added at 08C and the resulting mixture was stirred at RT for 5h. After removal of the solvent, treatment with water and extraction with Et2 o. The Et2O extract was dried (magnesium sulfate) and the solvent was removed on a rotary evaporator. Purification by chromatography (ether/hexane 1/1) gave 1.43g (67.5% yield) of a white solid, m.p.124-1268C.1HNMR (CDCl 3) d:7.3 (m, 5H), 7.2 (m, 2H), 5.8 (s, 1H), 5.1 (s, 2H), 3.8 (s, 3H), 3.7 (s, 3H).
4-benzyloxy-3-hydroxy-5-methoxybenzoic acid (10): methyl 4-benzylmethoxy-3-hydroxy-5-methoxybenzoate 9 (405 mg,1.4 mmol) was heated under reflux in 10ml of 30% aqueous potassium hydroxide and methanol for 1 hour. Excess solvent was removed on a rotary evaporator and 20ml of water was added. 12M hydrochloric acid was added dropwise to the mixture at pH 1. The white precipitate was washed with water and dried to give 317mg (82.4%) of 10 as a white solid, m.p.133-1358C.1HNMR (CDCl 3) d7.2-7.3 (m, 7H), 5.2 (s, 1H), 5.1 (s, 2H), 3.8 (s, 3H).
4-benzyloxy-3-hydroxy-5-methoxybenzoyl chloride (11): a mixture of acid 10 (317 mg,1.15 mmol) and thionyl chloride (1.19 g,10 mmol) in toluene (5 ml) was heated under reflux until no more gas was evolved (2 h), and the reaction mixture was concentrated under reduced pressure. To remove the excess thionyl chloride, the residue was repeatedly dissolved in toluene (210 ml) and evaporated to dryness to give acid chloride 11 as an oil, which was used directly in the subsequent reaction.
3-fluoro-1-propanol (12): compound 12 was prepared from 3-chloro-1-propanol. 18A mixture of 18.9g (0.2 mol) of 3-chloro-1-propanol, 23.3g (0.4 mol) of KF and 30g of ethylene glycol was heated under vigorous stirring at 175-1808C. During the reaction, the product is distilled continuously at 130-1608 ℃. After 3h, 8.17g of a colourless liquid are collected. The crude 3-fluoropropanol was distilled twice. Yield 8.17g (54%). 1HNMR (CDCl 3) d1.8 (m, 2H).
Paralylsulfonyl chloride (9.8 g,50.2 mmol) and pyridine (12 g) were stirred at 08C while 3-fluoro-1-propanol (3.92 g,50 mmol) was slowly added. Stirring was continued for 1 hour, and a white precipitate formed. The mixture was diluted with water and 12M hydrochloric acid was added until no pyridine smell was present and the resulting mixture was extracted multiple times with Et2 o. The combined extracts were washed sequentially with water, aqueous sodium bicarbonate and finally with water. After drying (magnesium sulfate) and removal of Et2O, distillation gave 3-fluoropropyl p-to 1-ene sulfonate (7.63 g, 65.9%) as a colorless liquid. 1HNMR (CDCl 3) d1.8 (m, 2H), 2.3 (s, 3H), 4.0 (m, 2H), 4.2 (m, 2H), 7.2 (m, 2H), 7.6 (m, 2H).
A mixture of compound 9 (560 mg,1.9 mmol), 928mg (4 mmol) of 3-fluoropropyl para-toluenesulfonate and NaH (50 mg,4 mmol) was placed in 10ml of DMF and stirred at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in DMF and purified by chromatography (ether/hexane, 1/1) to give 425mg (50%) of oil. 1HNMR (CDCl 3) d2.0 (m, 2H), 3.8 (s, 6H), 4.0 (m, 2H), 4.3 (m, 2H), 5.0 (s, 2H), 7.3 (m, 5H), 7.4 (m, 2H).
Acid (15): this compound was synthesized from 570mg (1.64 mmol) of compound 14 and yielded 370mg (68%) of oil according to the described method 10. 1HNMR (CDCl 3) d2.0 (m, 2H), 3.7 (s, 3H), 3.9 (m, 2H), 4.4-4.5 (m, 2H), 5.0 (s, 2H), 7.3 (m, 5H), 7.4 (m, 2H).
l chloride ion (16): this compound was synthesized from compound 15 according to the procedure of 11 and used directly in the next reaction.
3- (3-Fluoropoxy) -4- (benzoyloxy) -N- ((1- (dimethyllamino) cyclopentyl) methyl) -5-methoxybenzamide (3). 3- (3-Fluoroepoxy) -4- (-benzyl) -5-methoxybenzoyl chloride 16 (409 mg, 1.16 mmol) in dry THF (10 mL) was added dropwise to a solution of 1-aminomethyl-1-dimethylcyclopentane 5 (210 mg, 1.5 mmol) and Et3N (151 mg, 1.5 mmol) in 15min. The reaction was warmed to room temperature and stirred overnight. The precipitate was removed and the residue was purified by chromatography (EtOAc/MEOH, 1/9) to give 174mg (34.3%) of oil. Dissolved in methanol and then excess hydrochloric acid was added to Et2 o. Evaporation to dryness produced the hydrochloride salt 3 as chewing gum. 1HNMR (CDCl 3) d1.4-1.6 (m, 8H), 1.9 (m, 2H), 2.1 (s, 6H), 3.4 (s, 2H), 3.7 (s, 3H), 4.0 (m, 2H), 4.4-4.5 (m, 2H), 5.0 (s, 2H), 7.1-7.3 (m, 7H)
4-benzamide: this compound was synthesized from 5 (168 mg,1.2 mmol) and 11 (2.46 g,8.5 mmol) according to procedure 3. Yield 188mg (41.0%); hydrochloride salt: chewing gum. 1HNMR (CDCl 3) d1.3 (m, 2H), 1.5 (m, 4H), 1.7 (m, 2H), 2.2 (s, 6H), 3.2 (s, 2H), 3.8 (s, 3H), 5.2 (s, 2H), 5.7 (s, 1H), 6.9 (m, 2H), 7.3-7.4 (m, 5H) analysis found C,65.90; h,7.39; n,6.22. Calculated as C23H31ClN2O4: c,63.51; h,7.18; n,6.44
Two-step/one-step radiofluorination and alkylation: the fluoride was formed by reaction with RDS-11-11211MeV anion cyclotron, 170 (% 18O,18O (p, n) 18F). The [18F ] fluoride aqueous solution was transferred to a 12 ml test tube (red top vacuum vessel 1, BD) containing a mixture of potassium carbonate (4 mg) and 222-22 (20 mg) and then dried by azeotropic distillation with acetonitrile (40.5 ml) at 1208C (oil bath) Ar (g). After cooling to room temperature, the residue was dissolved in 0.5ml of acetonitrile, 12mg of 1, 3-propanediol di-p-tosylate was added, the tube was sealed, and heated at 858C for 15min. The analysis was performed by HPLC analysis (10 ml). The radiofluoridation labeling yield was calculated from the area% of the radioactive peak at tR4.6min by comparison with the reference compound. The solvent was evaporated under the action of Ar (g). This residue is used directly for alkylation.
A solution of 4-methyl-benzamide hydrochloride (2) (5 mg) in N, N-dimethylformamide (DMF, 0.5 ml) and NaH (1.3 mg) was added, the tube was capped, and then heated to 1408C. The analysis was performed by HPLC analysis (10 ml). The alkylation yield was calculated from the area% of the radioactive peak at tR7.8 min. After alkylation was complete (after 30min of reaction), DMF was evaporated in 808C vacuum. The residue was dissolved with ethyl acetate (2 ml), extracted with water (3 ml), and then the organic layer was passed through a plug filled with sodium sulfate. The solvent was removed and the residue was redissolved in 300ml MeOH and purified by semi-preparative HPLC to collect the [18f ]3 corresponding fraction. After the solvent was removed on a rotary evaporator, the residue was dissolved in ethanol, and diluted with physiological saline to finally obtain a 10% ethanol-physiological saline solution.
The PET radioactive tracer [18F ]3 is synthesized by alkylation of a precursor 2 and 3- [18F ] fluoropropyl ester, and the radioactive ligand has high specific activity, high radiochemical purity and sufficient radiochemical yield and can be used for PET research of animals.
While the fundamental and principal features of the invention and advantages of the invention have been shown and described, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (4)

1. A PET radiotracer for imaging the glycine transporter Glyt2, characterized by: comprising
Using a fluoropropyl substituted benzamide analogue as a potential petgyt 2 radiotracer, radiolabelling the analogue by substituting one of the methoxy groups with a fluoroalkyl ether;
the saponification reaction of methyl ester is utilized to obtain asymmetric substituted acid, the latter half of the polymerization synthesis is condensed by using potassium cyanide and dimethylamine through the direct sequence of cyclopentanone to obtain aminobutyronitrile 4, and then the aminobutyronitrile is reduced by using aluminum hydride generated in situ to obtain diamine. The final assembly of the ligand is an ester 14 completed by the Williamson reaction between phenol and 3-fluoropropyl ester (by reaction of 3-chloro-1-propanol with potassium fluoride in ethylene glycol followed by esterification with p-toluenesulfonyl chloride pyridine), the methyl ester is hydrolyzed (acid 15), then converted to acid chloride ion and reacted with diamine to give the target ligand, acid 10 is converted to acid chloride with thionyl chloride 11 for the synthesis of phenolic precursors and reacted with diamine 5 in THF at room temperature;
the preparation method comprises the steps of synthesizing the 3- [18f ] fluoropropyl mesylate [18f ] serving as a marked intermediate by a two-step one-pot method, reacting the 3- [18f ] fluoropropyl mesylate [18f ] with 1, 3-propanediol in the presence of potassium carbonate and potassium carbonate-222 to obtain the 3- [18f ] fluoropropyl tosylate, wherein the marked radioactive intermediate is not separated, but directly undergoes alkylation reaction in the same pot after acetonitrile is evaporated.
2. A PET radiotracer for imaging the glycine transporter Glyt2 according to claim 1, characterized in that: alkylation was performed by heating 3- [18F ] fluoropropyl ester at 1408C in the presence of NaH for 30min, HPLC analysis of the reaction mixture showing two radioactive peaks corresponding to retention times of 3- [18F ] fluoropropyl mesylate and [18F ]3, respectively; sampling at the intermediate time points indicated an initial rapid rate of alkylation followed by a slow increase to 30min.
3. A PET radiotracer for imaging the glycine transporter Glyt2 according to claim 1, characterized in that: for SPE, the reaction mixture was added to water and the aqueous mixture passed through a cartridge, washed with water, and the radioactive product eluted with methanol.
4. A PET radiotracer for imaging the glycine transporter Glyt2 according to claim 1, characterized in that: the recovery of ethyl acetate to extract [18f ]3 from the aqueous reaction mixture was 40%; after evaporation of ethyl acetate, the residue was dissolved in methanol and the crude product was purified by semi-preparative HPLC with a total radiochemical yield of [18f ]3 of 14-16% and a total synthesis time of about 128min, and by HPLC UV analysis, [18F ]3 had a radiochemical purity of >98% and a specific activity of 1462342GBq/mmol; stability tests showed that it was stable at 60 min.
CN202210775862.6A 2022-07-02 2022-07-02 PET radioactive tracer for imaging glycine transporter Glyt2 Pending CN117362192A (en)

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