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2-aryl benzothiazole compound with high affinity with a(BETA) plaque and preparation method and application thereof

A benzothiazole and compound technology, applied in the field of 2-arylbenzothiazole compounds, can solve the problem of lack of Aβ molecular probes, and achieve the effect of low initial brain uptake and fast blood clearance

Inactive Publication Date: 2014-01-08
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, SPECT (single photon emission computed tomography) imaging agents have not had an effective Aβ molecular probe due to limitations in the amount of brain into the brain or other in vivo properties.

Method used

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  • 2-aryl benzothiazole compound with high affinity with a(BETA) plaque and preparation method and application thereof
  • 2-aryl benzothiazole compound with high affinity with a(BETA) plaque and preparation method and application thereof
  • 2-aryl benzothiazole compound with high affinity with a(BETA) plaque and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1B

[0058] The synthesis of embodiment 1BTDPA and BTIDA compounds

[0059] 1. Synthetic intermediate 1

[0060] The compound 2-(4-(methylamino)phenyl)benzothiazole-6-hydroxyl (259.9mg, 1.0mmol) and K 2 CO 3 (429.9mg, 3.1mmol) was dissolved in 20mL of acetonitrile, after reflux reaction at 90°C for 2h, 1,3-dibromopropane (606.7mg, 2.7mmol) was added, and the reaction was continued for 3h, the solvent was rotary evaporated, and dichloromethane was added for suction filtration Potassium carbonate was removed, spin-dried, and petroleum ether was added to precipitate a pale yellow solid. The product was obtained by suction filtration. The structure was as follows, and the yield was 79.8%. 1 H NMR (400MHz, CDCl 3 )δ7.88(d,J=8.7Hz,2H),7.86(d,J=8.8Hz,1H),7.33(d,J=2.4Hz,1H),7.04(dd,J=8.9,2.5Hz, 1H), 6.65(d, J=8.7Hz, 2H), 4.17(t, J=5.8Hz, 2H), 3.64(t, J=6.4Hz, 2H), 2.91(s, 3H), 2.36(p, J=6.1Hz, 2H).

[0061]

[0062] 2. Synthetic intermediate 2

[0063] Intermediate 2 is prepared ...

Embodiment 2

[0145] Preparation of Example 2 Tc-99m-labeled BTDPA and BTIDA Compounds

[0146] The BTDPA and BTIDA compounds prepared in the above examples of the present invention can be labeled with the radionuclide Tc-99m by conventional methods in the prior art. For example, the compounds BT-3-IDA-Re, BT-5-DPA-Re and BT-6-IDA-Re will be described as examples.

[0147] The reaction route between Tc-99m-labeled BTDPA and BTIDA is as follows:

[0148]

[0149] 29. Labeled compound BT-5-DPA-Re

[0150] Put 5mg of sodium borohydride, 4mg of sodium carbonate and 20mg of sodium potassium tartrate into a 10mL penicillin vial, seal it, and vent the air with CO gas for 15min, add 3mL of sodium pertechnetate eluent, and place it in a water bath at 75°C for 30min , cooled to room temperature. Take 1mL [ 99m Tc(CO) 3 (H 2 O) 3 ] + Add 10mL of penicillin vial to adjust the pH value to about 7, then add 0.5mg of labeled intermediate 15, add appropriate amount of ethanol to dissolve it, pla...

Embodiment 32

[0153] Example 32-Effect experiment of arylbenzothiazole compounds

[0154] The compounds of the present invention are evaluated for their affinity through competition binding experiments and autoradiography experiments to fully verify their high affinity to Aβ plaques. The initial brain uptake and brain clearance of labeled compounds were evaluated by in vivo biodistribution experiments in normal mice.

[0155] 1. Competitive binding experiments

[0156] Competitive binding experiments (K i Determination): a certain concentration of Aβ 1-42 Aggregate protein with a certain concentration of radioligand [ 125 I] IMPY binding reaction occurs, and the compound to be tested of different concentrations is added simultaneously in the reaction system (respectively compound BT-3-DPA-Re, BT-5-DPA-Re, BT-3-Re, prepared in embodiment 1 and 2 IDA-Re~BT-6-IDA-Re, BTs-3-IDA-Re~BTs-6-IDA-Re) and [ 125 I] IMPY competes with each other, and the complex is separated after equilibrium to ca...

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Abstract

The invention provides a 2-aryl benzothiazole compound with high affinity with A(beta) plaque and a preparation method and application thereof. The structure of the compound is shown by formula (I). In-vitro competitive binding experiments indicate that the kind of molecules have medium affinity with the A(beta) 1-42 aggregate; in-vitro autoradiography experiments indicate that the molecules marked by Tc-99m can be combined with the A(beta) plaque in blood vessels of the brain with specificity and high affinity; in-vivo bio-distribution experiments on a normal mice indicate that a developer partially marked by Tc-99m has the advantages of low initial brain extraction, fast blood removal and the like, and is expected to become a new single-photon A(beta) plaque developer for early-stage clinical diagnosis of CAA (cerebral amyloid angiopathy) or AD (Alzheimer's disease).

Description

technical field [0001] The invention relates to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine, in particular to a 2-arylbenzothiazole compound with high affinity with Aβ plaque, its preparation method and application. Background technique [0002] Abnormal deposition of β-amyloid protein is the culprit of many diseases, among which Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are all related to abnormal deposition of β-amyloid protein. Studies have shown that CAA is characterized by the deposition of β-amyloid (Aβ) on the cerebrovascular wall, which has obvious overlap with Alzheimer's disease (AD), and based on autopsy studies of AD and CAA patients, The Aβ plaque deposition in the brain of AD patients mainly exists in the brain parenchyma and cerebral cortex, while the Aβ plaque in CAA patients mainly deposits in the pia mater and cortical arterial vessel wall. [0003] Alzheimer's disease (Alzheimer's Disease, AD) i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F13/00A61K51/00A61K49/06A61P25/00A61P25/28A61K103/10
Inventor 崔孟超刘伯里贾建华
Owner BEIJING NORMAL UNIVERSITY
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