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Development and application of PDE10A receptor targeted positron drug [18F] P10A-1910

A P10A-1910, drug technology, applied in the field of positron drugs, can solve problems such as instability

Active Publication Date: 2022-02-18
THE FIRST AFFILIATED HOSPITAL OF JINAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This patent is to solve the existing PDE10A radioactive probe [ 18 F] MNI-659 is unstable in vivo, and a probe for the structure of a novel arylfluorobenzopyrimidine derivative was designed[ 18 F] P10A-1910, and synthesized pinacol precursor Pre1 and spirocyclic hypervalent iodine ylide precursor Pre2, through effective radioactivity 18 F labeling method, both methods synthesized novel PDE10A-targeted radiopharmaceuticals in high yield[ 18 F] P10A-1910

Method used

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  • Development and application of PDE10A receptor targeted positron drug [18F] P10A-1910
  • Development and application of PDE10A receptor targeted positron drug [18F] P10A-1910
  • Development and application of PDE10A receptor targeted positron drug [18F] P10A-1910

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Synthesis of Labeled Precursor Pre1

[0039] The synthetic route of the labeled precursor Pre1 can refer to Nucl.Med.Biol.2017, 55, 12-18., as follows:

[0040]

[0041] Starting from the raw material compound 3-hydroxyphthalic anhydride 1 (4.9g, 30mmol), using triethylamine (90mmol) as the base, under the heating condition of 50°C, in 1,4-dioxane (60mL) solvent React overnight with the compound β-alanine tert-butyl ester hydrochloride 2 (33mmol). After the reaction, add water to quench the reaction, extract with ethyl acetate, and spin dry to obtain a white solid 3 with a yield of 33%, which can be directly proceed to the next reaction. The crude hydrogen spectrum of compound 3 is 1 H NMR (400MHz, CDCl 3 )δ: 7.58–7.53(m, 1H), 7.36(d, J=7.2Hz, 1H), 7.15(d, J=8.4Hz, 1H), 3.89(t, J=7.3Hz, 2H), 2.63( t,J=7.3Hz,2H), 1.40(s,9H).

[0042] With acetonitrile (50mL) as the reaction solvent, compound 3 (2.9g, 10mmol) and 2-iodopropane (20mmol) were mixed in Cs ...

Embodiment 2

[0046] Example 2 Synthesis of Labeled Precursor Pre2

[0047]

[0048] Compound 8 (120 mg, 0.2 mmol) was dissolved in TFA (1.0 mL) and CHCl 3 (0.3mL), the oxidizing agent oxone (184mg, 0.3mmol) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction, the solvent in the reaction system was removed under reduced pressure. Dissolve the resulting solid with ethanol (5 mL), add 10% Na 2 CO 3 (0.5mL) dissolved SPIAd (95mg, 0.4mmol) in aqueous solution, and continued with 10% Na 2 CO 3 The aqueous solution adjusted the pH value of the reaction system to 9, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction was quenched by adding water, extracted with dichloromethane, and separated by flash column chromatography to obtain a white solid Pre2 with a yield of 72%. 1 H NMR (400MHz, DMSO) δ: 7.95(t, J=8.6Hz, 3H), 7.70(t, J=7.9Hz, 1H), 7.61(d, J=8.5Hz, 2H), 7.42(d, J =8.6Hz,1H),7.36–7.29(m,3H),4.78(p,J=...

Embodiment 3

[0049] Example 3 Synthesis of Standard Substance Inhibitor P10A-1910

[0050]

[0051] With pyridine (10mL) as the reaction solvent, compound 5 (500mg, 0.8mmol), triphenyl phosphite (1.2mmol) and 2-amino-4-methylbenzoic acid 6 (0.8mmol) were mixed under heating conditions at 100°C. ) was reacted for 4 hours, then cooled to room temperature, under the protection of nitrogen, 4-fluoroiodobenzene 9 (0.88 mmol) was added and reacted at 100°C for 4 hours. After the reaction, it was cooled to room temperature, the solvent pyridine was spun off, and a white solid P10A-1910 was obtained by flash column chromatography with a yield of 48%. 1 H NMR (300MHz, CDCl 3 )δ:8.12(d,J=8.1Hz,1H),7.58(dd,J=8.5,7.3Hz,1H),7.40(s,1H),7.35(dd,J=7.3,0.7Hz,1H), 7.32–7.26(m,3H),7.24–7.17(m,2H),7.17–7.13(m,1H),4.69(hept,J=6.1Hz,1H),4.10–4.02(m,2H),2.78( t,J=7.2Hz,2H),2.47(s,3H),1.39(s,3H),1.37(s,3H).

[0052] Two, positron drug in the present invention [ 18 F] Preparation method of P10A-1910

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Abstract

The invention relates to development and application of a PDE10A receptor targeted positron drug [18F] P10A-1910. The structure of the [18F] P10A-1910 is obtained by reacting a labeled precursor compound Pre1 or Pre2 with fluorine-18 negative ions in an organic solvent, and the structures of Pre1 and Pre2 are as shown in the specification.

Description

technical field [0001] The invention belongs to the field of positron drugs and relates to PDE10A receptor-targeted positron drugs [ 18 F] The development and application of P10A-1910, specifically related to the preparation and synthesis of the radiopharmaceutical and related labeling precursors, as well as the neuroimaging of live animals. Background technique [0002] Phosphodiesterase (PDEs) is a multigene family encoded by 21 genes, which are widely distributed in the central nervous system and peripheral nerves. Through hydrolysis, this family of enzymes can reduce the intracellular metabolic levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The 11 subfamilies of the PDE family can be divided into three categories according to the different selectivity to cAMP and cGMP: 1) cAMP-specific PDEs, such as PED4, 7 and 8; 2) cGMP-specific PDEs, such as PDE5, 6 and 9 3) cAMP and cGMP dual-specific PDEs, such as PDE1, 2, 3, 10 and 11. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D405/14C07F5/02C07B59/00A61K51/04A61K31/517A61K31/69A61P25/18A61P25/16A61P25/08A61P25/14A61K101/02
CPCC07D403/06C07D405/14C07F5/025C07B59/002A61K51/0459A61K31/517A61K31/69A61P25/18A61P25/16A61P25/08A61P25/14C07B2200/05Y02P20/55
Inventor 王璐肖智伟黎国聪魏俊杰朱鸿浩侯露蔡其君张玲玲徐浩
Owner THE FIRST AFFILIATED HOSPITAL OF JINAN UNIV