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Compound provided with good affinity and tangled with Abeta plaque and nerve fiber and preparation method thereof

A neurofibrillary tangles and compound technology, which is applied in the preparation of organic compounds, cyanide reaction preparation, chemical instruments and methods, etc., can solve the problems of large molecular weight, weak Aβ plaque affinity, and complex compound synthesis.

Active Publication Date: 2014-11-12
BEIJING NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2-Phenylimidazopyridine derivatives[ 123 I]IMPY was the first SPECT imaging agent to enter the clinical stage, but it was quickly eliminated due to its poor stability in vivo
The first reported near-infrared fluorescent molecular probe targeting Aβ plaques is AOI-987, but it has obvious shortcomings: First, the synthesis of this compound is relatively complicated; second, the molecule is charged, which is not conducive to passing through the blood-brain barrier. Weak affinity for Aβ plaques (K d =220nM); Finally, the Stokes shift is only 20nm, which is not conducive to imaging
In 2005, NIAD-4 was reported. Although this molecule meets the general requirements, it has high fat solubility due to two thiophene rings, and its ability to penetrate the blood-brain barrier is limited.
Similarly, the recently reported CRANAD-2 (curcumin derivative) and BODIPY-1 also have the disadvantages of large molecular weight, high fat solubility, and low brain uptake.

Method used

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  • Compound provided with good affinity and tangled with Abeta plaque and nerve fiber and preparation method thereof
  • Compound provided with good affinity and tangled with Abeta plaque and nerve fiber and preparation method thereof
  • Compound provided with good affinity and tangled with Abeta plaque and nerve fiber and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 Synthesis of derivatives based on naphthalene ring

[0055] 1. Synthetic intermediate 1

[0056] After 5.5 g of 6-bromo-2-naphthol was dissolved in 35 mL of dimethylamine aqueous solution (33%), 8.2 g of Na 2 S 2 o 5 , reacted in a 140°C autoclave for 18 hours. After stopping the reaction, ultrasonically wash with NaOH aqueous solution (1M) for 15 minutes, filter with suction, then wash the solid with NaOH aqueous solution (1M) and deionized water respectively, and dry at 70°C to obtain 4.4 g of light green solid. The yield is 65.8%, and the structure is as follows: 1 H NMR (400MHz, CDCl 3 )δ:7.83(s,1H),7.62(d,J=9.0Hz,1H),7.53(d,J=8.7Hz,1H),7.42(d,J=8.8Hz,1H,7.19(d,J =8.0Hz, 1H), 6.92(s, 1H), 3.06(s, 6H).

[0057] 2. Synthetic intermediate 2

[0058] After dissolving 11.4g of intermediate 1 in 50mL of anhydrous tetrahydrofuran, add 27.5mL of n-butyllithium (2.5M n-hexane solution) under nitrogen protection at -78°C, and stir for 30 minutes; then add 5....

Embodiment 2

[0128] Example 2 Synthesis of Molecular Probes Based on Benzene Rings

[0129] 37. Synthetic intermediate 37

[0130] 4-Dimethylaminocinnamaldehyde (578mg, 3.3mmol) and (1,3-dioxolanyl-2-methyl)triphenylphosphine bromide (1.36g, 3.2mmol) were dissolved in 25mL of anhydrous THF , 70 ° C reflux reaction 2h. Concentrated hydrochloric acid was added to the reaction system, and then the pH was adjusted to 7 with ammonia water. CH 2 Cl 2 The aqueous phase was extracted three times, the organic phase was dried over anhydrous magnesium sulfate, the solvent was removed by rotary evaporation, and column separation (petroleum ether: ethyl acetate = 4:1, volume ratio) gave a yellow solid (139 mg, 46.0%). 1 H NMR (400MHz, CDCl 3 )δ: 9.56(d, J=8.1Hz, 1H), 7.41(d, J=8.9Hz, 2H), 7.32-7.21(m, 1H), 6.95(d, J=15.3Hz, 1H), 6.82( dd, J = 15.3, 10.9 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.18 (dd, J = 15.0, 8.1 Hz, 1H), 3.03 (s, 6H).

[0131] 38. Synthesis of compound 38 (MAAD-1)

[0132] 4-Dim...

Embodiment 3

[0188] Example 3 Effect Experiment of Fluorescent Probe Molecules

[0189] 1. Determination of excitation and emission spectra of fluorescent probe molecules

[0190] 1.1 Experimental steps

[0191] (1) prepare the dichloromethane solution of compound, concentration is 10 -3 mol / L (1 mmol / L).

[0192] (2) Preparation of compound organic solution. Take 30 μL of the above solution and dilute to 3 mL with different organic solvents such as dichloromethane, tetrahydrofuran, methanol and DMSO to obtain a 10 μM solution.

[0193] (3) Preparation of compound PBS solution. Take 6 μL of the mother solution in step (1) with a microsampler, volatilize the dichloromethane, add 50 μL DMSO to dissolve the compound, then add 250 μL ethanol, add PBS buffer solution to 3 mL, and finally obtain a 2 μM PBS solution of the compound (containing 10 % ethanol).

[0194] (4) Fluorescence excitation and emission spectra of compounds were measured and recorded with RF-5301PC fluorescence spectrom...

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Abstract

The invention provides a compound provided with good affinity and tangled with an Abeta plaque and a nerve fiber. The structural general formula (I) of the compound is as shown in the specification, wherein W is a benzo-hexahydric aromatic ring or a hexahydric aromatic ring; R1 and R2 independently represent CH3, 11CH3, aryl, heteroaryl or (CH2)n'R4; n' is 2-6; R4 is H, OH, F or Cl; F is 18F or 19F; R3 is as shown in the specification; n is 0-5; and carbon-carbon double bonds are trans double bonds. The invention also provides a preparation method and an application of the compound. The compound can be directly used as a near-infrared probe for detecting entanglement of amyloid protein sediments and the nerve fiber in a body or a tissue sample, and needs to be marked by appropriate radioactive isotopes when being applied to nuclear medicine imaging. The compound is especially suitable for diagnosis of patients with the disease of entanglement of the amyloid protein sediments and the nerve fiber, including the alzheimer disease.

Description

technical field [0001] The invention relates to the field of imaging molecular probes, in particular to a compound with affinity to Aβ plaques and neurofibrillary tangles and a preparation method. Background technique [0002] Alzheimer's disease (AD), the most common form of dementia, has become the fourth leading killer after heart disease, tumor and stroke. At present, there are more than 5 million AD patients in our country, and with the aggravation of aging in our country, AD will become one of the main diseases affecting the health of the elderly. Research around AD mainly includes pathology, diagnosis, treatment and prevention, which has become an important disease research topic in the world. Amyloid deposition (Aβ protein) and neurofibrillary tangles are two major pathological features of AD. Studies have shown that Aβ protein deposition in the brain begins 5-10 years before the onset of AD, so the development of small molecule probe imaging agents targeting Aβ pr...

Claims

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Application Information

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IPC IPC(8): C07C255/42C07C253/30C07C221/00C07C225/22C07C227/10C07C229/44C07D319/06C09K11/06A61K49/00A61K51/04A61K101/02
Inventor 崔孟超刘伯里付化龙
Owner BEIJING NORMAL UNIVERSITY
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