Microtubule-associated protein Tau imaging compounds for Alzheimer's disease and precursors thereof

Abstract

The present invention discloses a series of nuclear medicine tracers that are combined with brain microtubule-associated protein Tau targeting compounds to produce a group of compounds of nuclear medicine that can be utilized for imaging of microtubule-associated protein Tau. When the positrons released by the decay encounter the electrons of the cells in the sample, utilizing the positron decay characteristics of fluorine-18 or iodine-124 isotope to generate mutual destruction reactions, a pair of opposite gamma rays is formed which are imaged by positron emission tomography. The compounds can be applied for the in vivo detection of microtubule-associated protein Tau deposits in the brain. The invention provides a strategy for diagnosis of Alzheimer's disease and a method to measure the efficacy of therapeutic drugs targeting microtubule-associated protein Tau.

Claims

1. A pharmaceutical compound of formula 1 or a pharmaceutically acceptable salt thereof, ##STR00020## wherein R1 is a molecule selected from the group consisting of H, I, .sup.123I, .sup.124I, .sup.125I, and .sup.131I; R2 is a molecule selected from the group consisting of H, I, .sup.123I, .sup.124I, .sup.125I, and .sup.131I; and R3 is a molecule selected from the group consisting of H, 2-p-toluenesulfonyloxypropoxyl, 2-fluoropropoxyl, [F-18]2-fluoropropoxyl, 2-p-toluenesulfonyloxyethoxyl, 2-fluoroethoxyl, [F-18]2-fluoroethoxyl, 2-p-toluenesulfonyloxymethoxyl, and 2-fluoromethoxyl, [F-18]2-fluoromethoxyl, wherein at least one of R1, R2 and R3 is not H.

2. The pharmaceutical compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is H; R2 is H; and R3 is a molecule selected from the group consisting of 2-p-toluenesulfonyloxypropoxyl, 2-fluoropropoxyl, [F-18]2-fluoropropoxyl, 2-p-toluenesulfonyloxyethoxyl, 2-fluoroethoxyl, [F-18]2-fluoroethoxyl, 2-p-toluenesulfonyloxymethoxyl, 2-fluoromethoxyl, and [F-18]2-fluoromethoxyl, wherein the structure of the molecule is shown with the following codes: TABLE-US-00001 Code IUPAC Structure INER-TAU- R3-OTs 7-(2-p- toluenesulfonyloxy- propoxy)-3-(2H- isoindol-2-yl) isoquinoline INER-TAU- R3 7-(2-fluoropropoxy)- 3-(2H-isoindol-2-yl) isoquinoline .sup.18F-INER- TAU-R3 [F-18]7-(2- fluoropropoxy)-3- (2H-isoindol-2-yl) isoquinoline INER-TAU- R2-OTs 7-(2-p- toluenesulfonyloxy- ethoxy)-3-(2H- isoindol-2-yl) isoquinoline INER-TAU- R2 7-(2-fluoroethoxy)-3- (2H-isoindol-2-yl) isoquinoline .sup.18F-INER- TAU-R2 [F-18]7-(2- fluoroethoxy)-3-(2H- isoindol-2-yl) isoquinoline INER-TAU- R1-OTs 7-(2-p- toluenesulfonyloxy- methoxy)-3-(2H- isoindol-2-yl) isoquinoline INER-TAU- R1 7-(2-fluoromethoxy)- 3-(2H-isoindol-2-yl) isoquinoline .sup.18F-INER- TAU-R1 [F-18]7-(2- fluoromethoxy)-3- (2H-isoindol-2-yl) isoquinoline

3. The pharmaceutical compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is H; R3 is H; and R2 is a molecule selected from the group consisting of I, .sup.123I, .sup.124I, .sup.125I, and .sup.131I, wherein the structure of the molecule is shown with the following codes: TABLE-US-00002 Code IUPAC Structure INER- TAU-I1 6-iodo-3-(2H- isoindol-2-yl) isoquinoline .sup.123I-INER- TAU-I1 [.sup.123I]6-iodo-3-(2H- isoindol-2-yl) isoquinoline .sup.124I-INER- TAU-I1 [.sup.124]6-iodo-3-(2H- isoindol-2-yl) isoquinoline .sup.125I-INER- TAU-I1 [.sup.125I]6-iodo-3-(2H- isoindol-2-yl) isoquinoline .sup.131I-INER- TAU-I1 [.sup.131I]6-iodo-3-(2H- isoindol-2-yl) isoquinoline

4. The pharmaceutical compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is H; R3 is H; and R1 is a molecule selected from the group consisting of I, .sup.123I, .sup.124I, .sup.125I, and .sup.131I, wherein the structure of the molecule is shown with the following codes: TABLE-US-00003 Code IUPAC Structure INER- TAU-I2 5-iodo-3-(2H- isoindol-2- yl)isoquinoline .sup.123I-INER- TAU-I2 [.sup.123I]5-iodo-3- (2H-isoindol-2- yl)isoquinoline .sup.124I-INER- TAU-I2 [.sup.124I]5-iodo-3- (2H-isoindol-2- yl)isoquinoline .sup.125I-INER- TAU-I2 [.sup.125I]5-iodo-3- (2H-isoindol-2- yl)isoquinoline .sup.131I-INER- TAU-I2 [.sup.131I]5-iodo-3- (2H-isoindol-2- yl)isoquinoline

5. A pharmaceutical composition comprising the pharmaceutical compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. A method for producing the pharmaceutical compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising the synthesis steps of: ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##

7. A method of Tau protein imaging in a biological sample using the pharmaceutical composition of claim 5, comprising the steps of: providing a cell and/or a tissue and/or an organ sample from a subject, contacting said sample with the pharmaceutical composition of claim 5, imaging said sample, wherein deposits of microtubule-associated protein Tau in said sample is detected.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 is a radio-TLC (radioactive thin layer chromatography) analysis diagram of the microtubule-associated protein Tau compound 29 of the present invention, in which the thin layer sheet Silica gel 60 F254 (Merck brand) is used for the radio-TLC analysis, the mobile phase is dichloromethane:methanol, the ratio is 80:20. The sample of compound 29 was spotted on the thin layer chromatographic sheet and use the mobile phase to elute, and the chromatographic sheet after elution was then analyzed with a radio-TLC imaging scanner (Brand BIOSCAN), and the mobile ratio of compound 29 (Ratio of flow, Rf) is about 0.8.

[0022] FIG. 2 is a radio-HPLC (radio-High Performance Liquid Chromatography) analysis diagram of the microtubule-associated protein Tau compound 29 of the present invention, in which the radio-HPLC (Waters brand) uses the column XSelect HSS T3 3.5 μm, and the mobile phase is a gradient from 60% acetonitrile plus 0.1% trifluoroacetic acid to 90% acetonitrile plus 0.1% trifluoroacetic acid in 30 minutes at a flow rate of 0.8 ml per minute, using a radioactive detector (BIOSCAN brand). The results of the analysis of the compound 29 sample by radio-HPLC showed that the retention time of its main peak was at about 22.503 minutes.

[0023] FIG. 3 is an image of the microtubule-associated protein Tau compound 29 of the present invention in P301L gene transgenic mice and control mice using positron emission tomography (nano PET/CT) analysis, in which P301L gene transgenic mice (source: United States JACKSON Research Center) refers to the mutation of proline to leucine at codon 301 of the encoded microtubule-associated protein Tau. These types of mutations can accelerate the formation of neurofibrillary tangles. P301L gene transgenic mice and control mice were injected through the tail vein with 0.46 millicuries (mCi) of compound 29 of the present invention, and after 30 minutes of distribution, radiography was performed on the mice using a positron emission tomography scanner (BIOSCAN). The image results showed that the drug accumulation of P301L in the brain of gene transgenic mice (A) was significantly greater than that of control mice (B).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Embodiment 1

Synthesis of INER-TAU-I1 Series Compounds

[0024] Synthesis of precursor 6-iodo-3-(2H-isoindol-2-yl) isoquinoline, comprising:

[0025] 1. Adding the compound 1, 6-fluoro-3-(2H-isoindol-2-yl) isoquinoline 9.5 mmole, to a saturated solution of ammonia dissolved in methanol, stirring and being reacted for 5 days at 120° C. to obtain compound 2, 3-(2H-isoindol-2-yl) isoquinoline-6-amine: MS (mass spectrometry) (m/z) 260.1 [M+H].sup.+.

[0026] 2. Suspending compound 2 in water, adding concentrated sulfuric acid at room temperature and heating to 70-80° C. to obtain a clear solution, and the mixed solution was cooled to 0° C. and sodium nitrate was added and reacted at 0° C. for 15 minutes, then potassium iodide, in which molar ratio of compound 2:sodium nitrate:potassium iodide=1:1.98:1.98, was added and reacted for 5 minutes to obtain compound 3, 6 iodo-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 371.0 [M+H].sup.+, as shown:

##STR00001##

[0027] Synthetic of tracer [.sup.123I]6-iodo-3-(2H-isoindol-2-yl) isoquinoline:

[0028] Adding sodium iodide ([.sup.123I]NaI) in 0.01N NaOH and Na.sub.2S.sub.2O.sub.5 to the reaction flask and is dried with nitrogen at 100° C., adding compound 3 dissolved in acetic acid and cuprous sulfate solution and reaction at 180° C. for 10 minutes, and after being re-dissolved in ethanol the compound 4 is obtained, as shown:

##STR00002##

[0029] Synthesis of tracer [.sup.124I]6-iodo-3-(2H-isoindol-2-yl) isoquinoline:

[0030] Sodium iodide ([.sup.124I]NaI) in 0.01N NaOH and Na.sub.2S.sub.2O.sub.5 was added to the reaction flask and dried with nitrogen at 100° C., then compound 3 dissolved in acetic acid and cuprous sulfate solution were added and reacted at 180° C. for 10 minutes, and after being re-dissolved in ethanol and purification the compound 5 is obtained:

##STR00003##

[0031] Synthesis of tracer [.sup.125I]6-iodo-3-(2H-isoindol-2-yl) isoquinoline:

[0032] Sodium iodide ([.sup.125I]NaI) in 0.01N NaOH and Na.sub.2S.sub.2O.sub.5 was added to the reaction flask and dried with nitrogen at 100° C., then compound 3 dissolved in acetic acid and cuprous sulfate solution were added and reacted at 180° C. for 10 minutes, and after being re-dissolved in ethanol and purification the compound 6 is obtained:

##STR00004##

[0033] Synthesis of tracer [.sup.131I]6-iodo-3-(2H-isoindol-2-yl) isoquinoline:

[0034] Sodium iodide ([.sup.131I]NaI) in 0.01N NaOH and Na.sub.2S.sub.2O.sub.5 was added to the reaction flask and dried with nitrogen at 100, then compound 3 dissolved in acetic acid and cuprous sulfate solution were added and reacted at 180° C. for 10 minutes, and after being re-dissolved in ethanol and purification the compound 7 is obtained:

##STR00005##

Embodiment 2

Synthesis of INER-TAU-I2 Series Compounds

[0035] Synthesis of precursor 5-iodo-3-(2H-isoindol-2-yl)isoquinoline, comprising:

[0036] 1. 3-chloroisoquinolin-5-amine compound 8 is dissolved in dichloromethane, and triethylamine and di-tert-butyl dicarbonate were added, in which molar ratio of compound 8:triethylamine:di-tert-butyl dicarbonate=1:2:1.2, the mixture was reacted at room temperature for 3 hours, and then concentrated and purified under reduced pressure to obtain compound 9, tert-butyl (3-chloroisoquinolin-5-yl) carbamate: MS (m/z) 279.1 [M+H].sup.+.

[0037] 2.3H-Indole and compound 9 were dissolved in tetrahydrofuran and added sodium 2-methylpropan-2-olate and t-BuXPhos palladium(II) biphenyl-2-amine mesylate were added, in which molar ratio of 3H-Indole:compound 9:sodium 2 -methylpropan-2-olate: t-BuXPhos palladium(II) biphenyl-2-amine mesylate=1.5:1:2:0.1, the mixed solution was filled with nitrogen and reacted at 50° C. for 16 hours, purified to obtain compound 10, tert-butyl 3-(2H-isoindol-2-yl)isoquinolin-5-ylcarbamate: MS (m/z) 360.2 [M+H].sup.+.

[0038] 3. Compound 10 was dissolved in dichloromethane solution, and trifluoroacetic acid, in which molar ratio of compound 10:trifluoroacetic acid=1:10, was added at room temperature and reacted for 1 hour, and then was extracted and purified to obtain compound 11, 3-(2H-isoindol-) 2-yl) isoquinolin-5-amine:MS (m/z) 260.1 [M+H].sup.+.

[0039] 4. Compound 11 was dissolved in 10% sulfuric acid solution, and sodium nitrate was added to react at ° C. for 20 minutes, then potassium iodide was added, in which compound 11:sodium nitrate:potassium iodide=1:2:2, and then extracted and purified for 10 minutes to obtain compound 12, 5-iodo-3-(2H-isoindol-2-yl)isoquinoline: MS (m/z) 371.0 [M+H].sup.+. as shown:

##STR00006##

[0040] Synthesis of tracer [.sup.123I]5-iodo-3-(2H-isoindol-2-yl)isoquinoline:

[0041] Sodium iodide ([.sup.123I]NaI) in 0.01N NaOH and Na.sub.2S.sub.2O.sub.5 were added to the reaction flask and dried with nitrogen at 100° C., and compound 12 dissolved in acetic acid and cuprous sulfate solution were added and reacted at 180° C. for 10 minutes, and after being re-dissolved in ethanol and purification the compound 13 is obtained:

##STR00007##

[0042] Synthesis of tracer [.sup.124I]5-iodo-3-(2H-isoindol-2-yl)isoquinoline:

[0043] Sodium iodide ([124I]NaI) in 0.01N NaOH and Na2S2O5 were added to the reaction flask and dried with nitrogen at 100° C., and compound 12 dissolved in acetic acid and cuprous sulfate solution were added and reacted at 180° C. for 10 minutes, and after being re-dissolved in ethanol and purification the compound 14 is obtained:

##STR00008##

[0044] Synthesis of tracer [.sup.125I]5-iodo-3-(2H-isoindol-2-yl)isoquinoline:

[0045] Sodium iodide ([.sup.125I]NaI) in 0.01N NaOH and Na2S2O5 were added to the reaction flask and dried with nitrogen at 100° C., and compound 12 dissolved in acetic acid and cuprous sulfate solution were added and reacted at 180° C. for 10 minutes, and after being re-dissolved in ethanol and purification the compound 15 is obtained:

##STR00009##

[0046] Synthesis of tracer [.sup.131I]5-iodo-3-(2H-isoindol-2-yl)isoquinoline:

[0047] Sodium iodide ([.sup.131I]NaI) in 0.01N NaOH and Na.sub.2S.sub.2O.sub.5 were added to the reaction flask and dried with nitrogen at 100° C., and compound 12 dissolved in acetic acid and cuprous sulfate solution were added and reacted at 180° C. for 10 minutes, and after being re-dissolved in ethanol and purification the compound 16 is obtained:

##STR00010##

Embodiment 3

Synthesis of INER-TAU-R1 Series Compounds

[0048] Synthesis of precursor 7-(2-p-toluenesulfonyloxymethoxy)-3-(2H-isoindol-2-yl) isoquinoline, comprising:

[0049] 1. 1,3-dichloro-7-methoxyisoquinoline compound 17 is dissolved in a mixed solution of acetic acid and 45% iodine hydride, and red phosphorous is added at room temperature, and the mixed solution is reacted at 100° C. for 4 hours, then cooled to room temperature and purified to obtain compound 18, 3-chloro-7-methoxyisoquinoline: MS (m/z) 194.0 [M+H].sup.+.

[0050] 2. 3H-Indole and compound 18 were dissolved in tetrahydrofuran and added sodium 2-methylpropan-2-olate and t-BuXPhos palladium(II) biphenyl-2-amine mesylate at room temperature, in which molar ratio of 3H-Indole:compound 18:sodium-methylpropan-2-olate:t-BuXPhos palladium(II) biphenyl-2-amine mesylate=0.41:1:1.33:0.03, and the mixed solution was filled with nitrogen and reacted at 50° C. for 16 hours and purified to obtain compound 19, 7-methoxy-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 275.1 [M+H].sup.+.

[0051] 3. Compound 19 was dissolved in dichloromethane solution, and boron tribromide was added at −78° C., in which molar ratio of compound 19:boron tribromide=1:1, and the mixture being reacted at room temperature for 16 hours and followed by extraction and purification to obtain the compound 20 3-(2H-isoindol-2-yl) isoquinoline-7-ol: MS (m/z) 261.1 [M+H].sup.+.

[0052] Compound 20 is dissolved in dimethylformamide, and potassium carbonate and 1-bromo-2-p-toluenesulfonyloxymethane were added, in which molar ratio of compound 20:potassium carbonate:1-bromo-2-p-toluenesulfonyloxymethane=1:2.07:1.53, and the mixture after being reacted for 16 hours at 30° C. and followed by extraction and purification to obtain the compound 21 7-(2-p-toluenesulfonyloxymethoxy)-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 445.1 [M+H].sup.+:

##STR00011##

[0053] Synthesis of standard 7-(2-fluoromethoxy)-3-(2H-isoindol-2-yl) isoquinoline:

[0054] Compound 20 is dissolved in dimethylformamide, and potassium carbonate and 1-bromo-2-fluoromethane were added, in which molar ratio of compound 20:potassium carbonate:1-bromo-2-fluoromethane=1:2.07:1.53, and the mixture being reacted at 30° C. for 16 hours and followed by extraction and purification to obtain the compound 22 7-(2-fluoromethoxy)-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 293.1 [M+H].sup.+:

##STR00012##

[0055] Synthesis of tracer [18F] 7-(2-fluoromethoxy)-3-(2H-isoindol-2-yl) isoquinoline:

[0056] Compound 21 was dissolved in acetonitrile, and potassium carbonate and Kryptofix 222 were added to react at 95° C. for 15 minutes and followed by purification to obtain the compound 23 [18F] 7-(2-fluoromethoxy)-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 292.1 [M+H].sup.+:

##STR00013##

Embodiment 4

Synthesis of INER-TAU-R2 Series Compounds

[0057] Synthesis of precursor 7-(2-p-toluenesulfonyloxyethoxy)-3-(2H-isoindol-2-yl) isoquinoline, comprising:

[0058] 1. compound 17, 1,3-dichloro-7-methoxyisoquinoline, is dissolved in a mixed solution of acetic acid and 45% iodine hydride, and red phosphorous is added at room temperature, and the mixed solution is reacted at 100° C. for 4 hours, then cooled to room temperature and purified to obtain compound 18 3-chloro-7-methoxyisoquinoline: MS (m/z) 194.0 [M+H].sup.+.

[0059] 2.3H-Indole and compound 18 were dissolved in tetrahydrofuran, and sodium 2-methylpropan-2-olate and t-BuXPhos palladium(II) biphenyl-2-aminemesylate were added at room temperature, in which molar ratio of 3H-Indole:compound 18:sodium 2-methylpropan-2-olate:t-BuXPhos palladium(II) biphenyl-2-amine mesylate=0.41:1:1.33:0.03, the mixed solution was filled with nitrogen and reacted at 50° C. for 16 hours and purified to obtain compound 19 7-methoxy-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 275.1 [M+H].sup.+.

[0060] 3. Compound 19 was dissolved in dichloromethane solution, and boron tribromide was added at −78° C., in which molar ratio of compound 19:boron tribromide=1:1, and then reacted at room temperature for 16 hours and followed by extraction and purification to obtain the compound 20 3-(2H-isoindol-2-yl) isoquinoline-7-ol: MS (m/z) 261.1 [M+H].sup.+.

[0061] 4. Compound 20 was dissolved in dimethylformamide, and potassium carbonate and 1-bromo-2-p-toluenesulfonyloxymethane were added, in which molar ratio of compound 20:potassium carbonate:1-bromo-2-p-toluenesulfonyloxymethane=1:2.07:1.53, and after being reacted at 30° C. for 16 hours and followed by extraction and purification to obtain the compound 24 7-(2-p-toluenesulfonyloxyethoxy)-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 459.1 [M+H].sup.+:

##STR00014##

[0062] Synthesis of standard 7-(2-fluoroethoxy)-3-(2H-isoindol-2-yl) isoquinoline:

[0063] Compound 20 was dissolved in dimethylformamide, and potassium carbonate and 1-bromo-2-fluoromethane were added, in which molar ratio of compound 20:potassium carbonate:1-bromo-2-fluoromethane=1:2.07:1.53, and reacted at 30° C. for 16 hours and followed by extraction and purification to obtain the compound 25, 7-(2-fluoroethoxy)-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 307.1 [M+H].sup.+:

##STR00015##

[0064] Synthesis of tracer [18F] 7-(2-fluoroethoxy)-3-(2H-isoindol-2-yl) isoquinoline:

[0065] Compound 24 was dissolved in acetonitrile, and potassium carbonate and Kryptofix 222 were added to react at 95° C. for 15 minutes and purified to obtain compound 26, [18F] 7-(2-fluoroethoxy)-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 306.1 [M+H].sup.+:

##STR00016##

Embodiment 5

Synthesis of INER-TAU-R3 Series Compounds

[0066] Synthesis of precursor 7-(2-p-toluenesulfonyloxypropoxy)-3-(2H-isoindol-2-yl) isoquinoline, comprising:

[0067] 1. 1,3-dichloro-7-methoxyisoquinoline compound 17 was dissolved in a mixed solution of acetic acid and 45% iodine hydride, and red phosphorous is added at room temperature, and the mixed solution was reacted at 100° C. for 4 hours, then cooled to room temperature and purified to obtain the compound 18 3-chloro-7-methoxyisoquinoline: MS (m/z) 194.0 [M+H].sup.+.

[0068] 2.3H-Indole and compound 18 were dissolved in tetrahydrofuran, sodium 2-methylpropan-2-olate and t-BuXPhos palladium(II) biphenyl-2-amine mesylate were added at room temperature, in which molar ratio of 3H-Indole:compound 18:sodium 2-methylpropan-2-olate:t-BuXPhos palladium(II) biphenyl-2-amine mesylate=0.41:1:1.33:0.03, and the mixed solution was filled with nitrogen and reacted at 50° C. for 16 hours and purified to obtain compound 19 7-methoxy-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 275.1 [M+H].sup.+.

[0069] 3. Compound 19 was dissolved in dichloromethane solution, and boron tribromide was added at −78° C., in which molar ratio of compound 19:boron tribromide=1:1, and then reacted at room temperature for 16 hours and followed by extraction and purification to obtain the compound 20 3-(2H-isoindol-2-yl) isoquinoline-7-ol: MS (m/z) 261.1 [M+H].sup.+.

[0070] 4. Compound 20 was dissolved in dimethylformamide, and potassium carbonate and 1-bromo-2-p-toluenesulfonyloxymethane were added, in which molar ratio of compound 20:potassium carbonate:1-bromo-2-p-toluenesulfonyloxymethane=1:2.07:1.53, and after being reacted at 30° C. for 16 hours and followed by extraction and purification to obtain the compound 27 7-(2-p-toluenesulfonyloxypropoxy)-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 473.2 [M+H].sup.+:

##STR00017##

[0071] Synthesis of standard 7-(2-fluoropropoxy)-3-(2H-isoindol-2-yl) isoquinoline:

[0072] Compound 20 was dissolved in dimethylformamide, and potassium carbonate and 1-bromo-2-fluoromethane, in which molar ratio of compound 20:potassium carbonate:1-bromo-2-fluoropropane=1:2.07:1.53, were added to react at 30° C. for 16 hours and followed by extraction and purification to obtain the compound 28 7-(2-fluoropropoxy)-3-(2H-isoindol-2-yl) isoquinoline: MS (m/z) 321.1 [M+H].sup.+:

##STR00018##

[0073] Synthesis of tracer [18F] 7-(2-fluoropropoxy)-3-(2H-isoindol-2-yl) isoquinoline, comprising:

[0074] 1. Compound 27 was dissolved in acetonitrile, and potassium carbonate and Kryptofix 222 were added to react at 95° C. for 15 minutes and purification to obtain the compound 29 [18F] 7-(2-fluoropropoxy)-3-(2H-isoindol-2-yl) isoquinoline was obtained.: MS (m/z) 320.1 [M+H].sup.+;

##STR00019##

[0075] 2. The obtained compound 29, [18F] 7-(2-fluoropropoxy)-3-(2H-isoindol-2-yl) isoquinoline, was analyzed by radio-TLC and radio-HPLC to confirm the purity is greater than 95%, as shown in FIG. 1 and FIG. 2.

[0076] Radio-TLC analysis uses TLC sheet silica gel 60 F254 (Merck), mobile phase is CH2Cl2: CH3OH=8:2; Radio-HPLC analysis uses XSelect HSS T3 column, mobile phase uses gradient method: from 60% acetonitrile+0.1% TFA to 90% acetonitrile+0.1% TFA in 30 minutes.

[0077] 0.46 mCi of compound 29 was injected into P301L gene transgenic mice and control mice, and after 30 minutes of distribution nano-PET/CT was used for contrast imaging. The image showed that the absorption of compound 29 in the brain of P301L gene transgenic mice was significantly higher than that of the control mice, as shown in FIG. 3.

[0078] In one preferred embodiment of the instant disclosure, there is provided a pharmaceutical composition comprising the pharmaceutical compound or a pharmaceutically acceptable salt thereof as described herein.

[0079] In another preferred embodiment of this disclosure, there is provided a method of Tau protein imaging in a biological sample using a pharmaceutical composition described herein, comprising the steps of: (1) providing a cell and/or a tissue and/or an organ sample from a subject, (2) contacting said sample with the pharmaceutical composition, and (3) imaging said sample, wherein deposits of microtubule-associated protein Tau in said sample is detected.

[0080] Based on the above, the novel diagnostic microtubule-related protein Tau imaging precursors, standards and tracers provided by the present invention can indeed achieve the characteristics of easy synthesis, high yield and better analytical accuracy. The content of the above description is only a description of the preferred embodiments of the invention, and all the amendments based on the technical means and scope of the invention, including modifications, changes or equivalent substitutions shall also fall within the scope of the claims of the present invention.