CN101293878B - Benzothiazole amino benzenes compounds, preparation method and application thereof - Google Patents
Benzothiazole amino benzenes compounds, preparation method and application thereof Download PDFInfo
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Abstract
一类如式I-III所示的苯并噻唑苯胺类化合物；其中R为H或CH3。其具有比现有化合物2-(4’-甲胺苯基)-6-羟基苯并噻唑更高的淀粉样蛋白特异结合活性。本发明还公开了其制备方法和在检测或显像淀粉样蛋白沉积和神经纤维缠结中的应用。该制备方法简单，其中位置选择性的18F标记方法为首次公开。该应用为首次采用PET成像技术成功显象活体啮齿类动物痴呆模型与正常样本脑内淀粉样蛋白沉积差异，以及首次应用核黄素类衍生物同时靶向淀粉样蛋白沉积和神经纤维缠结。 A class of benzothiazole aniline compounds represented by formula I-III; wherein R is H or CH 3 . It has higher amyloid specific binding activity than the existing compound 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole. The invention also discloses its preparation method and its application in detecting or imaging amyloid deposition and neurofibrillary tangles. The preparation method is simple, and the position-selective 18 F labeling method is disclosed for the first time. This application is the first time that PET imaging technology has been successfully used to visualize the difference of amyloid deposition in the brains of living rodent dementia models and normal samples, and the first application of riboflavin derivatives to simultaneously target amyloid deposition and neurofibrillary tangles. 
Description
Technical field
The present invention relates to the benzothiazole amino benzenes compounds of a class novelty, with and preparation method thereof and detect or video picture animal or human body tissue in application in the amyloid beta deposition.
Background technology
Presenile dementia (Alzheimer ' disease, be common a kind of senile dementia AD), such patient accounts for 60～70% of dull-witted patient's sum, it is characterized by irreversible memory impairment, lasting cognitive decline, and conduct disorder.Morbidity back patient generally can live 5-20 years, become the 4th cause of death after heart trouble, tumour and apoplexy (chief editor such as Lu Zuneng, practical electromyography. Beijing: People's Health Publisher, 2000, p878～880).Its pathological characteristics comprises extracellular β-amyloid (β-amyloid, A β) fiber laydown, the intracellular neurofibrillary tangles that is formed by hyperphosphorylation Tau albumen, and the damage of neurotransmitter (Nordberg A., Neurology, 2004,3,519).Whether having a large amount of amyloid beta depositions and neurofibrillary tangles in detection the dead brain is the unique method of present clinical definite senile dementia.
Riboflavin-S (Thioflavin-S, TFS) and riboflavin-T (Thioflavin-T TFT) is dyestuff at β in the brain section-amyloid patch.Riboflavin once was used as the pharmaceutical carrier of research and development and β-amyloid binding compounds.Its derivative as
3H-BTA-1 ([tritium] 2-(4 '-methylamine phenyl)-6-hydrogen benzothiazole) and
11C-6-OH-BTA-1 (PIB) ([carbon-11] 2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole), the potentiality that are combined with in nanometer chi footpath with presenile dementia patient postmortem cerebral tissue.The experiment of multiphoton microscope live body transgenic mouse has shown that the PIB that fluorescent emission is arranged can pass hemato encephalic barrier, and the mark amyloid beta deposition is removed from brain then.Grow up from riboflavin-T
125I-TZDM ([iodine-125] 2-(4 '-dimethylamine phenyl)-6-iodobenzene and thiazole) be so far with amyloid A β
1-40The compound that bonding force is the strongest (0.06nM).Kung and colleague thereof have reported a kind of new riboflavin derivative recently
125I-IMPY ([iodine-125] 6-iodo-2-(4 '-N, N dimethylamine) phenylimidazole [1,2-a] pyridine also), the senile plaque that is used for the mark transgenic mouse is succeedd, this derivative becomes the amyloid tracer agent (NicholsL. of another potential single photon emission tomography imaging technique (SPECT) video picture, Pike V.W., Cai L.-S., et al, Biol Psychiatry, 2006,59,940).MakotoH. waiting the people to utilize contains
19The F element and with the higher compound of amyloid avidity as the Magnetic resonance imaging toughener, progress (Makoto, H. make a breakthrough in live body detects the experiment of amyloid plaques; Iwata, N.; Matsuba, Y.; Sato, K; Sasamoto, K.; Saido, T.C.Nature neuroscience2005,8,4,527).But because the chemistry amount of using is bigger, cause damage to live body, thus at present also possibility do not enter clinical study, research in animal body is restricted.
W.E. the little Matisse Y. king of Ke Lunke and C.A. has applied for US application 60/227601 on August 24th, 2000, and has applied for Chinese patent in August 24 calendar year 2001, and open on October 6th, 2004.Publication number CN15352/68A.This patent disclosure series compound, and preparation method thereof and in the imaging body medicinal use in the amyloid beta deposition.This patent has contained following structural compounds:
Structure D (the 6/51st page in 01817884.7 specification sheets)
Wherein Z is S, NR ', O or C (R ')
2Y is NR
1R
2, OR
2Or SR
2Each R wherein
3-R
14Be selected from H, F, Cl, Br, I, low alkyl group, (CH respectively
2) OR ' (wherein n=1,2 or 3), CF
3, CH
2-CH
2X, O-CH
2CH
2X, O-CH
2CH
2CH
2X (wherein X=F, Cl, Br or I) etc.; In preferred embodiments, the substituent R of structure D
3-R
14At least one is selected from:
131I,
123I,
76Br,
75Br,
18F, CH
2CH
2X
*, O-CH
2-CH
2-CH
2X
*, O-CH
2-CH
2-CH
2-CH
2X
*(X wherein
*=
131I,
123I,
76Br,
75Br,
18F),
19F,
125I etc.Though comprised compound structure of the present invention in this patent, but in its especially preferred embodiment and specific embodiment, do not comprise this compounds, this patent does not provide the character of the target neurofibrillary tangles that this patent compound has yet simultaneously.
Only have in this patent and relate to
11The specific embodiment of C mark does not relate to
18The experiment content of F mark and data, and
18The F mark with
11The C mark is diverse two kinds of technology for present technique field personnel, regioselectivity
18The method of F mark is not this area routine techniques yet.In its specific embodiment, the method steps of synthetizing thiazolium ring is many, and condition is harsh relatively, is difficult for being applied to conventional production.
Lockhart A. has estimated in recent document and has entered clinically at present, is used for the PET small molecules probe of early diagnosis AD: [
11C]-PIB, [
11C]-SB13 and [
18F]-FDDNP (Lockhart A., DrugDiscovery Today, 2006.12Volume11, Numbers3/24: 1093-1099).[
18F]-FDDNP enters clinical study the earliest, and it is target amyloid plaques and neurofibrillary tangles simultaneously, but the concentrating only to distinguish than reference and exceed 30% of area-of-interest, specificity is not strong.[
11C]-PIB, [
11C]-SB13 demonstrates than high specific (exceeding 50-100%), but [
11C]-PIB clinical patients number far away more than [
11C]-SB13, the result is more reliable.The advantageous property of these three kinds of compounds makes them become the PET small molecules probe of potential early diagnosis AD, especially [
11C]-PIB.
But in addition the people is surprised is [
11C]-result of PIB in patient's brain but fail to display in animal pattern.Document ((Klunk W.E., Lopresti B.J., and MathisC.A., et al that Mathis C.A etc. delivers; The Journal of Neuroscience, November16,200525 (46): 10598-10606), will [
11C]-PIB carries out small animal position emission tomography (PET) video picture experiment and shows, distribute in the model mice brain not than significantly increasing in the normal mouse brain in presenilin genes 1/ amyloid precursor protein transgene mouse model (in this mouse brain express more amyloid beta deposition) brain.Experiment in vitro shows, the amyloid beta deposition in this mouse model brain can not with [
11C]-the PIB specific combination.
Prior art study of behaviour and pathology all with the dementia physiognomy with animal pattern and the research estimated of live body (as rat or mouse) in, yet there are no success employing PET imaging its with the open source literature of normal differences between samples success.
Summary of the invention
The objective of the invention is to disclose the benzothiazole amino benzenes compounds: suc as formula the 2-shown in the I (4 '-dimethylamine phenyl)-6-fluoro benzothiazole (F-N, N-Me, R=CH
3), or 2-(4 '-methylamine phenyl)-6-fluoro benzothiazole (F-N-Me, R=H); 2-shown in the formula II (4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole (O-FEt-PIB); And [fluoro-18] 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole shown in formula III ([
18F] O-FEt-PIB).
Wherein, R is H or CH
3
Another object of the present invention is open preparation method suc as formula the 2-shown in the I (4 '-dimethylamine phenyl)-6-fluoro benzothiazole compounds; comprise the steps: under 120～200 ℃; with 2-amino-5-fluorobenzene mercaptan and 4-methylamine phenylformic acid or 4-(dimethylamine) phenyl aldehyde, under rare gas element such as nitrogen protection, react and get final product.Wherein, the molar weight of 2-amino-5-fluorobenzene mercaptan and 4-methylamine phenylformic acid or 4-(dimethylamine) phenyl aldehyde than preferable be 10:1～1:10; What the time of reaction was preferable is 10 minutes～300 minutes.
Wherein, described 2-amino-5-fluorobenzene mercaptan can be made by following steps: under 160 ℃～180 ℃ of temperature, in basic solution, the reaction that is hydrolyzed gets final product with 2-amino-6-fluoro benzothiazole compounds.Described basic solution preferable for mass percent be 40～60% the KOH aqueous solution.
Another purpose of the present invention is open preparation method suc as formula the 2-shown in the II (4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole, comprise the steps: in aprotic solvent, with the amount of substance amount than being the 2-of 10:1～1:10 (4 '-methylamine phenyl)-6-hydroxybenzothiazole and p-methyl benzenesulfonic acid fluorine ethyl ester, add anhydrous alkali metal carbonate (as salt of wormwood, yellow soda ash etc.), alkaline metal iodide (as potassiumiodide, sodium iodide etc.) makes reaction solvent saturated, react, get final product.
Wherein, described solvent can be selected from (dimethyl formamide, N, N-dimethyl sulfoxide (DMSO), acetonitrile etc.), and preferable is dimethyl formamide; What the temperature of reaction was preferable is 80～120 ℃; The time of reaction can be 10～25 hours; After reaction was finished, preferable crossed column purification with product again.
A further object of the present invention is the preparation method of open [fluoro-18] 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole shown in formula III, comprise the steps: saturated anhydrous acetonitrile or the N of alkaline carbonate (as salt of wormwood or yellow soda ash), in the N dimethyl sulfoxide (DMSO), the 2-of 1～10mg (4 '-methylamine phenyl)-6-hydroxybenzothiazole, 1～1000mCi[fluoro-18 with prepared fresh] the fluoro ethyl p-toluenesulfonic esters reacts, gets final product.
What wherein, the temperature of reaction was preferable is 80～160 ℃; That the time of reaction is preferable is 2～60min.
Wherein, described [fluoro-18] fluoro ethyl can be made by following method: 1) obtain containing fluoro-18 ions, K by accelerator production
222And K
2CO
3Solution; Or the production of wash-out accelerator [
18F] obtain the residual fluoro-18 ionic QMA posts that have behind the FDG ([fluoro-18] deoxyglucose), dissolve in and contain K
222And K
2CO
3Solution; 2) dry fluoro-18 solions add the acetonitrile that is dissolved with two benzene methanesulfonic acid ethylene glycol then, dry up, and repeat 3 times, take out the reaction flask cooling then; 3) add CH
3CN, the oil bath reacting by heating, what temperature was preferable is 90～110 ℃; What the time was preferable is 5～10 minutes; The C of employing again that product is preferable
18The seppak post separates, and use dry back.
Wherein, after reaction was finished, preferable separated preparation with product through high performance liquid chromatography again.The condition of preferable high performance liquid chromatography is: chromatographic column is day Vydac C of island proper Tianjin company
18Post, diameter are 2.5mm, and length is 250mm, and packing material size is 10 μ m; Mobile phase A is a methyl alcohol; Mobile phase B is 0.1% trifluoroacetic acid aqueous solution, pH=2.52; Gradient condition be 0-2min to 100%B, 25min is to the aqueous solution of 30%B afterwards; Flow velocity 1mL/min; Ultraviolet 254nm detects; Collect the effluent liquid of 9-11min.
Further purpose of the present invention be disclose benzothiazole amino benzenes compounds of the present invention preparation detect or video picture animal, human body or tissue in application in the medicine of amyloid beta deposition, especially adopt the application in the medicine of positron emission computerized tomography technology (PET) or fluorescent imaging technology.
Benzothiazole amino benzenes compounds of the present invention can be made pharmaceutical composition with pharmaceutically acceptable any carrier, be used in detection or video picture animal, human body or the tissue, especially amyloid beta deposition in the brain, or be used to diagnose allelic homozygotic disease of presenile dementia, family's presenile dementia and aPoA POE B4 or syndromes.Administering mode can have multiple, as intravenous administration; Can adopt mr imaging technique (MRI), positron emission computerized tomography technology (PET) or single photon emission tomography imaging technique imaging techniques such as (SPECT) to detect afterwards.Video picture result's analysis can be by the combining of compound of the present invention in the comparative drug and brain region except that cerebellum, and the combination rate with the normal people compares again.When using the PET video picture, can set up standard, the acquisition diagnostic result by compound in the The compounds of this invention in the comparative drug and fluoro-18 deoxyglucoses at the ratio (or being called the hippocampus modulus) of the distribution of hippocampus.
When the medicine of compound of the present invention is used for examination of living tissue or dead back human body or animal tissues's detection amyloid beta deposition, can adopt following method: contain the solution of The compounds of this invention and formalin fixed or tissue slice FF or that paraffin embedding is good and hatch altogether, use the method for fluorescence or phosphorus screen video picture to detect deposition position then; Wherein, the solvent of solution is the aqueous ethanolic solution of 5-95%.
Agents useful for same of the present invention and compound be all commercially available getting except that specified otherwise.
Positive progressive effect of the present invention is:
(1) benzothiazole amino benzenes compounds of the present invention has higher specific combination activity with amyloid, and passes hemato encephalic barrier in animal or human's body easily.Compound of the present invention all shows the higher specific combination activity than known references compound [carbon-11] PIB (2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole).
(2) compound of the present invention can also combine with the neurofibrillary tangles specificity except closing with the amyloid plaque agllutination, and this was not mentioning in document or the patent in the past.
(3) compound of the present invention is the developing difference that successfully obtains to adopt positron emission computerized tomography (PET) amyloid beta deposition in live body rodent Model of Dementia and normal sample brain first, and this can be the dementia animal model screening and dull-witted patient's clinical diagnosis provides important reference information.
(4) several compounds that relate among formula I of the present invention, the II all have strong binding ability because of itself and amyloid and neural the entanglement, can reduce the intravital chemistry amount that is used for, thereby can be used as potential magnetic resonance imaging toughener at amyloid, avoid simultaneously causing damage too greatly to live body because of the chemistry amount.
(5) preparation method of the present invention is simple, the particular requirement of no high temperature, high pressure or responsive reagent, wherein Xin Ying regioselectivity
18The F marking method is for open first.
Description of drawings
Fig. 1 is 2-among the embodiment 8 (4 '-methylamine phenyl)-6-[
18F] the radioactivity thin-layer chromatogram of fluorine ethoxyl benzo thiazole, R
f=0.65, radiochemicsl purity 100%, developping agent 5% ethanol/methylene.
Fig. 2 is 2-among the embodiment 8 (4 '-methylamine phenyl)-6-[
18F] the fluorine ethoxyl benzo thiazole ([
18F] O-FEt-PIB) the radioactivity thin-layer chromatogram, R
f=0.15, the developping agent trichloromethane.
Fig. 3 is 2-among the embodiment 8 (4 '-methylamine phenyl)-6-[
18F] the fluorine ethoxyl benzo thiazole ([
18F] O-FEt-PIB) radioactivity high performance liquid phase figure, retention time K=18.2min, the high performance liquid phase condition is seen embodiment 5.
Fig. 4 be 2-among the effect embodiment 1 (4 '-methylamine phenyl)-6-fluoro benzothiazole with [
3H] PIB competes specificity in conjunction with experiment in conjunction with (per minute decays)～2-(4 '-methylamine phenyl)-6-fluoro benzothiazole mol ratio logarithmic graph in dull-witted people's brain homogenate.
Fig. 5 be 2-among the effect embodiment 1 (4 '-dimethylamine phenyl)-6-fluoro benzothiazole with [
3H] PIB competes specificity in conjunction with experiment in conjunction with (per minute decays)～2-(4 '-dimethylamine phenyl)-6-fluoro benzothiazole mol ratio logarithmic graph lab diagram in dull-witted people's brain homogenate.
Fig. 6 be 2-among the effect embodiment 1 (4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole with [
3H] PIB competes specificity in conjunction with experiment in conjunction with (per minute decays)～2-(4 '-methylamine phenyl)-6-fluorine ethoxy benzothiazole mol ratio logarithmic graph in dull-witted people's brain homogenate.
Fig. 7 be [tritium] 2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole among the effect embodiment 1 ([
3H] PIB) with dull-witted people's brain homogenate saturated combine the experiment specificity in conjunction with (per minute decays)～[
3H] PIB mol ratio logarithmic graph.
Fig. 8 is 2-among the effect embodiment 2 (4 '-methylamine phenyl)-6-[
18F] amyloid specificity bonded radioactive automatic developing figure in fluorine ethoxyl benzo thiazole and the dull-witted patient's postmortem cerebral hippocampal tissue.
Fig. 9 is F-N-Me and thioflavin S and dull-witted patient's postmortem cerebral tissue amyloid and neurofibrillary tangles specificity bonded fluorescent imaging figure among the effect embodiment 3
Figure 10 be among the effect embodiment 4 [
18F] FDG ([fluoro-18] deoxyglucose) and interior amyloid bonded positron computer layer imaging (PET) scintigram of normal rat brain.
Figure 11 is 2-among the effect embodiment 4 (4 '-methylamine phenyl)-6-[
18F] the fluorine ethoxyl benzo thiazole ([
18F] O-FEt-PIB) and interior amyloid bonded positron computer layer imaging (PET) scintigram of Model of Dementia rat brain.
Figure 12 is 2-among the effect embodiment 4 (4 '-methylamine phenyl)-6-[
18F] the fluorine ethoxyl benzo thiazole ([
18F] O-FEt-PIB) and interior amyloid bonded positron computer layer imaging (PET) scintigram of normal control rat brain.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Synthesizing of embodiment 12-amino-5-fluorobenzene mercaptan compound
The fluorine-based benzothiazole of 30.0g (closing 178mmol) 2-amino-6-is dissolved in 50wt%KOH (180gKOH is dissolved in the 180ml water) and the 40ml ethylene glycol, stirs, become the suspension turbid solution.This suspension heating refluxes, and solid all dissolves, and becomes pale yellow solution.Reflux after 48 hours, when cool to room temperature, add 300ml toluene, add the acetate neutralization of 180ml again.Separate organic phase, water is extracted by other 200ml toluene.Toluene is used dried over mgso again after washing.Obtain light yellow solid after the solvent evaporated, productive rate 50.1%, qualification result is as follows:
1H NMR (acetone-d
6, 500MHz), δ: 6.81 (dd, J=9,2.5Hz, 1H), 6.56 (t, 2H), 3.6 (br, s);
IR(KBr)ν：3427，2560，1615，1487，1406，1289，1200，1141，864，812，685，462cm
-1；
MS (m/z) is 142 (100), 98 (37) .C (%)
6H
6FNS, calculated value C50.33, H4.22, F13.27, N9.78, S22.39; Observed value C50.51, H4.82, N9.26, S22.17.
Synthesizing of embodiment 22-(4 '-methylamine phenyl)-fluorine-based benzothiazole of 6-
Fluorine-based benzenethiol 0.72g of 2-amino-5-(5.0mmol) and 4-methylamine phenylformic acid 0.80g (7.0mmol), add about 1g polyphosphoric acid, mechanical stirring, logical N2, elevated temperature to 200 ℃, reaction 2h, cooling, the wet chemical of adding 10% neutralization in the solid that reaction obtains, and add ethyl acetate extraction.Be spin-dried for solvent cross the flash post (n-hexane/ethyl acetate=4:1) is just separated the back recrystallization, and solid is crossed the flash post once more, obtains the 0.52g yellow solid at last, productive rate 21.6%, qualification result is as follows:
1H NMR (CDCl
3, 500MHz), δ: 7.84 (3H, 1H and 2H overlap), 7.44 (dd, J=9.0,2.5Hz, 1H), 7.10 (t, 1H), 6.68 (d, J=8.5Hz, 2H) 2.81 (s, 3H);
IR(KBr)ν：3312，3273，3289，1605，1564，1480，1450，1276，1250，1062，1049，1001，902，854，MS?m/z(％)：258(100)；
MS:C
14H
11FN
2S, calculated value 258.0627, measured value 258.0631.
Synthesizing of embodiment 32-(4 '-dimethylamine phenyl)-fluorine-based benzothiazole of 6-
Fluorine-based benzenethiol 0.77g of 2-amino-5-(5.4mmol) and 4-(dimethylamine) phenyl aldehyde 0.799g (5.4mmol) are dissolved among the anhydrous DMSO of 5ml, be heated to 120 ℃, reaction 25min, be cooled to room temperature, in the impouring water, with the ethyl acetate extraction twice of 30ml, organic layer washes and uses dried over mgso with water.Be spin-dried for solvent.The separation of flash post (qualification result is as follows for n-hexane/ethyl acetate=4:1), obtain the 0.373g faint yellow solid, productive rate 37.5%:
1H?NMR(acetone-d
6，500MHz)，δ:7.88(d，J＝8.9Hz，2H)，7.70(d，J＝8.9Hz，1H)，7.50(d，J＝2.5Hz，1H)，7.04(dd，J＝8.9，2.5Hz，1H)，6.80(2H)，3.05(d，J＝9.0Hz，6H)；
IR(KBr)ν：3447，2972，2917，1607，1489，1455，1365，1222，1166，1065，936，819，593cm
-1MS(m/z)(％)272(100)，256(13)；
MS:C
15H
23FN
2S, calculated value 272.0783, measured value 272.0781.
Synthesizing of embodiment 42-(4 '-dimethylamine phenyl)-fluorine-based benzothiazole of 6-
Fluorine-based benzenethiol 0.77g of 2-amino-5-(5.4mmol) and 4-(dimethylamine) phenyl aldehyde 1.598g (10.8mmol) are dissolved among the anhydrous DMSO of 5ml, be heated to 180 ℃, reaction 20min, be cooled to room temperature, in the impouring water, with the ethyl acetate extraction twice of 30ml, organic layer washes and uses dried over mgso with water.Be spin-dried for solvent.(qualification result is with embodiment 3 for n-hexane/ethyl acetate=4:1), obtain faint yellow solid, productive rate 39% for the separation of flash post.
Synthesizing of embodiment 52-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole (O-FEt-PIB)
With 103mg (0.4mmol) 2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole, Anhydrous potassium carbonate (55.4mg, 0.4mmol), potassiumiodide (61mg, 0.4mmol) and dimethyl formamide (DMF) 10ml add in the three-necked bottle successively, be heated with stirring to 80 ℃, drip and contain (14.8mg, 0.06mmol) the DMF solution 30ml of p-methyl benzenesulfonic acid fluorine ethyl ester.Drip and finish, isothermal reaction 20h, filtered while hot, filtrate decompression concentrates, and adds water, filter, washing, ethanol is washed, and obtains brown solid.Cross the flash post (silica gel, the purifying of n-hexane/ethyl acetate=4:1) obtain the yellow 2-(4 '-methylamine phenyl) of 21mg-6-fluorine ethoxyl benzo thiazole, and qualification result is as follows:
Analyze the HPLC condition: Vydac C18 post, diameter are 2.5mm, and length is 250mm, wherein packing material size is 10 μ m (Japan, Tianjin, island company), condition 1: moving phase: V70/30 acetonitrile/TEA phosphoric acid buffer (pH=7.20) flow velocity 0.5mL/min, ultraviolet 254nm detects.Retention time k=6.98min, Purity85%; Condition 2: moving phase: A:HPLC methyl alcohol, B:0.1% trifluoroacetic acid aqueous solution (pH=2.52) gradient condition is 0-2min100%B, 25min, 30% B, 40min100%B.Flow velocity 1mL/min, ultraviolet 254nm detects, retention time K=17.8min.
Thin-layer chromatography (developping agent: trichloromethane), R
f=0.22.
1H?NMR(CDC13，500MHz)δ：8.21(d，J＝8.5Hz，2H)，8.12(d，J＝9.0Hz，1H)，7.38(d，J＝8.5Hz，1H)，7.34(d，J＝9.3Hz，1H)，7.18(dd，J＝8.6，2.5Hz，2H)，4.75(dd，J＝5.5，9.0Hz，2H)，3.40(s，3H)；
IR(KBr)ν：3443，3265，2958，2924，1744，1720，1609，1561，1543，1489，1460，1446，1333，1261，1227，1208，1181，1083，1021，964，940，876，802cm
-1；MS?m/z(％)302(42)，255(100)，227(16)，95(23)；
MS:C
16H
15FN
2OS, calculated value 302.0889, measured value 302.0887.
Synthesizing of embodiment 62-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole (O-FEt-PIB)
With 103mg (0.4mmol) 2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole, Anhydrous potassium carbonate (55.4mg, 0.4mmol), potassiumiodide (61mg, 0.4mmol) and dimethyl formamide (DMF) 10ml add in the three-necked bottle successively, be heated with stirring to 120 ℃, drip and contain (256mg, 1.2mmol) the DMF solution 30ml of p-methyl benzenesulfonic acid fluorine ethyl ester.Drip and finish, isothermal reaction 20h, filtered while hot, filtrate decompression concentrates, and adds water, filter, washing, ethanol is washed, and obtains brown solid.Cross the flash post (silica gel, the purifying of n-hexane/ethyl acetate=4:1) obtains yellow 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole, qualification result is embodiment 5 simultaneously.
Synthesizing of embodiment 72-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole (O-FEt-PIB)
With 14.5mg (0.06mmol) 2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole, Anhydrous potassium carbonate (55.4mg, 0.4mmol), potassiumiodide (61mg, 0.4mmol) and dimethyl formamide (DMF) 10ml add in the three-necked bottle successively, be heated with stirring to 100 ℃, drip and contain (148mg, 0.6mmol) the DMF solution 30ml of p-methyl benzenesulfonic acid fluorine ethyl ester.Drip and finish, isothermal reaction 20h, filtered while hot, filtrate decompression concentrates, and adds water, filter, washing, ethanol is washed, and obtains brown solid.Cross the flash post (silica gel, the purifying of n-hexane/ethyl acetate=4:1) obtains yellow 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole, qualification result is embodiment 5 simultaneously.
Embodiment 82-(4 '-methylamine phenyl)-6-[
18F] the fluorine ethoxyl benzo thiazole ([
18F] O-FEt-PIB) synthetic
From accelerator production [
18F] obtain behind the FDG ([fluoro-18] deoxyglucose) residually having
18The QMA post of F-is measured activity 52.55mCi;
2. use the 40mgK that contains for preparing in advance
222And 6mgK
2CO
3Acetonitrile solution (volume ratio 3.54:0.46, altogether 4ml) 1.0ml, slowly drip washing is accomplished dropwise to fall, and measures activity 47.62mCi;
3. reaction flask is inserted in 100 ℃ of oil baths, feed N
210min dries up moisture, adds the 400ul acetonitrile to two benzene methanesulfonic acid ethylene glycol that is dissolved with 8.6mg, dries up, and repeats 3 times, takes out the reaction flask cooling then;
4. add 500 μ lCH
3CN, 100 ℃ of oil bath heating 10min.The point plate walk thin-layer chromatography (developping agent: trichloromethane) and the radioactivity high performance liquid phase identify intermediate product, the results are shown in Figure 1 and Fig. 2.(condition: Vydac C18 post, diameter are 2.5mm, and length is 250mm, wherein packing material size is 10 μ m (Japan, Tianjin, island companies), moving phase: A:HPLC methyl alcohol, B:0.1% trifluoroacetic acid aqueous solution (pH=2.52) gradient condition is 0-2min100%B, 25min, 30% B.Flow velocity 1mL/min, ultraviolet 254nm detects; Collect the effluent liquid of 9-11min).During end of synthesis, add the water of 4ml, vortex takes out whole liquid and crosses C18sep pak post, removes the liquid that drenches.With 2ml5:1 n-hexane/ethyl acetate drip washing C18sep pak pillar, use the drip washing of 2ml n-hexane/ethyl acetate again, collect and all drench fluid, record leacheate activity 3.95mCi.
5. insert in 100 ℃ of oil baths, feed N
2Dry up, cooling adds the super dry acetonitrile of 200ul, adds 3mg6-OH-BTA-1 (2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole), 200ul dimethyl sulfoxide (DMSO) and an amount of K again
2CO
3, reaction 20min, the some plate is walked thin-layer chromatography and radioactivity high performance liquid phase and is identified product, and utilizes high performance liquid phase to separate purification target product (condition is the same), the results are shown in Figure 3 and Fig. 4.
Embodiment 92-(4 '-methylamine phenyl)-6-[
18F] the fluorine ethoxyl benzo thiazole ([
18F] O-FEt-PIB) synthetic
1. obtain F-18 ion 1Ci by accelerator production, wherein contain K
222And K
2CO
3, in 100 ℃ of oil baths, feed N
210min dries up moisture, adds the 400ul acetonitrile to two benzene methanesulfonic acid ethylene glycol that is dissolved with 8.6mg, dries up, and repeats 3 times, takes out the reaction flask cooling then;
2. add 500 μ l CH
3CN, 110 ℃ are heated 8min down.During end of synthesis, add the water of 4ml, vortex takes out whole liquid and crosses C18sep pak post, removes the liquid that drenches.With 2ml5:1 n-hexane/ethyl acetate drip washing C18sep pak pillar, use the drip washing of 2ml n-hexane/ethyl acetate again, collect and all drench fluid, record leacheate activity 500mCi.
3.120 under ℃, feed N
2Dry up, cooling adds the super dry acetonitrile of 200 μ l, adds 3mg6-OH-BTA-1 (2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole), 100ul dimethyl sulfoxide (DMSO) and an amount of K again
2CO
3, reaction 10min, promptly.
Embodiment 102-(4 '-methylamine phenyl)-6-[
18F] the fluorine ethoxyl benzo thiazole ([
18F] O-FEt-PIB) synthetic
1. obtain F-18 ion 2Ci by accelerator production, wherein contain K
222And K
2CO
3, in 100 ℃ of oil baths, feed N
210min dries up moisture, adds the 400ul acetonitrile to two benzene methanesulfonic acid ethylene glycol that is dissolved with 8.6mg, dries up, and repeats 3 times, takes out the reaction flask cooling then;
2. add 500 μ l CH
3CN, 90 ℃ of oil bath heating 5min.During end of synthesis, add the water of 4ml, vortex takes out whole liquid and crosses C18sep pak post, removes the liquid that drenches.With 2ml5:1 n-hexane/ethyl acetate drip washing C18sep pak pillar, use the drip washing of 2ml n-hexane/ethyl acetate again, collect and all drench fluid, record leacheate activity 1000mCi.
3.80 under ℃, feed N
2Dry up, cooling adds the super dry acetonitrile of 500ul, adds 1mg6-OH-BTA-1 (2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole), 300ul dimethyl sulfoxide (DMSO) and an amount of K again
2CO
3, reaction 30min, qualification result is with embodiment 8.
Effect embodiment 1 benzothiazole compound with [
3H]-PIB at the competition of amyloid in the presenile dementia patient brain homogenate in conjunction with experiment
Following experimental procedure is an example with 2-(4 '-methylamine phenyl)-fluorine-based benzothiazole of 6-, and 2-(4 '-(dimethylamine) phenyl)-the fluorine-based benzothiazole of 6-is identical with it with the experimental procedure of 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole.
1. the preparation of solution
1) preparation 1 * 10
-3The dimethyl sulphoxide solution of the 2-of M (4 '-methylamine phenyl)-fluorine-based benzothiazole of 6-.
Dispose the dimethyl sulphoxide solution of 2-(4 '-methylamine phenyl)-fluorine-based benzothiazole of 6-of each concentration according to table 1.
The dimethyl sulphoxide solution preparation table of table 12-(4 '-methylamine phenyl)-fluorine-based benzothiazole of 6-
| Original solution concentration | The dimethyl sulfoxide (DMSO) consumption | Final concentration |
| 0.45mL10 -3M | 1.05mL | 1.5mL3×10 -4M |
| 0.15mL10 -3M | 1.35mL | 1.5mL1×10 -4M |
| 0.45mL10 -4M | 1.05mL | 1.5mL3×10 -5M |
| 0.15mL10 -4M | 1.35mL | 1.5mL1×10 -5M |
| 0.45mL10 -5M | 1.05mL | 1.5mL3×10 -6M |
| 0.15mL10 -5M | 1.35mL | 1.5mL1×10 -6M |
| 0.45mL10 -6M | 1.05mL | 1.5mL3×10 -7M |
| 0.15mL10 -6M | 1.35mL | 1.5mL1×10 -7M |
| 0.45mL10 -7M | 1.05mL | 1.5mL3×10 -8M |
| 0.15mL10 -7M | 1.35mL | 1.5mL1×10 -8M |
| 0.45mL10 -8M | 1.05mL | 1.5mL3×10 -9M |
| 0.15mL10 -8M | 1.35mL | 1.5mL1×10 -9M |
2) getting 1ml people's brain homogenate that homogenate is good (is divided in the 1.5ml dactylethrae,-80 ℃ of preservations, doctor Cai Lisheng by America NI H provides) add 1ml phosphoric acid buffer (PBS) dilution, join in the 15ml homogenizer and manually homogenate 5 times (calculating once back and forth) back and forth, operation needs to finish on ice.Use 8ml PBS drip washing homogenizer in addition, obtain 10ml solution and be kept in the 50ml beaker;
3) get 40 μ l1mCi/mL[
3H]-PIB solution, the alcohol dilution with 4.0ml obtains 4ml specific activity 1.00 μ Ci/100 μ LA solution;
(1) 280 μ lA solution adds the 6.72mlPBS dilution, obtains 4.00 * 10
-2μ Ci/100 μ L solution is kept in the egg type bottle;
(2) prepare 4L PBS (0.2mol/l, pH=7.2～7.4) and make the cell harvestor leacheate.
2. in conjunction with experiment
(1) tubulature
Press shown in the table 2, in 12 * 75mm borosilicate alkane pipe, add dimethyl sulphoxide solution and the 800ulPBS of the 6-F-BTA-1 (2-(4 '-methylamine phenyl)-fluorine-based benzothiazole of 6-) of 10ul different concns respectively.Vortex is until the distance of liquid level from one inch in test tube mouth.Add 100 μ L[
3H] PBS solution and the 100 μ L brain homogenate solution of 6-OH-BTA-1 (2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole).Vortex.Notice that 6-F-BTA-1 can directly add in the pipe, other solution should add along tube wall from the place that is lower than one inch of the mouth of pipe, and the mouth of pipe is sealed with sealing film;
Table 2 is in conjunction with experimental solutions preparation table
| Test tube number | 6-F-BTA-1/DMSO orDMSO | PBS | [ 3H]6-OH-BTA-1/ PBS | Brain homogenate solution |
| 1-4 | 10μLDMSO | 800μL | 100μL | 100μL |
| 5-8 | 10μL1×10 -9M | 800μL | 100μL | 100μL |
| 9-12 | 10μL3×10 -9M | 800μL | 100μL | 100μL |
| 13-16 | 10μL1×10 -8M | 800μL | 100μL | 100μL |
| 17-20 | 10μL3×10 -8M | 800μL | 100μL | 100μL |
| 21-24 | 10μL1×10 -7M | 800μL | 100μL | 100μL |
| 25-28 | 10μL3×10 -7M | 800μL | 100μL | 100μL |
| 29-32 | 10μL1×10 -6M | 800μL | 100μL | 100μL |
| 33-36 | 10μL3×10 -6M | 800μL | 100μL | 100μL |
| 37-40 | 10μL1×10 -5M | 800μL | 100μL | 100μL |
| 41-44 | 10μL3×10 -5M | 800μL | 100μL | 100μL |
| 45-48 | 10μL1×10 -4M | 800μL | 100μL | 100μL |
(2) hatch
In 37 ℃ of water-baths, liquid level was lower than water surface elevation in the pipe, with the hunting of frequency of 60 times/per minute two hours.Simultaneously, the differentiation pros and cons of marking on the Whatman GF/B filter paper, the poly-imines with 0.5% soaks;
(3) clean the cell harvestor pipeline with 1ml PBS, filter paper is attached on the corresponding position.Open suitable passage, begin to collect;
(4) take out with proteic filter paper with tweezers, put into liquid and dodge the measurement bottle, each adds 4mlCytoScint
TMScintillation solution, other three bottles are put wiping and are had or not contamination with detection, and other again three add 100 μ L4.00 * 10
-2μ Ci/100 μ L [
3H] PIB, and respectively add the 4ml scintillation solution.Whenever vortex 1min by all means leaves standstill lucifuge and spends the night;
(5) use liquid scintillation survey meter measurement count, experimental data is by GraphPad Prism4 software processes, obtained a series of anti-S curves (2-(4 '-methylamine phenyl)-fluorine-based benzothiazole of 6-(Fig. 5) with the unit point match, and calculate the suitableeest IC of each compound 2-(4 '-(dimethylamine) the phenyl)-fluorine-based benzothiazole of 6-(Fig. 6) and 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole (Fig. 7)),
50Value, pass through again [
3H] PIB ([tritium] 2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole) and dull-witted brain homogenate bonded saturation curve (Fig. 8), obtain each compound K i value, the result is as shown in table 3.
The affinity costant K of amyloid in table 3 benzothiazole amino benzenes compounds and the dementia people brain homogenate
i
| Benzothiazole amino benzenes compounds | K i(nmol) |
| 2-(4 '-methylamine phenyl)-fluorine-based benzothiazole of 6- | 0.20 |
| 2-(4 '-(dimethylamine) the phenyl)-fluorine-based benzothiazole of 6- | 0.31 |
| 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole (O-FEt-PIB) | 0.17 |
| 2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole (PIB) | 1.59 |
Show as seen the K of PIB thus
iValue is the numerical value maximum in last table, exceeds an order of magnitude approximately than compound of the present invention.Explanation thus, several compounds of the present invention all show the higher avidity than known references Compound P IB.
Effect embodiment 2[
18F] amyloid specificity bonded radioactive automatic developing in O-FEt-PIB and the dull-witted patient's postmortem cerebral hippocampal tissue
The thick dull-witted patient's postmortem cerebral hippocampal of 6 μ m is organized the paraffin serial section, through dimethylbenzene, after the ethanol dewaxing, draws circle with neutral gum in organization edge, immerse again and remove unnecessary natural gum in the ethanol, then half and 200 μ L60 μ Ci/200 μ L [
18F] the PBS solution of O-FEt-PIB at room temperature hatches 25min altogether, and second half section is added to be made into saturated solution into PIB, and all the other are identical.With the PBS solution on PBS flush away surface, immerse each 1min in the second alcohol and water more respectively.Use phosphorus screen video picture 10min, the result as shown in Figure 9.Black region is the radioactivity district that concentrates among the figure, and left figure does not add PIB.Can find out obviously among the figure that adding behind the PIB radioactivity district that concentrates obviously reduces, show [
18F] O-FEt-PIB can combine with the amyloid specificity in the human brain tissue.
Effect embodiment 3F-N-Me and thioflavin S and dull-witted patient's postmortem cerebral tissue amyloid and neurofibrillary tangles specificity bonded fluorescent imaging figure
Dull-witted patient's postmortem cerebral tissue is handled with effect embodiment 2, the brain section of removing neutral gum washs through phosphoric acid buffer, at 40% ethanol that contains 100 μ M F-N-Me and thioflavin S respectively and 60% distilled water, hatched under the room temperature 10 minutes in the solution of pH=10.Use distilled water wash, immersed again in 80% the ethanolic soln contain 0.2%NaOH 2 minutes, and then immersed in the distilled water 10 minutes.Slice, thin piece dries the back to be observed under fluorescent microscope.As shown in Figure 9, left side figure is the fluorescent imaging figure of F-N-Me, and arrow is depicted as the position of amyloid plaques, and border circular areas is the position of neurofibrillary tangles.Right figure is the fluorescent imaging figure of thioflavin S, and arrow is depicted as amyloid plaques, coincide with middle graph patch position.
Effect embodiment 4[
18F] animalcule positron computer layer imaging (PET) experiment of O-FEt-PIB in the rat model brain
6 microgram amyloids are injected at right half cerebral hippocampal place at rat model, and left half brain is as contrasting from body; The physiological saline of the right half injection of brain isodose of normal control group.Detect its right brain by immunohistochemical methods and whether express excessive amyloid, detect on its study of behaviour by water maze laboratory and whether change.The result shows that this model meets right brain amyloid content and is higher than left brain, and memory is than normal control difference.
2mCi[
18F] the PBS solution of O-FEt-PIB in rat model and normal control, carries out microPET scanning 10min by intravenous injection behind the 5min, and the result is shown in Figure 11 and 12.As seen from the figure, [
18F] O-FEt-PIB in the right brain of model mouse than in left brain, having more 0.0001mCi (left 0.0006379mCi, right 0.0007445mCi), and left and right sides brain distribution basic identical (left 0.0005269mCi, right 0.0005372mCi) in the normal control group.Figure 10 be [
18F] FDG ([fluoro-18] deoxyglucose) and the interior amyloid bonded PET scintigram of normal rat brain.Can clearly be seen that by Figure 10,11 and 12, [
18F] O-FEt-PIB shown with [
18F] distribute in the different brain of FDG, the latter contains through unique of drugs approved by FDA listing at present
18The positron emitting tracer of F.
In the specific embodiment of the invention, be used for synthetic reagent 2-amino-6-fluoro-benzothiazole, aminomethyl phenyl formic acid available from Fluka chemical reagents corporation; Aminomethyl phenyl formic acid is available from Aldrich ChemicalCompany; N, the N-dimethylbenzaldehyde is provided free by Taizhou, Zhejiang credit industry doctorization company limited; Dementia people brain homogenate provides (homogenate once more before the use) by America NI H doctor Cai Lisheng; Rat model is provided by Jiangsu atomic medicine institute; Other reagent is all available from Shanghai chemical reagents corporation (unprocessed before using).The use instrument is: AVANCE500 nuclear magnetic resonance analyser (BRUKER); AVATAR370FT-IR infrared spectrometer (Thermo Nicolet); MicroMass GCT CA055 mass spectrograph; BeckmanLC-6500 liquid scintillation survey meter (U.S.); ZT II type bull cell harvestor.
Claims (13)
1. benzothiazole amino benzenes compounds: suc as formula the 2-shown in the I (4 '-(methylamine or dimethylamine) phenyl)-6-fluoro benzothiazole, suc as formula the 2-shown in the II (4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole, and [fluoro-18] 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole shown in formula III;
Wherein, R is H or CH
3
2. the preparation method suc as formula the 2-shown in the I (4 '-(methylamine or dimethylamine) phenyl)-6-fluoro benzothiazole as claimed in claim 1; comprise the steps: under 120～200 ℃; 2-amino-5-fluorobenzene mercaptan and 4-methylamine phenylformic acid or 4-(dimethylamine) phenyl aldehyde under protection of inert gas, are reacted and get final product.
3. the preparation method suc as formula the 2-shown in the II (4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole as claimed in claim 1, comprise the steps: in aprotic solvent, with amount of substance amount ratio 10: 1～1: 10 2-(4 '-methylamine phenyl)-6-hydroxybenzothiazole and p-methyl benzenesulfonic acid fluorine ethyl ester, add anhydrous alkali metal carbonate, alkaline metal iodide makes reaction solvent saturated, react, get final product.
4. the preparation method of benzothiazole amino benzenes compounds as claimed in claim 3, it is characterized in that: described anhydrous alkali metal carbonate is salt of wormwood, yellow soda ash.
5. the preparation method of benzothiazole amino benzenes compounds as claimed in claim 3, it is characterized in that: described alkaline metal iodide is a potassiumiodide, sodium iodide.
6. preparation method as claimed in claim 3 is characterized in that: the temperature of described reaction is 80～120 ℃.
7. the preparation method of [fluoro-18] 2-(4 '-methylamine phenyl)-6-fluorine ethoxyl benzo thiazole shown in formula III as claimed in claim 1, comprise the steps: anhydrous acetonitrile or N that alkaline carbonate is saturated, in the N dimethyl sulfoxide (DMSO), the 2-of 1～10mg (4 '-methylamine phenyl)-6-hydroxybenzothiazole, 1～1000mCi[fluoro-18 with prepared fresh] the fluoro ethyl p-toluenesulfonic esters reacts, gets final product.
8. the preparation method of benzothiazole amino benzenes compounds as claimed in claim 7, it is characterized in that: described alkaline carbonate is salt of wormwood or yellow soda ash.
9. preparation method as claimed in claim 7 is characterized in that: described temperature of reaction is 80～160 ℃.
10. method as claimed in claim 7 is characterized in that: the time of described reaction is 2～60 minutes.
11. method as claimed in claim 7 is characterized in that: after described reaction is finished, product is separated preparation through high performance liquid chromatography, get final product.
12. the medicine of benzothiazole amino benzenes compounds as claimed in claim 1 amyloid beta deposition in preparation detection or video picture animal, human body or tissue or the application in its effective ingredient.
13. application as claimed in claim 12 is characterized in that: described medicine is the video picture of positron emission computerized tomography technology or fluorescent imaging technology or mr imaging technique medicine.
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| WO2006014381A2 (en) * | 2004-07-02 | 2006-02-09 | University Of Pittsburgh | Use of thioflavin radiolabeled derivatives in amyloid imaging gor assessing anti-amyloid therapies |
| CN1784392A (en) * | 2003-03-14 | 2006-06-07 | 匹兹堡大学 | Benzothiazole derivative compounds,compositions and uses |
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| WO2003068269A1 (en) * | 2002-02-13 | 2003-08-21 | Amersham Plc | Benzothiazole derivatives for in vivo imaging of amyloid plaques |
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