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Novel deuterium substituted positron emission tomography (PET) imaging agents and their pharmacological application

A technology of pharmacy and deuterium atoms, which is applied in the direction of radioactive preparations in vivo, echo chromatography, drug combination, etc.

Active Publication Date: 2020-01-10
FIVE ELEVEN PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the differences in physical and chemical properties between hydrogen and deuterium are relatively small (Meanwell, J. Med. Chem. 2011, 54:2529-91), deuterated compounds can respond to biological and chemical processes optimally developed by hydrogen Significant impact

Method used

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  • Novel deuterium substituted positron emission tomography (PET) imaging agents and their pharmacological application
  • Novel deuterium substituted positron emission tomography (PET) imaging agents and their pharmacological application
  • Novel deuterium substituted positron emission tomography (PET) imaging agents and their pharmacological application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0234] Synthesis of Compound Ia

[0235] Option 6

[0236]

[0237] Synthesis of compound Ia-2: (2R,3R,11R)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1- a] Isoquinoline-2,9-diol

[0238] A mixture of 9-benzyl protected DTBZ (Ia-1, 380 mg, 0.96 mmol) and 10% dry Pd / C (15 mg) in THF (10 mL) and EtOH (5 mL) was dissolved in H 2 Stirring was continued for 6 hours. The reaction mixture was filtered and washed with EtOH (10 mL) and THF (10 mL). The solvent was removed in vacuo to afford Ia-2 (255 mg, 87%) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )δ6.68(s,1H),6.67(s,1H),3.87(s,3H),3.44-3.38(m,1H),3.16-2.97(m,4H),2.66-2.56(m,2H) ,2.49-2.42(m,1H),1.99(t,J=2.01Hz,1H),1.79-1.68(m,2H),1.57-1.45(m,3H),1.12-1.05(m,1H),0.97 -0.93(m,6H). C 18 h 27 NO 3 [M+H] + The HRMS calculated value is 306.2069 and the measured value is 306.2100.

[0239]

[0240] Synthesis of Compound Ia-4: [1,1,2,2,3,3-D 6 ]-propane-1,3-diylbis(4-methylbenzenesulfonate)

[0241] To a...

Embodiment 2

[0251] In Vitro Binding Assay for Ki Determination of AV-133 Relative to AV-133-D6 (Ia)

[0252] Tissue homogenates of striatum (excised from rat brains) were prepared in 50 mM HEPES (pH 7.5) and 0.3 M sucrose. Check compound in 10 -7 to 10 -12 Competing for binding in the M concentration range 18 F-AV-133 or 18 F-AV-133-D6( 18 F-Ia) (0.15-0.2 nM) capacity. Binding assays were performed in glass tubes (12 x 75mm) with a final volume of 0.25 mL. Non-specific binding was defined with 10 μM (±)-tetrabenazine (TBZ). After incubation at room temperature for 90 min, bound ligand was separated from free ligand by filtration through a glass fiber filter. Wash the filter three times with 4 mL of ice-cold PBS buffer (pH 7.4), and use a gamma counter (WIZARD 2 , Perkin-Elmer) counted the radioactivity on the filter. Data were analyzed to determine IC using the nonlinear least squares curve fitting program LIGAND 50 , and Ki was calculated by the Cheng-Prusoff equation using 0.1...

Embodiment 3

[0259] Comparison of FP-DTBZ biodistribution data in rats: 18 F-FP-(+)DTBZ vs. 18 F-FP-DTBZ-D6( 18 F-Ia)

[0260]

[0261] Three rats per group were used for each biodistribution study. Under isoflurane anesthesia, inject 0.2 mL of saline solution containing 20 μCi of radiotracer into the femoral vein. Rats were sacrificed by cardiotomy under isoflurane anesthesia at the indicated times. The target organ is removed and weighed, and the radioactivity is counted. Percentage of dose for each organ was calculated by comparing tissue counts to counts measured simultaneously at 1% of the initial dose (100-fold diluted aliquot of injected material). Brain regional distribution was measured in rats following intravenous injection of the radiotracer. Samples from different brain regions (cortex, striatum, hippocampus, cerebellum and hypothalamus) were dissected, weighed and counted. Calculate the percent dose / g for each sample by comparing the sample counts to the counts for ...

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PUM

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Abstract

The present invention relates to deuterated compounds according to Formula I-A, Formula II-A, Formula II-D, and Formula III-A. These compounds can be used as PET imaging agents for evaluating Parkinson's Disease, Alzheimer Disease, and for determining specific serotonin reuptake inhibitor (SSRIi) activity for treatment of depression. The present invention also relates to pharmaceutical compositions comprising a pharmaceutical acceptable carrier and a compound of Formula I-A, Formulae II-A, Formula II-D, or Formula III-A, or a pharmaceutically acceptable salt thereof.

Description

[0001] Background of the invention [0002] Deuterium (D) is a stable isotope of hydrogen (H). Although the differences in physical and chemical properties between hydrogen and deuterium are relatively small (Meanwell, J. Med. Chem. 2011, 54:2529-91), deuterated compounds can respond to biological and chemical processes optimally developed by hydrogen Significant impact. The lipophilicity of deuterium substitution is slightly lower than that of hydrogen, ΔlogP=-0.006, and the molar volume of deuterium is 0.140cm smaller than that of hydrogen 3 / mol / per atom. Carbon-deuterium (C-D) bonds are shorter than carbon-hydrogen (C-H) bonds The activation energy for breaking a C-D bond is thus significantly higher relative to a C-H bond. Functionally, this would reduce the cleavage rate of C–D bonds by a factor of 6.7 compared to that of C–H bonds (Kuchar, Molecules 2015, 20:16186-220), which could have a profound impact on drug pharmacokinetic properties. [0003] Recent reports on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/06C07F7/10
CPCA61K51/0455C07B2200/05C07D213/63C07D213/64C07C217/80C07C271/28C07B59/00A61K51/0406A61K51/04C07B59/001C07B59/002C07D405/04C07D471/04C07C323/37A61K51/0453C07D277/66C07D221/06A61K51/0419C07B59/004A61B6/037A61K51/0431
Inventor 吴泽辉查智豪刘福涛K·普莱索S·R·崔H·F·孔
Owner FIVE ELEVEN PHARMA INC
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