CN101466711A - Novel compound having affinity for amyloid - Google Patents

Abstract

The present invention provides a compound which has affinity with amyloid, shows sufficiently rapid clearance from normal tissues and is suppressed in toxicity such as mutagencity. Provided is a compound represented by the following formula (1) or a salt thereof: wherein A 1 , A 2 , A 3 and A 4 independently represents a carbon or nitrogen; R<1> is a halogen substituent; R<2> is a halogen substituent; and m is an integer of 0 to 2, provided that at least one of R<1> and R<2> is a radioactive halogen substituent, at least one of A 1 , A 2 , A 3 and A 4 represents a carbon, and R<1> binds to a carbon represented by A 1 , A 2 , A 3 or A 4 as well as a low-toxic diagnostic agent comprising a compound represented by the preceding formula or a salt thereof.

Description

The new compound that amyloid is had affinity

Technical field

[0001] the present invention relates to be used to diagnose the compound of cerebral retrogressive disease.More specifically, the present invention relates in alzheimer's disease and other and amyloid are accumulated the diagnosis of diseases associated, to be used for compound lesions position detection amyloid.

Background technology

[0002] the disease general designation that is caused by precipitation in the various in vivo organ or tissues of the fibrous protein that are known as amyloid is made amyloidosis.The common trait of amyloidosis is that the fibrous protein that are known as amyloid that are rich in β-layer (sheet) structure precipitate in various organs systemicly or in the site locally, to such an extent as to triggered dysfunction in organ or tissue.

[0003] alzheimer's disease (below be called AD) is a kind of typical amyloidosis, known it be a kind of disease that causes by dementia.Along with the precipitation accumulation of amyloid in brain, this disease is fatefulue, therefore, it is said, this is a kind ofly to compare the disease that more is subjected to social concerns with other amyloidosis.In recent years, AD patient's quantity of the developed country of aging society increases sharply, and has therefore caused social concern.

[0004] from the viewpoint of histopathology, AD is characterised in that three kinds of pathologic findings in brain find, i.e. the development of senile plaque, the formation of neurofibrillary tangle and neuron loss widely.Senile plaque has the structure of mainly being made up of amyloid, it is said that it is clearly in initial period that AD falls ill, therefore, and in clinical symptom generation precontract 10 or in brain, will find this pathology phenomenon more for many years.

[0005] diagnosis AD, be included in diagnostic imaging (diagnostic imaging) for example the combination of CT and MRI help to carry out the various evaluations (for example, Hasegawa scale, ADAS-Jcog and MMSE) of various cognitive functions down.But, lower based on method diagnostic sensitivity in the morbidity commitment of the evaluation of these cognitive functions, in addition, exist diagnostic result to be subjected to the problem of individual congenital cognitive function influence.Current, when AD patient is still alive, in fact can not carry out making a definite diagnosis of AD, need be because make a definite diagnosis to the examination of living tissue (non-patent literature 1) of disease portion.

[0006] simultaneously, a report points out, the amyloid that constitutes senile plaque is the agglutinator of amylaceous β albumen (below be called A β).Simultaneously, a lot of reports point out that A β agglutinator has formed and caused the toxic β of neurocyte-layer structure.Based on these discoveries, so-called " amyloid chain reaction hypothesis " proposed, the brain precipitation that it proposes A β has caused downstream phenomenon, the i.e. formation of neurofibrillary tangle and neuron loss (non-patent literature 2).

[0007], attempt to use the compound that has a high affinity with the amyloid thing that serves as a mark to carry out detecting in the body of AD recently based on these facts.

The a lot of such probe that is used for the diagnostic imaging of brain amyloid is hydrophobic low-molecular weight compound, and itself and amyloid have the affinity of height, and the brain transitivity is very high, and with various radioactive substances for example ¹¹C, ¹⁸F and ¹²³The I mark.For example, there is report to point out, ¹¹C or radioactive halogen-labeled compound comprise for example 6-iodo-2-[4 '-(N of various thioflavin derivatives, the N-dimethylamino) phenyl] benzothiazole (below be called TZDM) and 6-hydroxyl-2-[4 '-(N-methylamino) phenyl] benzothiazole (below be called 6-OH-BTA-1) (patent documentation 1, non-patent literature 3); Stilbene compound for example (E)-4-methylamino-4 '-hydroxyl stibene (below be called SB-13) and (E)-4-dimethylamino-4 '-iodine stibene (below be called m-I-SB) (patent documentation 2, non-patent literature 4, non-patent literature 5); Benzoxazole derivative is 6-iodo-2-[4 '-(N for example, the N-dimethylamino) phenyl] benzoxazole (below be called IBOX) and 6-[2-(fluorine) oxyethyl group]-2-[2-(2-dimethylamino thiazole-5-yl) vinyl] benzoxazole (non-patent literature 6, non-patent literature 7); The DDNP derivative is 2-(1-{6-[(2-fluoro ethyl) (methyl) amino for example]-the 2-naphthyl } ethylidene) propane dinitrile (below be called FDDNP) (patent documentation 4, non-patent literature 8); With imidazopyridine derivatives 6-iodo-2-[4 '-(N, N-dimethylamino) phenyl for example] imidazo [1,2-a] pyridine (below be called IMPY) (patent documentation 3, non-patent literature 9).In addition, to being used for some probe of diagnostic imaging, carried out human body image research, and reported with the normal people and compared in AD patient's brain, have significant radioactivity to accumulate (non-patent literature 10, non-patent literature 11, non-patent literature 12, non-patent literature 13).

[0008] [patent documentation 1] JP-T-2004-506723

[patent documentation 2] JP-T-2005-504055

[patent documentation 3] JP-T-2005-512945

[patent documentation 4] JP-T-2002-523383

[non-patent literature 1] J.A.Hardy ﹠amp; G.A.Higgins, " Alzheimer ' sDisease:The Amyloid Cascade Hypothesis. ", Science, 1992,256, p.184-185

People such as [non-patent literature 2] G.McKhann, " Clinical diagnosis ofAlzh eimer ' s disease:Report of the NINCDS-ADRDA Work Groupunder the auspices of Department of Health and Human ServicesTask Force on Alzheimer ' s Disease. ", Neurology, 1984,34, p.939-944

People such as [non-patent literature 3] Z.-P.Zhuang, " RadioiodinatedStyrylbenzenes and Thioflavins as Probes for Amyloid Aggregates. ", J.Med.Chem., 2001,44, p.1905-1914

People such as [non-patent literature 4] Masahiro Ono, " 11C-Labelled stilbenederivatives as A β-aggregate-specific PET imaging agents forAlzheimer ' s disease. ", Nuclear Medicine and Biology, 2003,30, p.565-571

People such as [non-patent literature 5] H.F.Kung, " Novel Stilbenes as Probes foramyloidplaques. ", J.American Chemical Society, 2001,123, P.12740-12741

People such as [non-patent literature 6] Zhi-Ping Zhuang, " IBOX (2-(4 '-dimethylaminophenyl)-6-iodobensoxazole): a ligandfor imaging amyloid plaques in the brain ", Nuclear Medicine andBiology, 2001,28, p.887-894

People such as [non-patent literature 7] Furumoto Y, " [ ¹¹C] BF-227:A New ¹¹C-Labelled 2-Ethenylbenzoxazole Derivative for Amyloid-β PlaquesImaging. ", European Journal of Nuclear Medicine and MolecularImaging, 2005,32, Sup.1, P759

People such as [non-patent literature 8] Eric D.Agdeppa, " 2-Dialkylamino-6-Acylmalononitrile Substituted Naphthalenes (DDNP Analogs): Novel Diagnostic and Therapeutic Tools in Alzheimer ' s Disease. ", Molecular Imaging and Biology, 2003,5, p.404-417

People such as [non-patent literature 9] Zhi-Ping Zhuang, " Structure-ActivityRelationship of Imidazo[1; 2-a] pyridines as Ligands for Detecting β-Amyloid Plaques in the Brain. ", J.Med.Chem, 2003,46, p.237-243

People such as [non-patent literature 10] W.E.Klunk, " Imaging brain amyloid inAlzheimer ' sdisease with Pittsburgh Compound-B. ", Ann.Neurol.2004,55, p.306-319

People such as [non-patent literature 11] Nicolaas P.L.G.Verhoeff, " In-VivoImaging of Alzheimer Disease β-Amyloid With[11C] SB-13 PET. ", American Journal of Geriatric Psychiatry, 2004,12, p.584-595

People such as [non-patent literature 12] Hiroyuki Arai, " [11C]-BF-227AND PET toVisualize Amyloid in Alzheimer ' s Disease Patients ", Alzheimer ' s ﹠amp; Dementia:The Journal of the Alzheimer ' s Association, 2006,2, Sup.1, S312

People such as [non-patent literature 13] Christopher M.Clark, " Imaging Amyloidwith I123IMPY SPECT " Alzheimer ' s ﹠amp; Dementia:The Journal of theA1zheimer ' s Association, 2006,2, Sup.1, S342

Summary of the invention

The problem that the present invention will solve

[0009] as mentioned above, disclosing that each compound can be used as with the amyloid is the probe of the diagnostic imaging of object, and has explored its clinical application.

Experiment in normal mouse shows, with [ ¹²⁵I] TZDM, IBOX and the m-I-SB of mark can transfer in the brain after using 2 minutes.But the removing of these compounds from healthy tissues is inadequate, and can accumulate (people such as JP-T-2005-512945:Zhi-Ping Zhuang along with the passing of using the back time in brain gradually, Nuclear Medicine andBiology, 2001,28, P.887-894; People such as H.F.Kung, J.Am.Chem.Soc., 2001,123, p.12740-12741).When the removing from healthy tissues is insufficient, just a problem has appearred: accumulate the site amyloid and can not obtain enough contrasts.[ ¹¹C] SB-13 of mark shown that in the experiment of rat it has the removing performance from healthy tissues, but that removing speed also is far from being is enough fast (people such as Masahiro Ono, Nuclear Medicine andBiology, 2003,30, p.565-571).

[0010] simultaneously, according to disclosure, as with [ ¹²⁵I] shown in the experimental result of compound of mark, compound with imidazopyridine skeleton for example IMPY has and transfers in the brain after using and the character of accumulating on amyloid, and it also has the advantageous property from healthy tissues rapidly removed different with above-claimed cpd.But IMPY is a kind of compound that is positive in reverse mutation test.For with the probe of this compound, must take into full account dosage and administering mode (international open WO03/106439) as diagnostic imaging.

It is reported that FDDNP also is positive in reverse mutation test.(international open WO03/106439).

[0011] the diagnostic imaging probe of target amyloid is preferably removed rapid enough with the excellent affinity of amyloid and as IMPY from healthy tissues, but can suppress for example compound of mutagenicity of toxicity again.But, the compound with above-mentioned character was not also disclosed.

In addition, according to the result (with reference to following Comparative Example I I-6) of our research, verified, IMPY does not have to accumulate on sedimentary white matter or other sites amyloid non-specificly.As the AD diagnostic reagent, the non-specific of site that employed compound must be able to suppress beyond the amyloid precipitation site accumulated, and still, also do not disclose the compound with such character.

[0012] the present invention in view of what follows finishes just, wherein discloses each compound as the probe of the diagnostic imaging of target amyloid, but also not having compound to be proved has clinical permissible character; The object of the present invention is to provide a kind ofly to have affinity, demonstrate and from healthy tissues, remove rapid enough, suppressed for example compound of mutagenicity of toxicity in addition for amyloid.

Solve the method for problem

[0013] inventor has been found that from having imidazopyridine-phenyl skeleton or similar skeleton, wherein phenyl and has one group of compound that can obtain to satisfy above-mentioned needs the compound of the carbon atom that links to each other with Sauerstoffatom, has finished the present invention thus.

[0014] particularly, according to an aspect of the present invention, provide the compound shown in the following formula (1):

[0015]

Or its salt and comprise the hypotoxicity diagnostic reagent of the alzheimer's disease of the compound or its salt shown in the above-mentioned formula (1).

[0016] in formula (1), R ¹And R ²Be halogenic substituent, at least one in them is the radiohalogen substituting group.Various elements can be used as halogen, preferably fluorine, bromine or iodine can be used.As radiohalogen, can use various elements, halogen is preferably selected from ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I or ¹³¹I, halogen more preferably is selected from ¹⁸F, ¹²³I or ¹²⁵I.

[0017] A ₁, A ₂, A ₃And A ₄Represent carbon or nitrogen independently of one another, necessary is at least one the expression carbon in them.Preferably, A ₁, A ₂, A ₃And A ₄In three or more expression carbon, more preferably they all represent carbon.In formula (1), R1 and A ₁, A ₂, A ₃Or A ₄Shown carbon links to each other.

In addition, m is the integer of 0-2.R ¹Binding site A preferably ₃Shown carbon, that is, and the carbon of 6-position.

[0018] according to another aspect of the present invention, provide the compound shown in a kind of following formula (2):

[0019]

[0020] or its salt.

[0021] in formula (2), R ³Be to be selected from non-radioactive halogen substituting group, nitro substituent, alkyl chain to have the trialkyl stannyl substituting group of 1-4 carbon atom and the group of triphenyl stannyl.As the trialkyl stannyl substituting group, can use various substituting groups, preferably use trimethylammonium stannyl substituting group and tributyl stannyl substituting group.

[0022] R ⁴Be to be selected from non-radioactive halogen substituting group, mesyloxy substituting group, trifluoro-methanesulfonyl oxy substituting group or the substituent group of aromatic series sulfonyloxy.As aromatic series sulfonyloxy substituting group, preferably can use toluenesulphonic acids, nitrobenzene-sulfonic acid and Phenylsulfonic acid.

[0023] as R ³And R ⁴The non-radioactive halogen substituting group, can use various halogens, but preferably can use can as the halogen of the target spot of the nucleophilic substitution reaction that uses radioactive fluorine or can as with the halogen of the target spot of the isotope exchange reaction of radioiodine, more preferably can use chlorine, iodine or bromine.Preferred R ³And R ⁴In at least one be the non-radioactive halogen substituting group.

[0024] A ₅, A ₆, A ₇And A ₈Represent carbon or nitrogen independently of one another, necessary is at least one the expression carbon in them.Preferably, A ₅, A ₆, A ₇And A ₈In three or more expression carbon, more preferably they all represent carbon.In formula (2), R3 and A ₅, A ₆, A ₇Or A ₈Shown carbon links to each other.

In addition, n is the integer of 0-2.

[0025] in addition,, provide a kind of compound with imidazopyridine-phenyl skeleton according to the present invention, wherein, phenyl 4 '-carbon atom of position replaces by Sauerstoffatom and end or the unsubstituted alkyl chain links to each other.R ³Binding site A preferably ₇Shown carbon, that is, and the carbon of 6-position.

[0026] particularly, another aspect of the present invention provides the compound shown in the following formula (3):

[0027]

Or its salt, and the hypotoxicity diagnostic reagent that comprises the alzheimer's disease of the compound or its salt shown in the above-mentioned formula (3).Particularly, the compound or its salt shown in the above-mentioned formula (3) provides the hypotoxicity of alzheimer's disease and the diagnostic reagent of high specific.The hypotoxicity of the alzheimer's disease here and the diagnostic reagent of high specific are meant a kind of like this diagnostic reagent, it has the character of accumulating on amyloid, and accumulate in other sites hardly, even or accumulate also and can remove rapidly from those other sites, therefore, in the time of using back one fixed length, shown high degree of specificity to the amyloid image.

[0028] in formula (3), R ⁵It is the radiohalogen substituting group.As R ⁵, can use various radiohalogens, preferred radiohalogen is selected from ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I, more preferably halogen is selected from ¹⁸F or ¹²³I.

R ⁶Be to be selected from hydrogen, hydroxyl, methoxyl group, carboxyl, amino, N-methylamino, N, the group of N-dimethylamino and cyano group.R ⁶Preferably hydrogen, hydroxyl, carboxyl or amino, more preferably hydrogen or hydroxyl, preferred especially hydroxyl.

[0029] A ₉, A ₁₀, A ₁₁And A ₁₂Represent carbon or nitrogen independently of one another, necessary is at least one the expression carbon in them.Preferably, A ₉, A ₁₀, A ₁₁And A ₁₂In three or more expression carbon, more preferably they all represent carbon.In formula (3), R ⁵With A ₉, A ₁₀, A ₁₁Or A ₁₂Shown carbon links to each other.In addition, R ⁵Binding site A preferably ₁₁Shown carbon, that is, and the carbon of 6-position.

In addition, p is the integer of 0-2.

[0030] according to another aspect of the present invention, provide the compound shown in a kind of following formula (4):

[0031]

[0032] or its salt.

[0033] in formula (4), R ⁷Be to be selected from trialkyl ammonium group, the alkyl chain that non-radioactive halogen substituting group, nitro substituent, alkyl chain have 1-4 carbon atom to have the trialkyl stannyl substituting group of 1-4 carbon atom and the group of triphenyl stannyl.As the non-radioactive halogen substituting group, can use can as the halogen of the target spot of the nucleophilic substitution reaction that uses radioactive fluorine or can as with the halogen of the target spot of the isotope exchange reaction of radioiodine, more preferably can use chlorine, iodine or bromine.As the trialkyl stannyl substituting group, can use various substituting groups, preferably use trimethylammonium stannyl substituting group and tributyl stannyl substituting group.

[0034] R ⁸Be to be selected from hydrogen, hydroxyl, methoxyl group, carboxyl, amino, N-methylamino, N, the group of N-dimethylamino and cyano group.R ⁸Preferably hydrogen, hydroxyl, carboxyl or amino, more preferably hydrogen or hydroxyl, preferred especially hydroxyl.

[0035] A ₁₃, A ₁₄, A ₁₅And A ₁₆Represent carbon or nitrogen independently of one another, necessary is at least one the expression carbon in them.Preferably, A ₁₃, A ₁₄, A ₁₅And A ₁₆In three or more expression carbon, more preferably they all represent carbon.In formula (4), R ⁷With A ₁₃, A ₁₄, A ₁₅Or A ₁₆Shown carbon links to each other.In addition, R ⁷Binding site A preferably ₁₅Shown carbon, that is, and the carbon of 6-position.

In addition, q is the integer of 0-2.

The invention effect

[0036] the invention provides and a kind ofly have affinity for amyloid, from healthy tissues, remove rapid enough, and suppress for example compound of mutagenicity of toxicity, and the hypotoxicity diagnostic reagent of alzheimer's disease, provide a kind of in addition and had high affinity for amyloid, and good compound in the amyloid image in vivo, and a kind of diagnostic reagent that has high degree of specificity for alzheimer's disease.

Description of drawings

[0420] Fig. 1-the 1st, 6-tributyl stannyl-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 1-2 is 6-bromo-2-[4 '-(3 ＂-tolysulfonyl oxygen base propoxy-) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 1-the 3rd, 6-bromo-2-[4 '-(2 ＂-tolysulfonyl oxygen base oxethyl) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 1-the 4th, 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 1-the 5th, 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-synthetic route of 6-iodine imidazo [1,2-a] pyridine.

Fig. 1-the 6th, 6-bromo-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 1-the 7th, 2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-synthetic route of 6-iodine imidazo [1,2-a] pyridine.

Fig. 1-the 8th, 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-synthetic route of 6-iodine imidazo [1,2-a] pyridine.

Fig. 1-the 9th, [ ¹²⁵I]-synthetic route of 2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine.

Fig. 1-the 10th, the synthetic route of 2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine.

Fig. 1-the 11st, the amyloid concentration in the sample solution and the relation of radioactive concentration.

Fig. 1-12 (a) is the autoradiogram(ARGM) of the brain section after injection Compound I-7, and Fig. 1-12 (b) is the fluorescence microscope images (enlarged view in the site of injection amyloid suspension) of the painted sample of thioflavin T.

Fig. 1-the 13rd, 6-tributyl stannyl-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 1-14 (a) is the autoradiogram(ARGM) at injection Compound I-9 back brain section, and Fig. 1-14 (b) is the fluorescence microscope images (enlarged view in the site of injection amyloid suspension) of the painted sample of thioflavin T.

Fig. 2-the 1st, 2-[4 '-(2-hydroxyl-oxethyl) phenyl]-synthetic route of 6-iodine imidazo [1,2-a] pyridine (on-radiation iodate form).

Fig. 2-the 2nd, 6-tributyl stannyl-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 2-the 3rd, the synthetic route of 2-(4 '-ethoxyl phenenyl)-6-iodine imidazo [1,2-a] pyridine (on-radiation iodate form).

Fig. 2-the 4th, the synthetic route of 6-tributyl stannyl-2-(4 '-ethoxyl phenenyl) imidazo [1,2-a] pyridine.

Fig. 2-5 (a) is in injection ¹²³The autoradiogram(ARGM) of brain section behind the I-IMPY, Fig. 2-5 (b) are the fluorescence microscope images (enlarged view in the site of injection amyloid suspension) of the painted sample of thioflavin T.

Fig. 2-6 (a) is at injection 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³I] autoradiogram(ARGM) of brain section behind iodine imidazo [1, the 2-a] pyridine, Fig. 2-6 (b) is the fluorescence microscope images (enlarged view in the site of injection amyloid suspension) of the painted sample of thioflavin T.

Fig. 2-7 (a) be the injection 2-(4 '-ethoxyl phenenyl]-6-[ ¹²³I] autoradiogram(ARGM) of brain section behind iodine imidazo [1, the 2-a] pyridine, Fig. 2-7 (b) is the fluorescence microscope images (enlarged view in the site of injection amyloid suspension) of the painted sample of thioflavin T.

Fig. 2-the 8th, 2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-synthetic route of 6-iodine imidazo [1,2-a] pyridine (on-radiation iodate form).

Fig. 2-the 9th, 6-tributyl stannyl-2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 2-the 10th, 2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl]-synthetic route of 6-iodine imidazo [1,2-a] pyridine (on-radiation iodate form).

Fig. 2-the 11st, 6-tributyl stannyl-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl] synthetic route of imidazo [1,2-a] pyridine.

Fig. 2-12 (a) is the autoradiogram(ARGM) of brain section behind injection Compound I I-4, and Fig. 2-12 (b) is the fluorescence microscope images (enlarged view in the site of injection amyloid suspension) of the painted sample of thioflavin T.

Fig. 2-13 (a) is the autoradiogram(ARGM) of brain section behind injection Compound I I-6, and Fig. 2-13 (b) is the fluorescence microscope images (enlarged view in the site of injection amyloid suspension) of the painted sample of thioflavin T.

Embodiment

[0037] The synthetic method of the compound of I. above-mentioned formula (1) or (2)

(synthetic method of the precursor compound of radioactive halogen-labeled compound)

Below, with 6-tributyl stannyl-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] imidazo [1,2-a] pyridine is example, describes the synthetic method of precursor compound of the radioactive halogen-labeled compound of one embodiment of the invention.

[0038] at first, with 4 '-hydroxy acetophenone and cupric bromide reaction, preparation 2-bromo-4 '-hydroxy acetophenone (Fig. 1-1, operation 1).At this moment, can carry out this reaction according to usual way, for example at document King, L.Carroll and Ostrum, G.Kenneth, Journal ofOrganic Chemistry, 1964,29 (12), the method described in p.3459-3461.

[0039] then, with the 2-bromo-4 of above-mentioned preparation '-hydroxy acetophenone and 2-amino-5-bromopyridine reaction, with preparation 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine (Fig. 1-1, operation 2).Can finish this operation according to following method.

[0040] at first, with 2-bromo-4 '-hydroxy acetophenone and 2-amino-5-bromopyridine be dissolved in inert solvent for example in the acetonitrile, they were reacted 2 to 6 hours each other, with the be white in color hydrobromate of sedimentary 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine of preparation.The solvent of Shi Yonging can be acetonitrile or other solvents that are usually used in same reaction, for example methyl alcohol and acetone in this case.Temperature of reaction can be the temperature that allows backflow, for example when solvent is acetonitrile is 90 ℃.The amount of employed solvent can be the amount that is enough to influence reaction, but should be noted in the discussion above that and will be difficult to obtain the precipitation of reaction product if solvent is too many.For example, when in this reaction, use be the 2-bromo-4 that is equivalent to the 10mmol amount '-during hydroxy acetophenone, the amount of employed solvent can be about 40～50mL.

[0041] then, filtering reacting solution is to reclaim precipitation.This white precipitate is suspended in the mixing solutions of methanol (1:1).Then, the saturated aqueous solution of sodium bicarbonate is added wherein with the amount excessive very bigly with respect to the suspendible precipitation, with release as sedimentary 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine.With the sedimentation and filtration that newly produces, to reclaim 6-bromo-2-as this operation target compound (4 '-hydroxy phenyl) imidazo [1,2-a] pyridine (Fig. 1-1, operation 2).The not special restriction of the amount of the mixing solutions of water/methyl alcohol is as long as it is enough to the influence reaction.But, should be noted in the discussion above that if the amount of mixing solutions is too much, will interference product separate out.For example, when use be the 2-bromo-4 that is equivalent to the 10mmol amount '-during hydroxy acetophenone, the amount of the mixing solutions of operable water/methyl alcohol is about 40～100mL.To the not special restriction of the amount of sodium bicarbonate, as long as it is excessive very bigly with respect to being precipitated as reaction substrate above-mentioned.For example, when reacting under these conditions, the amount that joins the saturated aqueous solution of the sodium bicarbonate in the reaction soln can be about 25mL.

[0042] then, with the 6-bromo-2-of above-mentioned preparation (4 '-hydroxy phenyl) imidazo [1,2-a] pyridine thorough drying, and be dissolved in N, dinethylformamide is to wherein adding salt of wormwood and 3-bromo-1-fluoropropane.At room temperature reaction soln is stirred and spends the night, obtain 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] imidazo [1,2-a] pyridine (Fig. 1-1, operation 3).The amount of employed salt of wormwood is the hydrobromic amount that can neutralize and during reaction be produced by 3-bromo-1-fluoropropane, and typical mol ratio is about twice of auxiliary material 3-bromo-1-fluoropropane.Can use the 3-bromo-1-fluoropropane excessive with respect to reaction substrate, typical mol ratio is about 1.5 times of reaction substrate 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine.

[0043] with 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl that is obtained] imidazo [1,2-a] pyridine is dissolved in diox, after adding triethylamine, adds the tetrakis triphenylphosphine palladium of two (tributyl tins) and catalytic amount.This reaction mixture is heated, and reacted about 24 hours down at about 90 ℃, and distillation removes and desolvates then, carry out chromatographic refining, to obtain 6-tributyl stannyl-2-[4 '-(3 ＂-fluorine propoxy-) phenyl as target compound] imidazo [1,2-a] pyridine (Fig. 1-1, operation 4).At this moment, the amount of employed two (tributyl tins) can be the amount that satisfies with respect to the excessive condition of reaction substrate, particularly, its mol ratio is with respect to reaction substrate 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] about 1.5 times of imidazo [1,2-a] pyridine.

[0044] when to obtain substituting group in the 6-position of imidazopyridine ring be the substituent compound of trialkyl stannyl beyond the tributyl stannyl substituting group, can in operation 4, use various two (trialkyltins) of suitable purpose to replace two (tributyl tins).For example, when synthesizing when having trimethylammonium stannyl substituting group as substituent compound, can in operation 4, carry out and above-mentioned same reaction with two (tin trimethyls) in the 6-position.

[0045] binding site of the functional group on the imidazopyridine ring is the compound of the carbon atom beyond the carbon of 6-position, can have bromine and pyridine ring replaces the 2-amino-5-bromopyridine in the operation 2 to obtain at each compound of different loci bonding by use.For example, when the binding site of functional group is the 8-position carbon of imidazopyridine ring, can use 2-amino-3-bromopyridine to replace 2-amino-5-bromopyridine in the operation 2.

[0046] in addition, the marker site of radiohalogen is the substituent precursor compound of alkoxyl phenyl that links to each other with the carbon atom of the 2-position of imidazopyridine ring, can replace 3-bromo-1-fluoropropane in the operation 3 by using 3-bromo-1-propyl alcohol, compound and Tosyl chloride or the same thing that generates reacted and obtain.For example, can synthesize 6-bromo-2-[4 '-(3 ＂-tolysulfonyl oxygen base propoxy-) phenyl by following method] imidazo [1,2-a] pyridine.

[0047] at first, with the 6-bromo-2-of above-mentioned preparation (4 '-hydroxy phenyl) imidazo [1,2-a] pyridine is dissolved in N, dinethylformamide, replenish this solution with salt of wormwood and 3-bromo-1-propyl alcohol, and at room temperature stir and spend the night, obtain 6-bromo-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl] imidazo [1,2-a] pyridine.It is dissolved in pyridine, and replenishes Tosyl chloride under ice bath, reaction at room temperature obtains 6-bromo-2-[4 '-(3 ＂-tolysulfonyl oxygen base propoxy-) phenyl as target compound then] imidazo [1,2-a] pyridine.The amount of employed Tosyl chloride can be excessive with respect to reaction substrate in this case, and typical mol ratio is reaction substrate 6-bromo-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl] about 2 times of imidazo [1,2-a] pyridine.

[0048] with the 2-position phenyl bonded alkoxy group substituting group and 4 of imidazopyridine ring '-compound that another position beyond the position links to each other, for example, 3 '-position has 6-tributyl stannyl-2-[3 '-(3 ＂-fluorine propoxy-) phenyl of fluorine propoxy-] imidazo [1,2-a] pyridine, can be synthetic according to reaction same as described above, except in operation 1, use 3 '-hydroxy acetophenone replaces 4 '-hydroxy acetophenone is as reaction raw materials.

[0049] (synthetic method of radioactive halogen-labeled compound)

Then, with 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine is example, describes the preparation method of radioactive halogen-labeled compound according to another aspect of the present invention.

[0050] for 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²³I] preparation of iodine imidazo [1,2-a] pyridine, at first obtain to be used for mark [ ¹²³I] IodineSodium Solution.[ ¹²³I] radioiodine for example can be target spot by using with xenon, the currently known methods that is exposed under the proton bombardment obtains.By use currently known methods should [ ¹²³I] radioiodine make [ ¹²³I] IodineSodium Solution, be used for mark.

[0051] then, with labelled precursor 6-tributyl stannyl-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] imidazo [1,2-a] pyridine is dissolved in the inert organic solvents, to wherein add will [ ¹²³I] the iodine piece is dissolved in solution, acid and the oxygenant of water, makes its reaction to obtain 2-[4 '-(3 ＂-fluorine propoxy-) phenyl as target compound]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.As the inert organic solvents of this precursor compound of dissolving, can use with labelled precursor with [ ¹²³I] the iodine piece do not have reactive all kinds of SOLVENTS, preferably can use methyl alcohol.

[0052] as acid, can use various acid, preferred hydrochloric acid.

For the not special restriction of oxygenant,, preferably use hydrogen peroxide or Peracetic Acid as long as it can make the iodine oxidation in reaction soln.The amount of the oxygenant that is added can be the amount that is enough to iodine oxide in reaction soln.

[0053], can synthesize by the labelled precursor that uses the radiohalogen that is fit to this purpose to come mark to be fit to synthetic purpose with the radioactive halogen-labeled compound beyond the iodine.For example, for Synthetic 2-[4 '-(3 ＂-[ ¹⁸F] the fluorine propoxy-) phenyl]-6-bromine imidazo [1,2-a] pyridine, can be in the presence of phase-transfer catalyst and salt of wormwood, with labelled precursor 6-bromo-2-[4 '-(3 ＂-tolysulfonyl oxygen base propoxy-) phenyl] imidazo [1,2-a] pyridine with [ ¹⁸F] the fluoride ion reaction.

[0054] method of the compound of the synthetic above-mentioned formula (3) of II. or (4)

(synthetic method of the precursor compound of radioactive halogen-labeled compound)

Below, with 6-tributyl stannyl-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl] imidazo [1,2-a] pyridine is example, describes the method according to the precursor compound of the halogen-labeled compound of one embodiment of the invention synthesizing radioactive.

[0055] in order to prepare 6-tributyl stannyl-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl] imidazo [1,2-a] pyridine, at first, with 4 '-hydroxy acetophenone and cupric bromide reaction, preparation 2-bromo-4 '-hydroxy acetophenone (Fig. 2-1, operation 1).At this moment, can carry out this reaction according to usual way, for example at document King, L.Carroll and Ostrum, G.Kenneth, Journal ofOrganic Chemistry, 1964,29 (12), the method described in p.3459-3461.

[0056] then, with the 2-bromo-4 of above-mentioned preparation '-hydroxy acetophenone and 2-amino-5-iodine pyridine reaction, with preparation 2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 2-1, operation 2).Can finish this operation according to following method.

[0057] at first, with 2-bromo-4 '-hydroxy acetophenone and 2-amino-5-iodine pyridine be dissolved in inert solvent for example in the acetonitrile, they were reacted 2 to 6 hours each other, with the be white in color hydrobromate of sedimentary 2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine of preparation.The solvent of Shi Yonging can be acetonitrile or other solvents that are usually used in same reaction, for example methyl alcohol and acetone in this case.Temperature of reaction can be the temperature that allows backflow, for example when solvent is acetonitrile is 110 ℃.The amount of employed solvent can be the amount that is enough to influence reaction, but should be noted in the discussion above that and will be difficult to obtain the precipitation of reaction product if solvent is too many.For example, when in this reaction, use be the 2-bromo-4 that is equivalent to the 10mmol amount '-during hydroxy acetophenone, the amount of employed solvent can be about 40～80mL.

[0058] then, filtering reacting solution is to reclaim precipitation.This white precipitate is suspended in the mixing solutions of methanol (1:1).Then, the saturated aqueous solution of sodium bicarbonate is added wherein with the amount excessive very bigly with respect to the suspendible precipitation, with release as sedimentary 2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine.With the sedimentation and filtration that newly produces, to reclaim 2-as this operation target compound (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 2-1, operation 2).The not special restriction of the amount of the mixing solutions of methanol is as long as it is enough to the influence reaction.But, should be noted in the discussion above that if the amount of mixing solutions is too much, with separating out of interference product.For example, when use be the 2-bromo-4 that is equivalent to the 10mmol amount '-during hydroxy acetophenone, the amount of the mixing solutions of operable methanol is about 40 to 100mL.To the not special restriction of the amount of sodium bicarbonate, as long as it is excessive very bigly with respect to the above-mentioned precipitation as reaction substrate.For example, when reacting under these conditions, the amount that joins the saturated aqueous solution of the sodium bicarbonate in the reaction soln can be about 50mL.

[0059] here, ethylene bromohyrin and tert-butyl diphenyl chlorosilane (TBDPSC1) are reacted each other, with other preparation 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane (Fig. 2-1, operation 3).At this moment, can carry out this reaction according to usual way, for example at document OrganicSyntheses, Coll.Vol.10, p.170 (2004); Vol.79, the p.59 method described in (2002).

[0060] then, with the 2-of above-mentioned preparation (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine thorough drying, and be dissolved in N, dinethylformamide is to wherein adding salt of wormwood and 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane.With this mixture at about 90 ℃ of following stir abouts after 2 hours, add saturated sodium-chloride water solution, use ethyl acetate extraction, concentrate ethyl acetate layer, carry out chromatographic refining, obtain 2-[4 '-(2 ＂-tert-butyl diphenyl siloxy-oxyethyl group) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 2-1, operation 4).The amount of employed salt of wormwood is the hydrobromic amount that can neutralize and during reaction be produced by 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane, and typical mol ratio is about 2～3 times of auxiliary material 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane.In addition, can use 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane excessive with respect to reaction substrate, typical mol ratio is about 1.5 times of reaction substrate 2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine.

[0061] then; with tetrabutyl ammonium fluoride with 2-[4 '-(2 ＂-tert-butyl diphenyl siloxy-oxyethyl group) phenyl that is obtained]-6-iodine imidazo [1; 2-a] the t-butyldiphenylsilyl deprotection of pyridine; obtain 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1; 2-a] pyridine (Fig. 2-1, operation 5).At this moment, can carry out this reaction according to usual way, for example at document Organic Syntheses, Coll.Vol.9, p.417 (1998); Vol.74, the p.248 method described in (1997).

[0062] with 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl that is obtained]-6-iodine imidazo [1,2-a] pyridine is dissolved in diox, triethylamine added wherein.Then, the tetrakis triphenylphosphine palladium with two (tributyl tins) and catalytic amount adds wherein.This reaction mixture is heated, and reacted about 24 hours down at about 90 ℃, and distillation removes and desolvates then, carry out chromatographic refining, to obtain 6-tributyl stannyl-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl as target compound] imidazo [1,2-a] pyridine (Fig. 2-2, operation 1).At this moment, the amount of employed two (tributyl tins) can be the amount that satisfies with respect to the excessive condition of reaction substrate, particularly, its mol ratio is with respect to reaction substrate 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-about 1.5 times of 6-iodine imidazo [1,2-a] pyridine.

[0063] when the substituent compound of trialkyl stannyl that obtains beyond the 6-of imidazopyridine ring bit substituent is tributyl stannyl substituting group, can use various two (trialkyltins) that are fit to purpose to replace two (tributyl tins) in the operation 1 at Fig. 2-2.For example, when synthesizing when having trimethylammonium stannyl substituting group as substituent compound, can carry out and above-mentioned same reaction with two (tin trimethyls) in the operation 1 at Fig. 2-2 in the 6-position.

[0064] binding site of the functional group on the imidazopyridine ring is the compound of the carbon atom beyond the carbon of 6-position, can replace the 2-amino-5-iodine pyridine in Fig. 2-1, the operation 2 to obtain at each compound of different loci bonding by using wherein iodine and pyridine ring.For example, when the binding site of functional group is the 8-position carbon of imidazopyridine ring, can use 2-amino-3-iodine pyridine to replace 2-amino-5-iodine pyridine in Fig. 2-1, the operation 2.

[0065] (synthetic method of radioactive halogen-labeled compound)

Then, be example with radioiodinated compound, the method for preparing radioactive halogen-labeled compound is according to another aspect of the present invention described.

[0066] radioiodinated compound is synthetic, can be by being dissolved in inert organic solvents by the precursor compound of the mark of method for preparing, add by currently known methods obtain [ ¹²³I] IodineSodium Solution etc., make it to react and carry out to wherein adding acid and oxygenant.As the inert organic solvents of precursor compound of this mark of dissolving, can use with labelled precursor with [ ¹²³I] there is not reactive all kinds of SOLVENTS between the sodium iodide etc., preferably can use methyl alcohol.

[0067] as acid, can use various acid, preferred hydrochloric acid.

For the not special restriction of oxygenant, as long as it can make iodine oxidation, preferably hydrogen peroxide or Peracetic Acid in reaction soln.The amount of the oxygenant that is added can be the amount that is enough to iodine oxide in reaction soln.

[0068] with the radioactive halogen-labeled compound beyond the iodine, can be by synthesizing with the radioactive halogen-labeled labelled precursor that is fit to synthetic purpose that is fit to this purpose.For example, for synthetic 6-[ ¹⁸F] fluoro-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl] imidazo [1,2-a] pyridine, can be in the presence of phase-transfer catalyst and salt of wormwood, with labelled precursor 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl] 6-iodo imidazo [1,2-a] pyridine with [ ¹⁸F] the fluoride ion reaction.

[0069] (preparation of diagnostic reagent of the present invention and using method)

Diagnostic reagent of the present invention can be prepared into solution, same with other well-known radioactive diagnostic agents, it comprises the of the present invention radioactive halogen-labeled compound that is mixed in optional water, normal saline solution or the Ringer's solution that is adjusted to suitable pH.At this moment, should regulate this compound concentrations to the concentration that is no more than the stability of guaranteeing this compound.For the not special restriction of the dosage of this compound, as long as it is enough to obtain to use the distributed image of medicament.For example, iodo-123 ( ¹²³I) compound of mark and fluoro-18 ( ¹⁸F) in the situation of the compound of mark, can vein or the about 50-600MBq/60kg one-tenth of topical application body weight for humans.Can will use the distribution video picture of medicament by currently known methods.For example, can by the SPECT device with iodo-123 ( ¹²³I) tagged compound video picture, and can by PET device with fluoro-18 ( ¹⁸F) tagged compound video picture.

Embodiment

[0070] below, will the present invention be described in more detail by embodiment, comparative example and reference example.But these examples do not limit the scope of the invention.

Example I

In the following embodiments, the title at each compound that uses in the experiment defines shown in table 1-1.

[0071] table 1-1

The compound title	Popular name
		Compound I-1	6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] imidazo [1,2-a] pyridine
Compound I-2	2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyridine
		Compound I-3	6-bromo-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl] imidazo [1,2-a] pyridine
Compound I-4	2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-6-iodine imidazo [1,2-a] pyridine
		Compound I-5	2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyridine
Compound I-6	2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ 125I] iodine imidazo [1,2-a] pyridine
		Compound I-7	2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ 123I] iodine imidazo [1,2-a] pyridine
Compound I-8	6-bromo-2-[4 '-(3 ＂-[ 18F] the fluorine propoxy-) phenyl] imidazo [1,2-a] pyridine
		Compound I-9	2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-6-[ 123I] iodine imidazo [1,2-a] pyridine

[0072] Example I-1:6-tributyl stannyl-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] miaow Azoles is synthesizing of [1,2-a] pyridine also

[0073] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-1, operation 1).

[0074] with the 2-bromo-4 of 2.15g (being equivalent to 10.0mmol) '-2-amino-5-bromopyridine of hydroxy acetophenone and 1.74g (being equivalent to 10.0mmol) is dissolved in the 50mL acetonitrile.Under 105 ℃, with gained solution reflux 6 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 20mL water and 20mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 25mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1, the 2-a] pyridine (Fig. 1-1, operation 2) of 2.41g (being equivalent to 8.32mmol).

[0075] with the 6-bromo-2-of the dewatered 290mg of thorough drying (being equivalent to 1.0mmol) (4 '-hydroxy phenyl) imidazo [1,2-a] pyridine is dissolved in the N of 10mL, in the dinethylformamide, to wherein adding the 413mg salt of wormwood of (being equivalent to 3.0mmol).1-bromo-3-fluoro-propane with 138 μ L (being equivalent to 1.5mmol) replenishes this mixture, at room temperature stirs then 20.5 hours.After reaction finishes, reaction soln is poured in the water, use chloroform extraction 3 times.With the chloroform layer that the saturated nacl aqueous solution washing merges, use anhydrous sodium sulfate drying, filter and concentrate.By recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name; Japan's analytical industry corporate system); Chromatographic column: 2 JAIGEL2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: chloroform) make with extra care the gained crude product, obtain 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl of 302mg (being equivalent to 0.866mmol)] imidazo [1,2-a] pyridine (Fig. 1-1, operation 3).

[0076] with 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl of 85mg (being equivalent to 0.24mmol)] imidazo [1,2-a] pyridine is dissolved in the 10mL De diox, to the triethylamine that wherein adds 2mL.Then, to the tetrakis triphenylphosphine palladium of two (tributyl tins) that wherein add 185 μ L (being equivalent to 0.36mmol) and 20mg (catalytic amount).Descending stirring after 24 hours at 90 ℃ reaction mixture, underpressure distillation removes and desolvates.By preparation type TLC (elutriant: hexane/ethyl acetate=6/4) refining residue.Again by recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name; Japan's analytical industry corporate system); Chromatographic column: 2 JAIGEL2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: refining gained crude product chloroform) obtains the 42mg 6-tributyl stannyl-2-[4 ' of (being equivalent to 74.2 μ mol)-(3 ＂-fluorine propoxy-) phenyl] imidazo [1,2-a] pyridine (Fig. 1-1, operation 4).

[0077] gained 6-tributyl stannyl-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of imidazo [1,2-a] pyridine.

[0078] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 8.01-7.93 (m, 1H), 7.91-7.87 (m, 2H) 7.75-7.74 (m, 1H), 7.63-7.58 (m, 1H), 7.20-7.11 (m, 1H), 7.00-6.95 (m, 2H), 4.67 (dt, J _HF=47.0Hz, J=6.0Hz, 2H), 4.15 (t, J=6.0Hz, 2H), 2.20 (dquint, J _HF=26.1Hz, J=6.0Hz, 2H), 1.64-1.47 (m, 6H), 1.39-1.31 (m, 6H), 1.19-1.04 (m, 6H), 0.91 (t, J=7.2Hz, 9H)

[0079] Example I-2:2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²⁵ I] iodine imidazo [1,2-a] Synthesizing of pyridine

[0080] to 6-tributyl stannyl-2-[4 '-(3 ＂-fluorine propoxy-) phenyl of 53 μ L] methanol solution of imidazo [1,2-a] pyridine (concentration: 1mg/mL), add the hydrochloric acid of the 1mol/L of 100 μ L, 11.1MBq [ ¹²⁵I] 10% (w/v) hydrogen peroxide of sodium iodide (volume is 20 μ L) and 10 μ L.After this mixture is at room temperature left standstill 10 minutes, carry out HPLC under the following conditions, to obtain 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²⁵I] iodine imidazo [1,2-a] pyridine utmost point branch.

[0081] HPLC condition:

Chromatographic column: Phenomenex Luna C18 (trade(brand)name; By the Phenomenex corporate system; Size: 4.6 x 150mm)

Moving phase: 0.1% trifluoroacetic acid/acetonitrile=20/80 → 0/100 (17 minutes, linear gradient)

Flow velocity: 1.0mL/ minute

Detector: the UV, visible light extinction photometer (detects wavelength: 282nm) and radioactive counter (Raytest company corporate system; Model: STEFFI)

[0082] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C18 Cartridges, the Waters corporate system; The loading level of filler: 130mg), so that this post absorptive collection 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²⁵I] iodine imidazo [1,2-a] pyridine.Water with 1mL washes this post, allows 1mL ethanol pass through then, with wash-out 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²⁵I] iodine imidazo [1,2-a] pyridine.The radioactive activity of the compound that is obtained is 5.5MBq (synthetic when just having finished).In addition, carry out TLC under the following conditions and analyze, the result, the radiochemical purity of this compound is 96.0%.

[0083] TLC analysis condition:

TLC plate: RP-18F254 (trade(brand)name; By Merck ﹠ Co., Inc.'s system)

Launch phase: methanol=20/1

Detector: biometric image analyser, BAS-2500 (model: BAS-2500; By Fuji Photo Film Co., Ltd.'s system)

[0084] example I-3:2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²³ I] iodine imidazo [1,2-a] Synthesizing of pyridine

[0085] to 6-tributyl stannyl-2-[4 '-(3 ＂-fluorine propoxy-) phenyl of 70 μ L] methanol solution of imidazo [1,2-a] pyridine (concentration: 1mg/mL), add the 1mol/L of 100 μ L hydrochloric acid, 260-330MBq [ ¹²³I] sodium iodide (volume is 30-60 μ L), the 1mmol/L sodium iodide of 20 μ L and 10% (w/v) hydrogen peroxide of 20 μ L.This mixture is being carried out HPLC in heating under 50 ℃ after 10 minutes under the condition identical with example I-2, to obtain 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine utmost point branch.

[0086] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C18 Cartridges, the Waters corporate system; The loading level of filler: 130mg), so that this post absorptive collection 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.Water with 1mL washes this post, allows 1mL ethanol pass through then, with wash-out 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.When synthesizing end just, the radioactive activity of the compound that is obtained is 112-153MBq.In addition, under the condition identical, carry out TLC and analyze with example I-2, the result, the radiochemical purity of this compound is 97.0%.

[0087] Example I-4:6-bromo-2-[4 '-(3 ＂-tolysulfonyl oxygen base propoxy-) phenyl] miaow Azoles is synthesizing of [1,2-a] pyridine also

[0088] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-2, operation 1).

[0089] with the 2-bromo-4 of 2.15g (being equivalent to 10.0mmol) '-2-amino-5-bromopyridine of hydroxy acetophenone and 1.74g (being equivalent to 10.0mmol) is dissolved in the 50mL acetonitrile.Under 105 ℃, with gained solution reflux 6 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 20mL water and 20mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 25mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1, the 2-a] pyridine (Fig. 1-2, operation 2) of 2.41g (being equivalent to 8.32mmol).

[0090] the dewatered 6-bromo-of 1.45g (being equivalent to 5.0mmol) thorough drying 2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine is dissolved in the N of 50mL, in the dinethylformamide, to wherein adding the 2.07g salt of wormwood of (being equivalent to 15.0mmol).3-bromo-1-propyl alcohol with 680 μ L (being equivalent to 7.5mmol) replenishes this mixture, at room temperature stirs then 17 hours.After reaction finishes, reaction soln is poured in the water, use chloroform extraction 3 times.With the chloroform layer that the saturated nacl aqueous solution washing merges, use anhydrous sodium sulfate drying, filter and concentrate.Recrystallization gained crude product from methyl alcohol obtains 6-bromo-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl of 1.28g (being equivalent to 3.67mmol)] imidazo [1,2-a] pyridine (Fig. 1-2, operation 3).

[0091] with 6-bromo-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl of 177mg (being equivalent to 0.5mmol)] imidazo [1,2-a] pyridine is dissolved in the pyridine of 10mL, adds the 197mg Tosyl chloride of (being equivalent to 1.0mmol) under ice bath.After reaction soln is at room temperature stirred 16 hours, be poured in the water, use chloroform extraction 3 times.With the chloroform layer that the saturated nacl aqueous solution washing merges, use anhydrous sodium sulfate drying, filter and concentrate.By recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name; Japan's analytical industry corporate system); Post: 2 JAIGEL2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: chloroform) make with extra care the gained crude product, obtain 6-bromo-2-[4 '-(3 ＂-tolysulfonyl oxygen base propoxy-) phenyl of 87mg (being equivalent to 0.17mmol)] imidazo [1,2-a] pyridine (Fig. 1-2, operation 4).

[0092] gained 6-bromo-2-[4 '-(3 ＂-tolysulfonyl oxygen base propoxy-) phenyl] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of imidazo [1,2-a] pyridine.

[0093] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 8.26-8.24 (m, 1H), 7.84-7.80 (m, 2H), 7.77-7.74 (m, 2H), 7.74 (s, 1H), 7.50 (d, J=9.7Hz, 1H), and 7.26-7.23 (m, 2H), 7.21 (dd, J=9.7,2.0Hz, 1H), and 6.84-6.80 (m, 2H), 4.26 (t, J=6.0Hz, 2H), 3.98 (t, J=6.0Hz, 2H), 2.35 (s, 3H), 2.13 (quintet, J=6.0Hz, 2H).

[0094] ¹³C-NMR (solvent: chloroform-d1, resonant frequency: 125MHz): δ 158.67,146.53,144.79,144.08, and 132.77,129.80,127.87,127.81,127.28,126.20,125.43,117.87,114.63,107.40,106.76,66.97,63.08,28.85,21.60.

[0095] Example I-5:6-bromo-2-[4 '-(3 ＂-[ ¹⁸ F] the fluorine propoxy-) phenyl] imidazo [1,2-a] Synthesizing of pyridine

[0096] allow and comprise [ ¹⁸F] H of fluoride ion ₂ ¹⁸O (radioactive activity 4210MBq, gauged value when synthetic beginning) is by Sep-Pak Light QMA (trade(brand)name; By the Waters corporate system), with absorption and collect [ ¹⁸F] fluoride ion.Then, allow wet chemical (66.7mmol/L, 0.3mL) and 20mg (being equivalent to 53.2 μ mol) Kryptofix 222 (trade(brand)names; By Merck ﹠ Co., Inc.'s system) the 1.5mL acetonitrile solution by post with wash-out [ ¹⁸F] fluoride ion.

[0097] under helium flow, elutriant is heated to 100 ℃ with vaporize water, replenishes the azeotropic evaporate to dryness with acetonitrile (0.3mL * 2).To the foregoing description I-4 synthetic 6-bromo-2-[4 ' that wherein adds 5mg (being equivalent to 10.0 μ mol)-(3 ＂-tolysulfonyl oxygen base propoxy-) phenyl] the 1.0mL dimethyl formamide solution of imidazo [1,2-a] pyridine, 130 ℃ of heating 10 minutes down.After reaction soln is cooled to 30 ℃, use ether (3.5mL * 3) postreaction solution at every turn, allow it pass through Sep-Pak Plus Silica (trade(brand)name again; By the Waters corporate system).The ethereal solution that has passed through is heated to 60 ℃ and concentrated under helium flow.Mixing solutions with methanol/triethylamine=800:200:1 of 2mL dilutes this concentrated solution.

[0098] by HPLC (post: Capcell Pak C18 MG (15mm i.d.x 250mm, by Shiseido Co., Ltd. makes); Elutriant: methanol/triethylamine=700/300/1) refining gained solution.Water with 100mL dilutes the elutriant utmost point branch that comprises target compound, allows it pass through Sep-Pak Plus C18 (trade(brand)name then; By the Waters corporate system), with absorption and collection target compound.Allow the water of 20mL wash then by post.Allow 4mL ethanol by this post then, with wash-out 6-bromo-2-[4 '-(3 ＂-[ ¹⁸F] the fluorine propoxy-) phenyl] ethanolic soln of imidazo [1,2-a] pyridine.The gained radioactive activity is 769MBq (back 107 minutes of synthetic beginning).Analyze according to the TLC under the following condition, its radiochemical purity is 95.9%.

[0099] TLC analysis condition:

TLC plate: silica gel 60F ₂₅₄(trade(brand)name; By Merck ﹠ Co., Inc.'s system)

Launch phase: chloroform/methanol/triethylamine=500/10/0.5

Detector: Rita Star (trade(brand)name; By the Raytest corporate system)

[0100] Example I-6:6-bromo-2-[4 '-(2 ＂-tolysulfonyl oxygen base oxethyl) phenyl] miaow Azoles is synthesizing of [1,2-a] pyridine also

[0101] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-3, operation 1).

[0102] with the 2-bromo-4 of 2.15g (being equivalent to 10.0mmol) '-2-amino-5-bromopyridine of hydroxy acetophenone and 1.74g (being equivalent to 10.0mmol) is dissolved in the 50mL acetonitrile.Under 105 ℃, with gained solution reflux 6 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 20mL water and 20mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 25mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1, the 2-a] pyridine (Fig. 1-3, operation 2) of 2.41g (being equivalent to 8.32mmol).

[0103] ethylene glycol with 621mg (being equivalent to 10.0mmol) is dissolved in the methylene dichloride of 100mL.Under ice bath, in this solution, add the 3.49g silver suboxide of (being equivalent to 15.0mmol), the Tosyl chloride of the potassiumiodide of 350mg (being equivalent to 2.1mmol) and 2.10g (being equivalent to 11.0mmol).The gained mixture was stirred 2 hours down at 0 ℃.From reaction mixture, leach insolubles, wash with ethyl acetate again.Washings and filtrate are merged, concentrate this mixture.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=1/1) make with extra care the gained crude product, obtain 2-hydroxyethyl-p-toluenesulfonic esters (Fig. 1-3, operation 3) of 643mg (being equivalent to 2.97mmol).

[0104] in the 10mL tetrahydrofuran solution of 639mg (being equivalent to 2.95mmol) 2-hydroxyethyl-p-toluenesulfonic esters, add 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1, the 2-a] pyridine of 388mg (being equivalent to 1.34mmol) and the triphenylphosphine of 780mg (being equivalent to 2.97mmol).To the N that wherein adds 6mL, dinethylformamide is to dissolve content fully again.In this reaction mixture, add the diisopropyl azodiformate of 0.58mL (being equivalent to 2.95mmol).After reaction mixture is at room temperature stirred 17 hours, concentrated reaction solution.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=65/35) refining gained crude product.From dividing, the utmost point that comprises target compound leaches the insoluble substance in the chloroform.In addition, by recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name; Japan's analytical industry corporate system); Post: 2 JAIGEL2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: refining gained crude product chloroform) obtains the 79.7mg 6-bromo-2-[4 ' of (being equivalent to 164 μ mol)-(2 ＂-tolysulfonyl oxygen base oxethyl) phenyl] imidazo [1,2-a] pyridine (Fig. 1-3, operation 4).

[0105] gained 6-bromo-2-[4 '-(2 ＂-tolysulfonyl oxygen base oxethyl) phenyl] the NMR measurement result of imidazo [1,2-a] pyridine is as follows.

[0106] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: dimethyl formamide-d7, resonant frequency: 500MHz): δ 8.73-8.71 (m, 1H), 8.19-8.17 (m, 1H), and 7.81-7.77 (m, 2H), 7.73-7.70 (m, 2H), and 7.41-7.38 (m, 1H), 7.39-7.36 (m, 2H), 7.20 (dd, J=9.5,1.9Hz), 6.85-6.81 (m, 2H), 4.34-4.31 (m, 2H), and 4.19-4.15 (m, 2H).

[0107] ¹³C-NMR (solvent: dimethyl formamide-d7, resonant frequency: 125MHz): δ 158.32,145.91,145.24,143.84, and 133.15,130.18,127.83,127.54,127.19,127.15,126.90,117.56,114.86,108.73,105.80,69.28,65.88,20.69.

[0108] reference example I-1: 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] imidazo [1,2-a] pyrrole Synthesizing of pyridine (on-radiation fluorinated forms)

[0109] as the sample of estimating the affinity of compound of the present invention with amyloid, fat-soluble and mutagenicity, synthesize 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl of on-radiation fluorinated forms] imidazo [1,2-a] pyridine.

[0110] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-4, operation 1).

[0111] with the 2-bromo-4 of 2.15g (being equivalent to 10.0mmol) '-2-amino-5-bromopyridine of hydroxy acetophenone and 1.74g (being equivalent to 10.0mmol) is dissolved in the 50mL acetonitrile.Under 105 ℃, with gained solution reflux 6 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 20mL water and 20mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 25mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1, the 2-a] pyridine (Fig. 1-4, operation 2) of 2.41g (being equivalent to 8.32mmol).

[0112] the dewatered 6-bromo-of 290mg (being equivalent to 1.0mmol) thorough drying 2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine is dissolved in the N of 10mL, in the dinethylformamide, to wherein adding the 413mg salt of wormwood of (being equivalent to 3.0mmol).1-bromo-3-fluoro-propane with 138 μ L (being equivalent to 1.5mmol) replenishes this mixture, at room temperature stirs then 20.5 hours.After reaction finishes, reaction soln is poured in the water, use chloroform extraction 3 times.With the chloroform layer that the saturated nacl aqueous solution washing merges, use anhydrous sodium sulfate drying, filter and concentrate.By recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name; Japan's analytical industry corporate system); Post: 2 JAIGEL2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: chloroform) make with extra care the gained crude product, obtain 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl of 302mg (being equivalent to 0.866mmol)] imidazo [1,2-a] pyridine (Fig. 1-4, operation 3).

[0113] gained 6-bromo-2-[4 '-(3 ＂-fluorine propoxy-) phenyl] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of imidazo [1,2-a] pyridine.

[0114] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 8.23 (dd, J=1.9,0.2Hz, 1H), 7.88-7.83 (m, 2H), 7.51-7.48 (m, 1H), 8.21 (dd, J=9.5,1.9Hz, 1H), 6.99-6.95 (m, 2H), 4.67 (dt, ²J _HF=47.1Hz, J=5.9Hz, 2H), 4.15 (t, J=5.9Hz, 2H), 2.19 (dquint, ³J _HF=25.9Hz, J=5.9Hz, 2H).

[0115] ¹³C-NMR (solvent: chloroform-d1, resonant frequency: 125MHz): δ 159.01,146.61,144.07,127.81,127.38,126.15,125.41,117.87,114.78,107.41,106.71,80.71 (d, ¹J _CF=164.6Hz), 63.59 (d, ³J _CF=5.3Hz), 30.43 (d, ²J _CF=19.7Hz).

[0116] ¹⁹F-NMR (solvent: chloroform-d1, resonant frequency: 470MHz): δ-222.07 (dd, ²J _HF=47.1Hz, ³J _HF=25.9Hz).

[0117] Reference example I-2:2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyrrole Synthesizing of pyridine (on-radiation fluorinated forms)

[0118] as the sample of estimating the affinity of compound of the present invention with amyloid, fat-soluble and mutagenicity, synthesize 2-[4 '-(3 ＂-fluorine propoxy-) phenyl of on-radiation fluorinated forms]-6-iodine imidazo [1,2-a] pyridine.

[0119] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 8.18g (being equivalent to 60.0mmol) 4 '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-5, operation 1).

[0120] with the 2-bromo-4 of 441mg (being equivalent to 2.0mmol) '-2-amino-5-iodine pyridine of hydroxy acetophenone and 449mg (being equivalent to 2.0mmol) is dissolved in the 15mL acetonitrile.Under 110 ℃, with gained solution reflux 5 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 10mL water and 10mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 10mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains the 526mg 2-of (being equivalent to 1.56mmol) (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 1-5, operation 2).

[0121] the dewatered 2-of 673mg (being equivalent to 2.0mmol) thorough drying (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine is dissolved in the N of 25mL, in the dinethylformamide, to wherein adding the 831mg salt of wormwood of (being equivalent to 6.0mmol).1-bromo-3-fluoro-propane with 275 μ L (being equivalent to 3.0mmol) replenishes this mixture, at room temperature stirs then 24 hours.After reaction finishes, reaction soln is poured in the water, use chloroform extraction 3 times.The chloroform layer that water and saturated nacl aqueous solution washing merge is used anhydrous sodium sulfate drying, filters and concentrates.By quick silica gel column chromatography (elutriant: chloroform) make with extra care the gained crude product, again by recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name; Japan's analytical industry corporate system); Post: 2 JAIGEL2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: refining gained crude product chloroform) obtains the 349mg 2-[4 ' of (being equivalent to 0.881mmol)-(3 ＂-fluorine propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 1-5, operation 3).

[0122] gained 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-the NMR measurement result (internal standard substance: tetramethylsilane) as follows of 6-iodine imidazo [1,2-a] pyridine.

[0123] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 8.37-8.35 (m, 1H), 7.88-7.84 (m, 2H), 7.72 (s, 1H), 7.42-7.39 (m, 1H), 7.32 (dd, J=9.4,1.6Hz, 1H), 6.99-6.96 (m, 2H), 4.67 (dt, ²J _HF=47.0Hz, J=6.0Hz, 2H), 4.15 (t, J=6.0Hz, 2H), 2.20 (dquint, ³J _HF=25.9Hz, J=6.0Hz, 2H).

[0124] 1 ³C-NMR (solvent: chloroform-d1, resonant frequency: 125MHz): δ 159.01,146.23,144.16,132.36,130.28,127.42,126.05,118.31,114.77,106.90,80.72 (d, ¹J _CF=164.6Hz), 74.80,63.57 (d, ³J _CF=5.3Hz), 30.42 (d, ²J _CF=20.2Hz).

[0125] ¹⁹F-NMR (solvent: chloroform-d1, resonant frequency: 470MHz): δ-222.09 (dd, ²J _HF=47.0Hz, ³J _HF=25.9Hz).[0126] reference example I-3:6-bromo-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl] imidazo [1,2-a] pyrrole Synthesizing of pyridine (on-radiation fluorinated forms)

[0127] as the sample of estimating the affinity of compound of the present invention with amyloid, fat-soluble and mutagenicity, synthesize 6-bromo-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl of on-radiation fluorinated forms] imidazo [1,2-a] pyridine.

[0128] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-6, operation 1).

[0129] with the 2-bromo-4 of 2.15g (being equivalent to 10.0mmol) '-2-amino-5-bromopyridine of hydroxy acetophenone and 1.74g (being equivalent to 10.0mmol) is dissolved in the 50mL acetonitrile.Under 105 ℃, with gained solution reflux 6 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 20mL water and 20mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 25mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1, the 2-a] pyridine (Fig. 1-6, operation 2) of 2.41g (being equivalent to 8.32mmol).

[0130] the dewatered 6-bromo-of 578mg (being equivalent to 2.0mmol) thorough drying 2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine is dissolved in the N of 20mL, in the dinethylformamide, to wherein adding the 830mg salt of wormwood of (being equivalent to 6.0mmol).2-fluoro ethyl p-toluenesulfonic esters with 510 μ L (being equivalent to 3.0mmol) is replenished this mixture, at room temperature stirs then 44.5 hours.After reaction finishes, reaction soln is poured in the water, use chloroform extraction 3 times.The chloroform layer that water and saturated nacl aqueous solution washing merge is used anhydrous sodium sulfate drying, filters and concentrates.Chloroform/methanol=100/1), by recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name the gained crude product is by quick silica gel column chromatography (elutriant:; Japan's analytical industry corporate system); Post: 2 JAIGEL2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: chloroform), again by preparation type TLC (elutriant: chloroform/methanol=50:1) is refining, obtains 6-bromo-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl of 446mg (being equivalent to 1.33mmol)] imidazo [1,2-a] pyridine (Fig. 1-6, operation 3).

[0131] gained 6-bromo-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of imidazo [1,2-a] pyridine.

[0132] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

1H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 8.23-8.21 (m, 1H), 7.87-7.84 (m, 1H), 7.72 (s, 1H), 7.51-7.47 (m, 1H), 7.20 (dd, J=9.5,1.9Hz, 1H), 7.01-6.97 (m, 2H), 4.84-4.71 (m, 2H), and 4.30-4.21 (m, 2H).

[0133] ¹³C-NMR (solvent: chloroform-d1, resonant frequency: 125MHz): δ 158.62,146.46,144.06,127.85,127.41,126.58,125.42,117.87,114.91,107.49,106.74,81.86 (d, ¹J _CF=170.8Hz), 67.15 (d, ²J _CF=20.2Hz).

[0134] ¹⁹F-NMR (solvent: chloroform-d1, resonant frequency: 470MHz): δ-223.80 (dd, ²J _HF=47.4Hz, ³J _HF=27.6Hz).

[0135] Reference example I-4:2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-6-iodine imidazo [1,2-a] pyrrole Synthesizing of pyridine (on-radiation fluorinated forms)

[0136] as the sample of estimating the affinity of compound of the present invention with amyloid, fat-soluble and mutagenicity, synthesize 2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl of on-radiation fluorinated forms]-6-iodine imidazo [1,2-a] pyridine.

[0137] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-7, operation 1).

[0138] with the 2-bromo-4 of 441mg (being equivalent to 2.0mmol) '-2-amino-5-iodine pyridine of hydroxy acetophenone and 449mg (being equivalent to 2.0mmol) is dissolved in the 15mL acetonitrile.Under 110 ℃, with gained solution reflux 5 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 10mL water and 10mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 10mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains the 526mg 2-of (being equivalent to 1.56mmol) (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 1-7, operation 2).

[0139] the dewatered 2-of 368mg (being equivalent to 1.1mmol) thorough drying (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine is dissolved in the N of 15mL, in the dinethylformamide, to wherein adding the 453mg salt of wormwood of (being equivalent to 3.3mmol).2-fluoro ethyl-p-toluenesulfonic esters with 280 μ L (being equivalent to 1.6mmol) is replenished this mixture, at room temperature stirs then 22 hours.After reaction finishes, reaction soln is poured in the water, use chloroform extraction 3 times.The chloroform layer that water and saturated nacl aqueous solution washing merge is used anhydrous sodium sulfate drying, filters and concentrates.Hexane/ethyl acetate=1/1), again by recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name the gained crude product is by quick silica gel column chromatography (elutriant:; Japan's analytical industry corporate system); Post: 2 JAIGEL 2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: chloroform) refining, obtain the 222mg 2-[4 ' of (being equivalent to 0.580mmol)-(2 ＂-fluorine oxyethyl group) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 1-7, operation 3).

[0140] gained 2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-the NMR measurement result (internal standard substance: tetramethylsilane) as follows of 6-iodine imidazo [1,2-a] pyridine.

[0141] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 8.35-8.33 (m, 1H), 7.88-7.84 (m, 2H), 7.70 (s, 1H), 7.39 (d, J=9.4Hz, 1H), 7.31 (dd, J=9.4,1.8Hz, 1H), 7.01-6.97 (m, 2H), 4.84-4.71 (m, 2H), and 4.30-4.22 (m, 2H).

[0142] ¹³C-NMR (solvent: chloroform-d1, resonant frequency: 125MHz): δ 158.62,146.08,144.16,132.38,130.30,127.44,126.52,118.30,114.91,106.99,81.86 (d, ²J _CF=170.8Hz), 74.82,67.15 (d, ³J _CF=20.6Hz).

[0143] ¹⁹F-NMR (solvent: chloroform-d1, resonant frequency: 470MHz): δ-223.74 (dd, ²J _HF=47.4Hz, ³J _HF=27.7Hz).

[0144] Reference example I-5:2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyrrole Synthesizing of pyridine (on-radiation fluorinated forms)

[0145] as the sample of estimating the affinity of compound of the present invention with amyloid, fat-soluble and mutagenicity, synthesize 2-[4 '-(3 ＂-fluorine propoxy-) phenyl of on-radiation fluorinated forms]-6-iodine imidazo [1,2-a] pyridine.

[0146] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-8, operation 1).

[0147] with the 2-bromo-4 of 646mg (being equivalent to 3.0mmol) '-2-amino-5-iodine pyridine of hydroxy acetophenone and 668mg (being equivalent to 3.0mmol) is dissolved in the 20mL acetonitrile.Under 110 ℃, with gained solution reflux 8 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 10mL water and 10mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 15mL, usefulness supersound washing device was with mixture supersound process 3 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains the 737mg 2-of (being equivalent to 2.19mmol) (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 1-8, operation 2).

[0148] the dewatered 2-of 339mg (being equivalent to 1.0mmol) thorough drying (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine is dissolved in the N of 20mL, in the dinethylformamide, to wherein adding the 414mg salt of wormwood of (being equivalent to 3.0mmol).1-bromo-3-fluoro-propane with 138 μ L (being equivalent to 1.5mmol) replenishes this mixture, at room temperature stirs then 22 hours.After reaction finishes, reaction soln is poured in the water, use chloroform extraction 3 times.With the chloroform layer that the saturated nacl aqueous solution washing merges, use anhydrous sodium sulfate drying, filter and concentrate.At N, recrystallization in the dinethylformamide obtains the 236mg 2-[4 ' of (being equivalent to 0.594mmol)-(3 ＂-fluorine propoxy-) phenyl with the gained crude product]-6-iodine imidazo [1,2-a] pyridine (Fig. 1-8, operation 3).

[0149] gained 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-the NMR measurement result (internal standard substance: tetramethylsilane) as follows of 6-iodine imidazo [1,2-a] pyridine.

[0150] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 500MHz): δ 9.27 (d, J=2.3Hz, 1H), 8.55 (d, J=2.3Hz, 1H), 8.15 (s, 1H), 7.94-7.90 (m, 2H), 7.06-7.02 (m, 2H), 4.62 (dt, ²J _HF=47.2Hz, J=6.1,2H), 4.14 (t, J=6.1Hz, 2H), 2.13 (dquint, ³J _HF=25.5Hz, J=6.1Hz, 2H).

[0151] ¹³C-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 125MHz): δ 159.16,154.12,146.54,146.26,139.00,127.60,126.06,115.21,106.52,81.15 (d, ¹J _CF=161.7Hz), 74.43,64.07 (d, ³J _CF=5.8Hz), 30.13 (d, ²J _CF=19.7HZ).

[0152] ¹⁹F-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 470MHz): δ-220.13 (tt, ²J _HF=47.2Hz, ³J _HF=25.5Hz).

[0153] Reference example I-6:[ ¹²⁵ I]-IMPY synthetic

[0154] according to following operation synthesize be used for estimating comparative example with the associativity of amyloid uses [ ¹²⁵I]-IMPY.

[0155] according in document (people such as Zhi-Ping Zhuang, J.Med.Chem, 2003,46, the p.237-243) method described in, synthetic 6-tributyl stannyl-2-[4 '-(N, the N-dimethylamino) phenyl] imidazo [1,2-a] pyridine, and be dissolved in methyl alcohol (concentration: 1mg/mL).In 53 μ L gained solution, add the hydrochloric acid of the 1mol/L of 75 μ L, the 13.5MBq of 20 μ L [ ¹²⁵I] 10% (w/v) hydrogen peroxide of sodium iodide and 10 μ L.With the solution of mixture after leaving standstill 10 minutes under 50 ℃, with this solution with the described identical condition of example I-2 under carry out HPLC, with obtain [ ¹²⁵I]-IMPY utmost point branch.

[0156] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) LightC18Cartridges, the Waters corporate system; The loading level of filler: 130mg), so that this post absorptive collection [ ¹²⁵I]-IMPY.Water with 1mL washes this post, allows 1mL ethanol pass through then, with wash-out [ ¹²⁵I]-IMPY.When just having finished, the radioactive activity of the compound that is obtained is 2.6MBq synthetic.In addition, with the described identical condition of example I-2 under carry out TLC and analyze, the result, the radiochemical purity of this compound is 98.0%.

[0157] Reference example I-7:[ ¹²³ I]-IMPY synthetic

[0158] according to following operation synthesize in being used for estimating the comparative example of logP octanol and the brain property accumulated, use [ ¹²³I]-IMPY.

[0159] according in document (people such as Zhi-Ping Zhuang, J.Med.Chem, 2003,46, the p.237-243) method described in, synthetic 6-tributyl stannyl-2-[4 '-(N, the N-dimethylamino) phenyl] imidazo [1,2-a] pyridine, and be dissolved in methyl alcohol (concentration: 1mg/mL).In 53 μ L gained solution, add the hydrochloric acid of the 1mol/L of 100 μ L, the 190-240MBq of 20-50 μ L [ ¹²³I] sodium iodide and the 1mmol/L IodineSodium Solution of 10 μ L, 10% (w/v) hydrogen peroxide of 10 μ L.With the solution of mixture after leaving standstill 10 minutes under 50 ℃, with this solution with the described identical condition of example I-2 under carry out HPLC, with obtain [ ¹²³I]-IMPY utmost point branch.

[0160] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C18 Cartridges, the Waters corporate system; The loading level of filler: 130mg), so that this post absorptive collection [ ¹²³I]-IMPY.Water with 1mL washes this post, allows 1mL ethanol pass through then, with wash-out [ ¹²³I]-IMPY.When just having finished, the radioactive activity of the compound that is obtained is 47-56MBq synthetic.In addition, with the described identical condition of example I-2 under carry out TLC and analyze, the result, the radiochemical purity of this compound is 98.0%.

[0161] Reference example I-8:2-(4 '-hydroxy phenyl)-6-[ ¹²⁵ I] iodine imidazo [1,2-a] pyridine Synthetic

[0162] in order to obtain calculating log _PHPLCFormula, according to following operation Synthetic 2-(4 '-hydroxy phenyl)-6-[ ¹²⁵I] iodine imidazo [1,2-a] pyridine.

[0163] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-9, operation 1).

[0164] with the 2-bromo-4 of 2.15g (being equivalent to 10.0mmol) '-2-amino-5-bromopyridine of hydroxy acetophenone and 1.74g (being equivalent to 10.0mmol) is dissolved in the 50mL acetonitrile.Under 105 ℃, with gained solution reflux 6 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 20mL water and 20mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 25mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1, the 2-a] pyridine (Fig. 1-9, operation 2) of 2.41g (being equivalent to 8.32mmol).

[0165] the 6-bromo-2-of 138mg (being equivalent to 0.476mmol) (4 '-hydroxy phenyl) imidazo [1,2-a] pyridine is dissolved in the 20mL De diox, to the triethylamine that wherein adds 2mL.Then, to the tetrakis triphenylphosphine palladium of two (tributyl tins) that wherein add 360 μ L (being equivalent to 0.713mmol) and 20mg (catalytic amount).Descending stirring after 22 hours at 90 ℃ reaction mixture, underpressure distillation removes and desolvates.By preparation type TLC (elutriant: hexane/ethyl acetate=1/4) refining residue.And then, by recirculation preparation HPLC (HPLC device: LC-908 (trade(brand)name; Japan's analytical industry corporate system); Post: 2 JAIGEL 2H (trade(brand)names; Japan's analytical industry corporate system) series connection; Moving phase: refining gained crude product chloroform) obtains the 47mg 6-tributyl stannyl-2-of (being equivalent to 94.9 μ mol) (4 '-hydroxy phenyl) imidazo [1,2-a] pyridine (Fig. 1-9, operation 3).

[0166] to the methanol solution of 53 μ L6-tributyl stannyl-2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine (concentration: 1mg/mL), add the hydrochloric acid of the 1mol/L of 75 μ L, the 136MBq of 40 μ L [ ¹²⁵I] 10% (w/v) hydrogen peroxide of sodium iodide and 10 μ L.With the solution of mixture after leaving standstill 10 minutes under 50 ℃, with this solution with the described identical condition of example I-2 under carry out HPLC, to obtain 2-(4 '-hydroxy phenyl)-6-[ ¹²⁵I] iodine imidazo [1,2-a] pyridine utmost point branch (Fig. 1-9, operation 4).

[0167] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C18 Cartridges, the Waters corporate system; The loading level of filler: 130mg), so that this post absorptive collection 2-(4 '-hydroxy phenyl)-6-[ ¹²⁵I] iodine imidazo [1,2-a] pyridine.Water with 1mL washes this post, allows 1mL ethanol pass through then, with wash-out 2-(4 '-hydroxy phenyl)-6-[ ¹²⁵I] iodine imidazo [1,2-a] pyridine.When just having finished, the radioactive activity of the compound that is obtained is 37.5MBq synthetic.In addition, with the described identical condition of example I-2 under carry out TLC and analyze, the result, the radiochemical purity of this compound is 96.5%.

[0168] Ginseng person example I-9:2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine synthetic

[0169] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 1-10, operation 1).

[0170] with the 2-bromo-4 of 441mg (being equivalent to 2.0mmol) '-2-amino-5-bromopyridine of hydroxy acetophenone and 449mg (being equivalent to 2.0mmol) is dissolved in the 15mL acetonitrile.Under 110 ℃, with gained solution reflux 5 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 10mL water and 10mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 10mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains the 526mg 2-of (being equivalent to 1.56mmol) (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 1-10, operation 2).

[0171] the NMR measurement result (internal standard substance: methyl-sulphoxide) as follows of gained 2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine.

[0172] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 500MHz): δ 8.86-8.84 (m, 1H), 8.14 (s, 1H), 7.78-7.74 (m, 2H), 7.40-7.35 (m, 2H), 6.86-6.82 (m, 2H).

[0173] ¹³C-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 125MHz): δ 158.08,145.87,143.87,132.48, and 131.72,127.67,124.99,118.14,116.14,108.02,75.85.

[0174] Example I-7 and Comparative Example I-1: with the mensuration of the associativity of amyloid

[0175] by following external affinity in conjunction with experimental examination compound of the present invention and amyloid.

[0176] (1) is with A β _1-40(peptide institute system) is dissolved in phosphate buffered saline buffer (pH7.4) and 37 ℃ of down vibrations 72 hours, with the suspension of the aggegation A β that obtains 1mg/mL (below, in the present embodiment, be called the amyloid suspension).

[0177] (2) according to document (Naiki, people such as H., Laboratory Investigation, 74P.374-383 (1996)) described method, based on the spectrophotofluorimetry that uses thioflavin T (by the Fluka corporate system), carry out the qualitative experiment of this amyloid suspension, to confirm that the aggegation A β that obtains is amyloid (condition determination: excitation wavelength 446nm, wavelength of fluorescence 490nm) in (1).

[0178] (3) modulation is by the ethanolic soln (radioactive concentration: 37MBq/mL) of the described method synthetic of example I-2 Compound I-6, dilute with the phosphate buffered saline buffer that comprises 0.1% bovine serum albumin (pH7.4), with preparation 2-[4 '-(3 ＂-fluorine propoxy-) phenyl]-6-iodine imidazo [1, the 2-a] total amount of pyridine is equivalent to the solution of 2nmol/L concentration.

What [0179] (4) added 50 μ L in each hole of 96 orifice plates is dissolved in the solution that the phosphate buffered saline buffer (pH 7.4) that comprises 0.1% bovine serum albumin obtains (the amyloid concentration in the solution regulate amyloid concentration) per sample 50 μ L as the solution (ultimate density is 400pM) of above-mentioned (3) preparation with the amyloid suspension, the same buffer that adds 150 μ L then, with the preparation ultimate density is 2.5,12.5,25,62.5,125,250,625 and the amyloid solution of 1000nmol/L.

[0180] (5) vibrate this microtest plate 3 hours down at 22 ℃ with command speed (400rpm).Allow each mixing solutions by glass fibre filter (trade(brand)name then; Mulutiscreen ^TM-FC is made by Millipore) filter, from free Compound I-6, to separate and amyloid bonded Compound I-6.

[0181] (6) are used to filter the glass fibre filter of this mixing solutions with phosphate buffered saline buffer (0.5mL * 5) washing that comprises 0.1% bovine serum albumin, use then the AutowellGamma system (by the Aloka corporate system, model: ARC-301B) measure the radioactivity of this glass fibre filter.

[0182] (7) calculate by the measurement result of (6) and the amount of the amount of amyloid bonded Compound I-6 and the amyloid that added between relation.With adding Compound I-2 (non-RI tagged compound) to concentration in above-mentioned (4) is that the sample of 100nM (ultimate density) is determined non-specific binding (example I-7).

[0183] (8) use synthetic in above-mentioned reference example I-6 [ ¹²⁵I]-IMPY, carry out obtaining contrasting data (Comparative Example I-1) with the same operation of above-mentioned (2)～(6).

[0184] show among Fig. 1-11 be the concentration of amyloid in sample solution and in above-mentioned (6) relation between the radiocounting of measuring on the glass fibre filter.Radioactivity on the glass fibre increases (embodiment 1-7) pro rata with the concentration (addition) of amyloid.Under this experimental conditions, amyloid and remain in the glass fibre with amyloid bonded compound.Therefore, the radiocounting on the glass fibre is the value of reflection and amyloid bonded compound amount.The slope of describing with respect to the figure of the radiocounting of amyloid concentration is the finger target value that can represent compound and amyloid bonded intensity.Owing to the raising along with amyloid concentration of the value of the radiocounting of Compound I-6 on glass fibre increases, enlightenment Compound I-the 6th, a kind of compound that has with amyloid bonded character.The straight slope of Compound I-6 greater than in the phase diagram [ ¹²⁵I]-slope of IMPY, so the affinity of its enlightenment Compound I-6 and amyloid greater than [ ¹²⁵I]-IMPY, known [ ¹²⁵I]-IMPY shown the strong affinity with amyloid.

The above results shows, Compound I-6 has very strong and amyloid bonded ability.

[0185] Example I-8 is to I-12, and Comparative Example I-2 arrives I-6: with the parent of amyloid Mensuration with property

By following external affinity in conjunction with experimental examination compound of the present invention and amyloid.

[0186] (1) is with A β _1-40(peptide institute system) is dissolved in phosphate buffered saline buffer (pH7.4), and 37 ℃ of down vibrations 62-72 hour, with the suspension of the aggegation A β that obtains 1mg/mL (below, be called the amyloid suspension in the present embodiment).

[0187] (2) according to document (Naiki, people such as H., Laboratory Investigation, 74P.374-383 (1996)) described method, based on the spectrophotofluorimetry that uses thioflavin T (making) by Fluka, carry out the qualitative experiment of this amyloid suspension, to confirm that the aggegation A β that obtains is amyloid (condition determination: excitation wavelength 446nm, wavelength of fluorescence 490nm) in (1).

[0188] (3) are according to document (Wang, people such as Y., J.Labelled CompoundsRadiopharmaceut. 44, S239 (2001)) described in method, by the preparation of labelled precursor 2-(4 '-aminophenyl) benzothiazole [ ¹²⁵I] 2-(3 '-iodo-4 '-aminophenyl) benzothiazole (below be called [ ¹²⁵I] 3 '-I-BTA-0), it is dissolved in the ethanol.With Congo red, thioflavin T and 6-methyl-2-[4 '-(N, N-dimethylamino) phenyl] benzothiazole (below be called 6-Me-BTA-2), directly weigh and use with the form of commercial reagent.

[0189] (4) are respectively according to document (Wang, people such as Y., J.Labelled CompoundsRadiopharmaceut. 44, S239 (2001)) and document (Zhuang, people such as Z.P., J.Med.Chem. 46, 237 (2003)) described in method come Synthetic 2-(3 '-iodo-4 '-aminophenyl) benzothiazole (below be called 3 '-I-BTA-0) and IMPY.

[0190] (5) preparation will [ ¹²⁵I] 3 '-I-BTA-0, each compound that is used for estimating and amyloid be dissolved in phosphate buffered saline buffer (pH 7.4) that comprises 0.1% bovine serum albumin and the sample of the ultimate density that makes them shown in table 1-2.The gained sample is filled in each holes of 96 orifice plates (the about 0.3mL of volume).

[0191] ultimate density of table 1-2 each compound in sample solution

[0192] (6) microtest plate that will be filled with sample solution with command speed (400rpm) 22 ℃ of vibrations 3 hours down.Allow each mixing solutions by glass fibre filter (trade(brand)name then; Mulutiscreen ^TM-FC is made by Millipore) filter, with from free [ ¹²⁵I] 3 '-separate among the I-BTA-0 with the amyloid bonded [ ¹²⁵I] 3 '-I-BTA-0.

[0193] (7) are used to filter the glass fibre filter of each sample solution with phosphate buffered saline buffer (pH7.4) washing (0.5mL * 5) that comprises 0.1% bovine serum albumin, use then the AutowellGamma system (by the Aloka corporate system, model: ARC-301B) measure the radioactivity of this glass fibre filter.This radioactivity is as the radioactive level of each sample solution, be used to calculate inhibiting rate (below, the radioactive level of sample when A represents that the compound concentrations that respectively is used for estimating is zero (0), B represent that the compound concentrations that respectively is used for estimating is the radioactive level of 0.001nmol/L sample when above).

[0194] (8) prepare the 6-Me-BTA-2 that comprises 15 μ mol/L respectively, 400pmol/L [ ¹²⁵I] 3 '-the A β of I-BTA-0 and 1 μ mol/L _1-40Solution, radioactive level is measured in the same operation of carrying out described in (6) and (7).The radioactive level of being measured is defined as the background radiation level, is used to calculate inhibiting rate (below be called BG).

[0195] (9) use the radioactive level of being measured in above-mentioned (7) and (8), and (1-1) obtains inhibiting rate by following formula.

[0196] $\frac{B-\mathrm{BG}}{A-\mathrm{BG}}x100(\%)---(1-1)$

[0197] draws logarithmic with respect to institute's assessing compound concentration by the figure of the inhibiting rate that is obtained, to obtain proximate straight line by method of least squares by the value of probit transformation.Use this line, estimate when radioactive level be the concentration of each assessing compound that does not contain a half of each assessing compound sample, with its be defined as each compound 50% inhibition concentration (below be called IC ₅₀The % value).Use this value as index, estimate and respectively to be used to the compound and amyloid (the aggegation A β that estimate _1-40) affinity.

[0198] respectively is used to the IC of the compound estimated _50%Value is shown in table 1-3.Compound I-1 has all shown IC less than 100 to I-5 _50%Value is compared with thioflavin T with Congo red, has and amyloid (aggegation A β _1-40) higher affinity.The result shows, Compound I-1 has good amyloid affinity to I-5.Especially, with 3 '-I-BTA-0 compares with 6-Me-BTA-2, and Compound I-1 is to I-4 and amyloid (aggegation A β _1-40) have higher affinity, have the affinity equal with IMPY.

[0199] IC of table 1-3 The compounds of this invention _50%Value

[0200] Example I-13 is to I-14, Comparative Example I-7: based on the branch system of disposition of octanol extraction process The mensuration of number

[0201] measure to adopt general known as the partition ratio of compound infiltration by the octanol extraction process of the index of hemato encephalic barrier (below be called BBB) (below be called logP _Octanol).

[0202] in the octanol of 2mL, adds inclusion compound I-7 (example I-13) and the solution of Compound I-8 (example I-14) and the 10mmol/L phosphate buffered saline buffer (pH7.4) of 2mL of 10 μ L, and stirred 30 seconds.With after low speed centrifuge (2000rpm x 60 minutes) this mixed solution of centrifugation, octanol layer and the water layer of each 1mL that takes a sample respectively, and with the AutowellGamma system (by the Aloka corporate system, model: ARC-301B) mensuration radiocounting.Use the radiocounting that is obtained, calculate logP according to formula (1-2) _Octanol

[0204] result is shown in table 1-4.The logP that Compound I-7 and I-8 show _OctanolValue is all between 1～3.Known porous is crossed the logP of the compound of BBB _OctanolValue between 1～3 (people such as Douglas D.Dischino, J.Nucl.Med., (1983), 24, p.1030-1038).Therefore, this shows that these two kinds of compounds all have the BBB perviousness suitable with IMPY.

[0205] table 1-4: the logP of compound of the present invention _OctanolValue

Experiment	Compound	logP OctanolValue
			Comparative Example I-7	[ 123I]-IMPY	2.1
Example I-13	Compound I-7	2.1
			Example I-14	Compound I-8	2.0

[0206] Example I-15 is to I-19, Comparative Example I-8: based on the partition ratio of HPLC Mensuration

[0207] measures partition ratio based on HPLC (below be called logPHPLC) by following method.Known to pH7.2 to 7.4, logP _HPLCShown and logP _OctanolBe worth identical numerical value, general known logP _OctanolBe compound the infiltrative index of BBB (people such as FrancoLombardo, J.Med.Chem., (2000), 43, p.2922-2927).

[0208] at first, to be dissolved in the methyl alcohol that comprises 10% methyl-sulphoxide with the concentration of 1mg/mL as the compound that be used for estimate of table shown in the 1-5 and prepare sample solution, sample solution with 1 μ L carries out the HPLC analysis under the following conditions, determines the elution time (t of solvent ₀) and the elution time (t of each compound _R).

[0209] table 1-5: the compound that in each experiment, is used to estimate

Experiment	The compound that is used to estimate
		Comparative Example I-8	IMPY
Example I-15	Compound I-1
		Example I-16	Compound I-2
Example I-17	Compound I-3
		Example I-18	Compound I-4
Example I-19	Compound I-5

[0210] HPLC condition:

Chromatographic column: Prodigy ODS (3) (product title; By the phenomenex corporate system; Size: 4.6 x 250mm)

Moving phase: the mixing solutions of 50mM phosphoric acid triethylamine (pH 7.2)/acetonitrile=40/60

Flow velocity: 0.7mL/ minute.

Detector: UV, visible light extinction photometer (detection wavelength: 282nm)

[0211] uses the t that obtains ₀And t _R, according to following calculating formula (1-3) obtain the retention factors that respectively is used to the compound estimated (below be called K ' _HPLCValue).

[0212]K′ _HPLC＝(t _R-t ₀)/t ₀...(1-3)

[0213] respectively with the synthetic 2-in above-mentioned reference example I-8 of 10 μ L (4 '-hydroxy phenyl)-6-[ ¹²⁵I] iodine imidazo [1,2-a] solution (radioactive concentration 37MBq/mL) of the solution (radioactive concentration 37MBq/mL) of pyridine and the Compound I-6 of 10 μ L joins in the octanol of the 2mL of preparation respectively, adds the 10mmol/L phosphate buffered saline buffer (pH7.4) of 2mL again in solution separately.With separately solution stirring after 30 seconds, with solution with 2000rpm centrifugation 60 minutes.The octanol that takes out each 1mL respectively mutually and water, by Autowell Gamma system (by the Aloka corporate system, model: ARC-301B) measure radioactivity.Based on the radioactivity that is obtained, calculate logP according to above-mentioned formula (1-2) _OctanolValue.

[0214] in addition, with Compound I-2 and the 2-for preparing in above-mentioned reference example I-9 (4 '-hydroxy phenyl)-solution of 6-iodine imidazo [1,2-a] pyridine carries out HPLC according to method same as described above respectively to be analyzed, to determine the K ' of each compound _HPLCValue.

[0215] construction drawing is wherein with respect to the log of Compound I-2 and 2-(4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine ₁₀K ' _HPLCValue is drawn Compound I-6 and 2-(4 '-hydroxy phenyl)-6-[ ¹²⁵I] logP of iodine imidazo [1,2-a] pyridine _OctanolValue is to determine the intercept on collinear slope and the Y-axis.Use these values, obtain following formula (1-4), condition is at pH7.2 to 7.4 time, logP _OctanolValue equals logP _HPLCValue.

[0216]logP _HPLC＝0.96(log ₁₀K′ _HPLC)+1.59...(1-4)

[0217] K ' that uses each compound of being estimated to obtain _HPLC, obtain the logP of each compound of being estimated according to above-mentioned formula (1-4) _HPLCValue.

[0218] result is shown in table 1-6.As the table shows, the logP of Compound I-1～Compound I-5 _HPLCValue is all between 1-3.As mentioned above, known porous is crossed the logP of the compound of BBB _OctanolValue between 1-3 (people such as Douglas D.Dischino, J.Nucl.Med., (1983), 24, p.1030-1038).In addition, known to pH7.2 to 7.4 time as mentioned above, logP _HPLCShown and logP _OctanolBe worth identical numerical value (people such as Franco Lombardo, J.Med.Chem., (2000), 43, p.2922-2927).The above results shows that Compound I-1～I-5 has the character of infiltration BBB.

[0219] table 1-6: the logP of compound of the present invention _HPLCValue

Experiment	Compound	logP HPLCValue
			Comparative Example I-8	[ 123I]-IMPY	2.1
Example I-15	Compound I-1	2.0
			Example I-16	Compound I-2	2.1
Example I-17	Compound I-3	1.9
			Example I-18	Compound I-4	1.9
Example I-19	Compound I-5	1.8

[0220] embodiment I-20 is to I-21, Comparative Example I-9: transitivity in brain and the property removed Mensuration

[0221] use Compound I-7 (example I-20) and Compound I-8 (example I-21), be determined at that radioactivity is accumulated in the male Wistar rat brain in (7 age in week) through the time variation.

[0222] under the condition of Thiopental Sodium anesthesia, with Compound I-7 be dissolved in the solution (example I-20) of the normal saline solution that comprises the 10mg/mL xitix, solution (example I-21) that Compound I-8 is dissolved in the normal saline solution that comprises the 10mg/mL xitix and above-mentioned reference example I-7 preparation [ ¹²³I]-each 0.05mL of solution (radioactive concentration 20-30MBq/mL) that IMPY is dissolved in the normal saline solution that comprises the 10mg/mL xitix is expelled in the tail vein of rat.After injection after 2,5,30 and 60 minutes by putting to death these rats from the abdominal aorta bloodletting, pipette brain, and with Autowell Gamma system (by the Aloka corporate system, model: ARC-301B) measure brain radioactivity (below, be called A in the present embodiment), carry out the mensuration of brain quality again.Simultaneously, measure the radioactivity (below, be called B in the present embodiment) of 1000 times of diluting soln 0.05mL of institute's injection solution according to mode same as described above.Use these measurement results, calculate the increased radioactivity (%ID/g) of dissecting time point per unit brain quality at each according to following formula (1-5).

At each time point, three animals are used for example I-20 and Comparative Example I-9, two animal is used for example I-21.

[0224] result is shown in table 1-7.As show shown in the 1-7, at the back 2 minutes time point of injection, accumulating that Compound I-7 and I-8 show be higher than [ ¹²³I]-IMPY, shown the trend of in 60 minutes, removing rapidly then.These results enlightenment, Compound I-7 and I-8 have with [ ¹²³I]-the suitable good brain transitivity of IMPY and the rapid removing from brain.

[0225] table 1-7: after intravenous injection, the increased radioactivity (rat) of compound of the present invention in brain

[0226] Example I-22: the proof of the image of amyloid in the brain

[0227] carries out following experiment and whether can make amyloid video picture in the brain with the compound of the present invention of upchecking.

[0228] (1) is with A β _1-40(peptide institute system) is dissolved in phosphate buffered saline buffer (pH 7.4), and 37 ℃ of down vibrations 72 hours, with the suspension of the aggegation A β that obtains 1mg/mL (below, be called the amyloid suspension in the present embodiment).

[0229] (2) are expelled to this amyloid suspension of 25 μ L (being equivalent to 25 μ g) in the amygdala of male Wistar rat (7 age in a week) side.In contrast, the phosphate buffered saline solution (pH 7.4) with 25 μ L is expelled in the amygdala of this rat opposite side.Check this rat after 1 day at injection amyloid suspension and phosphate buffered saline solution (pH7.4).

[0230] (3) are dissolved in Compound I-7 in the normal saline solution that comprises the 10mg/mL xitix, obtain sample solution (radioactive concentration is 32MBq/mL).With this solution by tail vein injection (dosage: 0.5mL, radioactive activity that gives: be equivalent to 16MBq) in rat.

[0231] (4) pipetted brain in back 60 minutes in injection, made the brain section of thickness 10 μ m with slicing machine (model: CM3050S is made by LEICA).This brain section was exposed on imaging plate 20 hours, then by using biometric image analyser (model: BAS-2500; By Fuji Photo Film Co., Ltd.'s system) carry out image analysis.

[0232] (5) carry out pathology dyeing with thioflavin T after finishing image analysis with biology-image analyzer, use fluorescent microscope (by NIKON's system; Model: TE2000-U type; Excitation wavelength: 400-440nm; Detect wavelength: 470nm) carry out video picture.Proved that thus amyloid is deposited in section and goes up (Fig. 1-12b).

[0233] Fig. 1-12 has shown autoradiogram(ARGM) and the painted image of thioflavin T by the brain section of the rat of injection amyloid in the brain.As shown in the drawing, in the amygdala of having injected amyloid suspension site, observe tangible radioactivity and accumulate.Accumulate the painted result of thioflavin T in site by radioactivity, proved accumulating the site to exist amyloid.On the other hand, compare, in the amygdala of injecting normal saline solution one side, do not observe tangible radioactivity and accumulate with other sites.

These result's enlightenments, Compound I-7 has the character of accumulating on IC amyloid, can make IC amyloid video picture.

[0234] Example I-23 arrives I-26: reverse mutation test

[0235] in order to check Compound I-1, I-2, the mutagenicity of I-4 and I-5 uses Salmonella typhimurium TA98 and TA100 to carry out reverse mutation test (below be called Salmonella reversion test).

[0236] under the condition that does not add S9mix and adding S9mix, carries out this test.Methyl-sulphoxide is used as negative control.Positive control is 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide under the situation that does not add S9mix, is the 2-amino anthracene under the situation that adds S9mix.

[0237] joining the amount of each sample on the test board, is 7 administrations (how much ratios 4) for Compound I-1 and I-5, and maximal dose is 1250 μ g/ plates, is 7 administrations (how much ratios 3) for Compound I-2 and I-4, and maximal dose is 5000 μ g/ plates.With given the test agent and bacterial strain (TA98 or TA100), after perhaps given the test agent, S9mix and bacterial strain being mixed, on the substratum of test board, mixture is divided into multilayer with soft agar, cultivated 48 hours down at 37 ℃ then.By judging after the cultivation colony number of the reverse mutation on the plate being counted, when the colony number of reverse mutation is not less than 2 times of negative control and display density dependency and increases, determine that mutagenicity is positive.

[0238] result is shown in table 1-8.With Compound I-1, I-2, the bacterium colony number average of the reverse mutation of each bacterial strain is less than the colony number in the group of handling with the negative control thing, no matter and whether added the add-on of S9mix and given the test agent in the group that I-4 and I-5 handle.From The above results, can judge, Compound I-1, I-2, I-4 and I-5 are negative in Salmonella reversion test, do not have mutagenicity.

[0239] result of table 1-8:Ames test

[0240] Example I-27:6-tributyl stannyl-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl] Synthesizing of imidazo [1,2-a] pyridine

[0241] the 6-bromo-2-[4 ' that 88mg (being equivalent to 0.260mmol) is obtained in reference example I-3-(2 ＂-fluorine oxyethyl group) phenyl] imidazo [1,2-a] pyridine is dissolved in the 10.0mL De diox, to the triethylamine that wherein adds 2.0mL.Then, to the tetrakis triphenylphosphine palladium of two (tributyl tins) that wherein add 0.20mL (being equivalent to 0.39mmol) and 20.1mg (catalytic amount).Descending stirring after 9 hours at 90 ℃ reaction mixture, underpressure distillation removes and desolvates.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=4/1) refining residue, obtain 6-tributyl stannyl-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl of 71.6mg (being equivalent to 0.131mmol)] imidazo [1,2-a] pyridine (Fig. 1-13, operation 1).

[0242] gained 6-tributyl stannyl-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of imidazo [1,2-a] pyridine.

[0243] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 7.97 (s, 1H), 7.90 (d, J=8.7Hz, 2H), 7.58 (d, J:8.7Hz, 1H), 7.14 (d, J=8.7Hz, 1H), 6.99 (d, J=8.7Hz, 2H), 4.77 (dt, J=47.2,4.1Hz, 2H), 3.99 (dt, J=28.0,4.1Hz, 2H), and 1.59-1.53 (m, 6H), 1.39-1.32 (m, 6H), 1.13-1.10 (m, 6H), 0.92 (t, J=7.3Hz, 9H)

[0244] 1 ³C-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 158.3,145.6,144.9,131.2, and 130.0,127.4,121.9,116.9,114.9,106.4,82.6,81.3,67.2,29.0,27.3,13.6,9.8.

[0245] Example I-28:2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-6-[ ¹²³ I] iodine imidazo [1,2-a] Synthesizing of pyridine

[0246] to 6-tributyl stannyl-2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl of 35 μ L] methanol solution of imidazo [1,2-a] pyridine (concentration: 1mg/mL), add the hydrochloric acid of the 1mol/L of 100 μ L, 614MBq [ ¹²³I] sodium iodide (volume is 100 μ L), 10% (w/v) hydrogen peroxide of the 1mol/L IodineSodium Solution of 10 μ L and 20 μ L.This mixture is being carried out HPLC in heating under 50 ℃ after 10 minutes under the condition identical with example I-2, to obtain 2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine utmost point branch.

[0247] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C8 Cartridges, the Waters corporate system; The loading level of filler: 130mg), so that this post absorptive collection 2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.Water with 1mL washes this post, allows 1mL ethanol pass through then, with wash-out 2-[4 '-(2 ＂-fluorine oxyethyl group) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.When just having finished, the radioactive activity of the compound that is obtained is 64MBq synthetic.In addition, carry out TLC under the following conditions and analyze, the result, the radiochemical purity of this compound is 97.0%.

[0248] TLC analysis condition:

TLC plate: silica gel 60F ₂₅₄(trade(brand)name; By Merck ﹠ Co., Inc.'s system)

Launch phase: chloroform/methanol/triethylamine=100/1/2

Detector: Rita Star (trade(brand)name; By the Raytest corporate system) [0249] Example I-29, Comparative Example I-10: based on the partition ratio of octanol extraction process Measure

[0250] with the normal saline solution of xitix that comprises 10mg/mL dilute respectively example I-28 preparation Compound I-9 diethyl ether solution (example I-29) and [ ¹²³I]-diethyl ether solution (Comparative Example I-10) of IMPY, regulate radioactive concentration to 20-30MBq/ml.In the octanol of 2mL, add each prepared sample solution of 10 μ L respectively, add the 10mmol/L phosphate buffered saline buffer (pH7.4) of 2mL again, stirred then 30 seconds.After with low speed centrifuge (2000rpm x60 minute) this mixture of centrifugation, take a sample respectively octanol layer and the water layer of each 1mL, and the mensuration of carrying out radiocounting separately with Autowell Gamma system (model: ARC-301B, by Aloka make).Use the radiocounting that is obtained, calculate logP according to formula (1-6) _Octanol

[0252] result is shown in table 1-9.The logP that Compound I-9 shows _OctanolValue is also between 1～3.Known porous is crossed the logP of the compound of BBB _OctanolValue between 1～3 (people such as DouglasD.Dischino, J.Nucl.Med., (1983), 24, p.1030-1038).Therefore, it shows that Compound I-9 has the BBB perviousness suitable with IMPY.

[0253] table 1-4: the logP of compound of the present invention _OctanolValue

Experiment	Compound	logP OctanolValue
			Comparative Example I-10	[ 123I]-IMPY	2.1
Example I-29	Compound I-9	2.1

[0254] Example I-30, Comparative Example I-11: the survey of transitivity in brain and the property removed Fixed (2)

[0254] use Compound I-9, be determined at that radioactivity is accumulated in the male Wistar rat brain in (7 age in week) through the time change.

[0256] preparation with Compound I-9 (embodiment 1-30) and in above-mentioned reference example, prepare [ ¹²³I]-IMPY (Comparative Example I-11) is dissolved in the normal saline solution that comprises the 10mg/mL xitix respectively and the solution (radioactive concentration 20-31MBq/mL) that forms respectively.Under the condition of Thiopental Sodium anesthesia, these injection of solution that are respectively 0.05mL are arrived in the tail vein of Wistar rat (7 age in week) separately.Injection 2,5, after 30 and 60 minutes by putting to death these rats from the abdominal aorta bloodletting, pipette brain, carry out the mensuration of brain quality, (detector models: SP-20 is by OHYO KOKEN KOGYO Co. to use the single passage analyser again, Ltd. make) measure the radioactivity (below, be called A in the present embodiment) of brain.Measure the radioactivity (below, be called B in the present embodiment) of the remainder of whole health according to mode same as described above.Use these measurement results, according to the increased radioactivity (%ID/g) of following formula (1-7) calculating in each time point per unit brain quality.

Three each time points that animal is used to test.

[0258] result is shown in table 1-10.As show shown in the 1-10, when the back 2 minutes time point of injection, Compound I-9 shown with [ ¹²³I]-the same significant radioactivity of IMPY accumulates, and shown the trend of removing rapidly in 60 minutes then.These results enlightenment, Compound I-9 have with [ ¹²³I]-transitivity from same good of IMPY to brain and have rapid removing from brain.

[0259] table 1-10: after intravenous injection, the increased radioactivity (rat) of compound of the present invention in brain

[0260] Example I-31: the image confirming of amyloid in the brain

[0261] (1) is with A β _1-42(with the pure pharmaceutical worker of light industry corporate system) is dissolved in phosphate buffered saline buffer (pH7.4), and 37 ℃ of vibrations 72 hours down, with the suspension of the aggegation A β that obtains 1mg/mL (below, be called the amyloid suspension in the present embodiment).

[0262] (2) are expelled to the amyloid suspension of 2.5 μ L (being equivalent to 25 μ g) in the amygdala of male Wistar rat (7 age in a week) side.In contrast, the phosphate buffered saline solution (pH 7.4) with 2.5 μ L is expelled in the amygdala of this rat opposite side.Check this rat after 1 day at injection amyloid suspension and phosphate buffered saline solution (pH 7.4).

[0263] (3) are dissolved in Compound I-9 in the normal saline solution of the xitix that comprises 10mg/mL, obtain sample solution (radioactive concentration in this sample solution is 21MBq/mL, example I-31).Under Thiopental Sodium anesthesia, with this solution by tail vein injection (dosage: 0.5mL, radioactive activity that gives: be equivalent to 11-15MBq) in rat.

[0264] (4) pipetted brain in back 60 minutes in injection, made the brain section of thickness 10 μ m with slicing machine (model: CM3050S is made by LEICA).This brain section was exposed on imaging plate 20 hours, then by using biology-image analyzer (model: BAS-2500; By Fuji Photo Film Co., Ltd.'s system) carry out image analysis.

[0265] (5) carry out pathology dyeing with thioflavin T after finishing image analysis with biology-image analyzer, by using fluorescent microscope (by NIKON's system; Model: TE2000-U type; Excitation wavelength: 400-440nm; Detect wavelength: 470nm) carry out video picture.Thereby proved that amyloid is deposited in this section and goes up (Fig. 1-14).

[0266] Fig. 1-14 has shown the autoradiogram(ARGM) and the painted image of thioflavin T of the brain section of the rat of injection amyloid in the brain.As shown in the drawing, injected in the corpse or other object for laboratory examination and chemical testing of Compound I-9, in the amygdala of having injected amyloid suspension one side, also observe tangible radioactivity and accumulate.On the other hand, compare, in the amygdala of injecting normal saline solution one side, do not observe tangible radioactivity and accumulate with other sites.On autoradiogram(ARGM), beyond the amyloid injection site, almost do not observe radioactive accumulating.By the painted result of thioflavin T, proved to exist amyloid (Fig. 1-14) in the site that radioactivity is accumulated.These result's enlightenments, Compound I-9 has the character of accumulating on IC amyloid, can make IC amyloid video picture.

[0267] Example I-32: chromosomal aberration test

[0268] in order to check Compound I-4 can bring out chromosome aberration, use Chinese hamster inoblast strain (CHL/IU cell), employing is by the interpolation of short-term facture or the culture systems of not adding S9, and 24 hours culture systems passing through continuous treatment process, carry out chromosomal aberration test.For all culture systems, the addition of given the test agent is set at 1.2,0.6,0.3 and 0.15mg/mL.

[0269] frequency of occurrences of the cell of chromosome aberration, compare obvious increase with negative control group, and when observing its dose-dependently, or when the frequency of occurrences obviously increases under single dose and observes circulation ratio, be judged to be the positive, in addition be judged to be feminine gender.

[0270] as the result of this test, in all culture systems of handling with Compound I-4, the frequency of occurrences and the negative control group of cell with structural aberration or quantity distortion (diploid) is suitable.On the other hand, the positive controls of each culture systems has shown that the frequency of occurrences of the cell with structural aberration obviously increases.Can judge that from The above results under this test conditions, the ability that Compound I-4 is brought out chromosome aberration is negative.

[0271] Example I-33: micronucleus test

[0272], has the bringing out property of the polychromatic erythrocyte (below be called MNPCE) of micronucleus with the medullary cell inspection of Crlj:CD1 (ICR) male mice for the mutagenicity of studying Compound I-4 (in the body).

[0273] dosage setting with test is 0mg/kg (negative control group), 250,500,1000 and 2000mg/kg (sample sets).Put to death mouse in single oral 24 with after 48 hours, preparation marrow cell coating plate sample is also observed.In addition, with MMC with 2mg/kg single dose intraperitoneal administration in positive controls, after administration, put to death mouse in 24 hours, prepare the marrow cell coating plate sample then and observe.

[0274] when confirming in each administration group that the frequency of occurrences of MNPCE demonstrates that dose-dependently increases or comparing with negative control group when demonstrating statistics and significantly increasing, is judged to be the positive, in addition is judged to be feminine gender.As statistical analysis, by the Wilcoxon rank test, ratio for the frequency of occurrences of MNPCE in each administration group and polychromatic erythrocyte (below be called PCE) and total red blood cell (below be called RBC), between given the test agent group and positive controls are with respect to negative control group or between each group, carry out test of significance, significance level is set at respectively less than 5% with less than 1%.

[0275] from the result of this test as can be seen, when the given the test agent group was compared with negative control group, the ratio of the frequency of occurrences of the MNPCE of given the test agent group and PCE and RBC was not observed statistical significant difference.On the other hand, when positive controls and negative control group were compared, the frequency of occurrences significance that observes the MNPCE of positive controls increased.Based on these results, judge that the mutagenicity (in the body) of given the test agent group is negative, because under above-mentioned test conditions, using Compound I-4 not observe has bringing out of micronucleus in bone marrow cells in mice.

[0276] Example II

In following embodiment, shown in table 2-1, define in the title of each compound that uses in the experiment.

[0277] table 2-1

The compound title	Popular name
		Compound I I-1	2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ 123I] iodine imidazo [1,2-a] pyridine
Compound I I-2	2-(4 '-ethoxyl phenenyl)-6-[ 123I] iodine imidazo [1,2-a] pyridine
		Compound I I-3	2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1,2-a] pyridine
Compound I I-4	2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ 123I] iodine imidazo [1,2-a] pyridine
		Compound I I-5	2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1,2-a] pyridine
Compound I I-6	2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl]-6-[ 123I] iodine imidazo [1,2-a] pyridine
		Compound I I-7	2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyridine

[0278] Example II-1:2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1,2-a] Synthesizing of pyridine (on-radiation iodate form)

[0279] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 8.18g (being equivalent to 60.0mmol) 4 '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, and in ethyl acetate/petroleum ether recrystallization, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 2-1, operation 1).

[0280] with the 2-bromo-4 of 441mg (being equivalent to 2.0mmol) '-2-amino-5-iodine pyridine of hydroxy acetophenone and 449mg (being equivalent to 2.0mmol) is dissolved in the 15mL acetonitrile.Under 110 ℃, with gained solution reflux 5 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 10mL water and 10mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 10mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains the 526mg 2-of (being equivalent to 1.56mmol) (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 2-1, operation 2).

[0281] in addition, the ethylene bromohyrin of 2.50g (being equivalent to 20.0mmol) and the imidazoles of 2.72g (being equivalent to 40.0mmol) are dissolved in the dimethyl formamide (DMF) of 10mL, and are cooled to 0 ℃.Then, to wherein adding the 5.50g tert-butyl diphenyl chlorosilane of (being equivalent to 20.0mmol) (TBDPSC1).After reaction mixture is at room temperature stirred 18 hours, add saturated nacl aqueous solution, use ethyl acetate extraction 3 times.With the ethyl acetate layer anhydrous sodium sulfate drying that merges, concentrating under reduced pressure.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=10/1) make with extra care the gained crude product, obtain 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane (Fig. 2-1, operation 3) of 7.04g (being equivalent to 19.4mmol).

[0282] the 200mg 2-of (being equivalent to 0.595mmol) (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine is dissolved in the dimethyl formamide of 3.0mL, to wherein adding the 247mg salt of wormwood of (being equivalent to 1.79mmol).Then to 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane that wherein adds 259mg (being equivalent to 0.714mmol).In that reaction mixture after 2 hours, is added saturated nacl aqueous solution in stirring under 90 ℃, use ethyl acetate extraction 3 times.With the ethyl acetate layer anhydrous sodium sulfate drying that merges, concentrating under reduced pressure.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=2/1) refining gained crude product, obtain the 368mg 2-[4 ' of (being equivalent to 0.595mmol)-(2 ＂-tert-butyl diphenyl siloxy-oxyethyl group) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 2-1, operation 4).

[0283] with the 368mg 2-[4 ' of (being equivalent to 0.595mmol)-(2 ＂-tert-butyl diphenyl siloxy-oxyethyl group) phenyl]-6-iodine imidazo [1,2-a] pyridine is dissolved in the tetrahydrofuran (THF) (THF) of 1.0mL, to the 1.0mol/L tetrahydrofuran solution 0.7mL that wherein adds tetrabutyl ammonium fluoride (TBAF).After reaction mixture is at room temperature stirred 2 hours, add ammonium chloride solution, add water and the 2.0mL acetonitrile of 5.0mL then.Then, filtering-depositing.Water and acetonitrile be the precipitation behind the washing and filtering successively, obtains the 226mg 2-[4 ' of (being equivalent to 0.595mmol)-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 2-1, operation 5).

[0284] gained 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-the NMR measurement result (internal standard substance: tetramethylsilane) as follows of 6-iodine imidazo [1,2-a] pyridine.

[0285] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 500MHz): δ 8.95 (m, 1H), 8.27 (s, 1H), 7.87 (d, J=8.7Hz, 2H), 7.54-7.46 (m, 2H), 7.04 (d, J=8.7Hz, 2H), 4.04 (t, J=4.6Hz, 2H), 3.73 (t, J=4.6Hz, 2H).

[0286] ¹³C-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 500MHz): δ 158.9,143.0,142.4,133.5, and 131.5,127.1,124.4,116.7,114.8,108.1,76.7,69.5,59.4.

[0287] Example II-2:6-tributyl stannyl-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl] Synthesizing of imidazo [1,2-a] pyridine

[0288] 2-[4 ' of the 100mg (being equivalent to 0.263mmol) that will in example II-1, obtain-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1,2-a] pyridine is dissolved in the 4.0mL De diox, to the triethylamine that wherein adds 2.0mL.Then, to the tetrakis triphenylphosphine palladium of two (tributyl tins) that wherein add 0.20mL (being equivalent to 0.39mmol) and 20.1mg (catalytic amount).Descending stirring after 21 hours at 90 ℃ reaction mixture, underpressure distillation removes and desolvates.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=1/2) refining residue, obtain 6-tributyl stannyl-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl of 75.3mg (being equivalent to 0.139mmol)] imidazo [1,2-a] pyridine (Fig. 2-2, operation 1).

[0289] gained 6-tributyl stannyl-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of imidazo [1,2-a] pyridine.

[0290] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 7.98 (s, 1H), 7.89 (d, J=8.7Hz, 1H), 7.75 (s, 1H), 7.56 (d, J=8.7Hz, 1H), 7.15 (d, J=8.7Hz, 1H), 6.98 (d, J=8.7Hz, 1H), 4.13 (t, J=4.6Hz, 2H), 3.99 (t, J=4.6Hz, 2H), 2.63 (s, 3H), 1.64-1.51 (m, 6H), 1.36 (sextet, J=7.3Hz, 6H), 1.19-1.06 (m, 6H), 0.92 (t, J=7.3Hz, 9H).

[0291] ¹³C-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 158.6,145.7,145.0,131.2, and 130.0,127.4,127.2,121.9,116.9,114.8,106.4,69.3,61.4,29.0,27.3,13.7,9.8.

[0292] Example II-3:2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³ I] the iodine imidazo Synthesizing of [1,2-a] pyridine

[0293] to 6-tributyl stannyl-2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl] imidazo [1,2-a] methyl alcohol/methyl-sulphoxide (blending ratio: 9/1) mixing solutions (concentration: 1mg/mL) among the 60 μ L of pyridine, the 1mol/L hydrochloric acid that adds 150 μ L, the 1mmol/mL sodium iodide of 15 μ L, the 274MBq of 250 μ L [ ¹²³I] 10% (w/v) hydrogen peroxide of sodium iodide and 15 μ L.With this mixture after leaving standstill 10 minutes under 50 ℃, carry out HPLC under the following conditions, to obtain 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine utmost point branch.

[0294] HPLC condition:

Chromatographic column: Phenomenex Luna C18 (trade(brand)name; By the Phenomenex corporate system; Size: 4.6 x 150mm)

Moving phase: 0.1% trifluoroacetic acid/acetonitrile=20/80 → 0/100 (17 minutes)

Flow velocity: 1.0mL/ minute

Detector: the UV, visible light extinction photometer (detects wavelength: 282nm) and radioactive counter (Raytest company corporate system; Model: STEFFI)

[0295] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C8 Cartridges, the Waters corporate system; The loading level of filler: 145mg), so that this post absorptive collection 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.Water with 1mL washes this post, allows the ether of 1mL pass through then, with wash-out 2-[4 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.When just having finished, the radioactive activity of the compound that is obtained is 22MBq synthetic.In addition, carry out TLC under the following conditions and analyze, the result, the radiochemical purity of this compound is 97%.

[0296] TLC analysis condition:

TLC plate: silica gel 60F ₂₅₄(trade(brand)name; By Merck ﹠ Co., Inc.'s system)

Launch phase: chloroform/methanol/triethylamine=100/1/2

Detector: Rita Star (trade(brand)name; By the Raytest corporate system)

[0297] Example II-4:2-(4 '-ethoxyl phenenyl)-6-iodine imidazo [1,2-a] pyridine is (non- The synthesizing radioiodination form)

[0298] the 30mL ethyl acetate is joined in the 2.72g cupric bromide of (being equivalent to 12.2mmol) obtains suspension, to wherein adding 4 of 1.00g (being equivalent to 6.09mmol) '-phenetole ethyl ketone, reflux gained mixture then.After 3 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate then.Residue is dissolved in ethyl acetate, and concentrates.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=10/1) refining gained crude product, obtain the 2-bromo-4 of 1.20g (being equivalent to 4.94mmol) '-phenetole ethyl ketone (Fig. 2-3, operation 1).

[0299] with the 2-bromo-4 of 1.20g (being equivalent to 4.94mmol) '-2-amino-5-iodine pyridine of phenetole ethyl ketone and 1.09mg (being equivalent to 4.95mmol) is dissolved in the 20mL acetonitrile.Under 110 ℃, with gained solution reflux 1.5 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.Then, with acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 10mL water and 5mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 20mL, usefulness supersound washing device was with mixture supersound process 10 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains the 1.64g 2-of (being equivalent to 4.50mmol) (4 '-ethoxyl phenenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 2-3, operation 2).

[0300] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of gained 2-(4 '-ethoxyl phenenyl)-6-iodine imidazo [1,2-a] pyridine.

[0301] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 500MHz): δ 9.06 (s, 1H), 8.38 (s, 1H), 7.86 (d, J=8.7Hz, 2H), 7.77-7.57 (m, 2H), 7.06 (d, J=8.7Hz, 2H), 4.10 (q, J=6.9Hz, 2H), 1.36 (t, J=6.9Hz, 3H).

[0302] 1 ³C-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 500MHz): δ 159.3,141.3,140.3,135.9, and 132.0,127.3,122.1,115.3,114.9,108.5,78.6,63.2,14.5.

[0303] Example II-5:6-tributyl stannyl-2-(4 '-ethoxyl phenenyl) imidazo Synthesizing of [1,2-a] pyridine

[0304] 2-of the 364mg (being equivalent to 1.00mmol) that will obtain in example II-4 (4 '-ethoxyl phenenyl)-6-iodine imidazo [1,2-a] pyridine is dissolved in the 4.0mL De diox, to the triethylamine that wherein adds 2mL.Then, to the tetrakis triphenylphosphine palladium of two (tributyl tins) that wherein add 0.76mL (being equivalent to 1.5mmol) and 76.3mg (catalytic amount).Descending stirring after 23 hours at 90 ℃ reaction mixture, underpressure distillation removes and desolvates.(elutriant: hexane/ethyl acetate=5/1) residue obtains 6-tributyl stannyl-2-(4 '-ethoxyl phenenyl) imidazo [1,2-a] pyridine (Fig. 2-4, operation 1) of 331mg (being equivalent to 0.628mmol) by quick silica gel column chromatography.

[0305] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of gained 6-tributyl stannyl-2-(4 '-ethoxyl phenenyl) imidazo [1,2-a] pyridine.

[0306] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 7.96 (s, 1H), 7.88 (d, J=8.7Hz, 1H), 7.74 (s, 1H), 7.58 (d, J=8.7Hz, 1H), 7.14 (d, J=8.7Hz, 1H), 6.96 (d, J=8.7Hz, 2H), 4.07 (q, J=6.9Hz, 2H), 1.63-1.49 (m, 6H), 1.43 (t, J=6.9Hz, 3H), 1.39-1.31 (m, 6H), 1.18-1.04 (m, 6H), 0.90 (t, J=7.3Hz, 9H).

[0307] ¹³C-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 159.0,145.7,145.2,131.2, and 130.1,127.4,126.7,121.9,117.0,114.8,106.4,63.6,29.1,27.4,15.0,13.8,9.9.

[0308] Example II-6:2-(4 '-ethoxyl phenenyl)-6-[ ¹²³ I] iodine imidazo [1,2-a] pyridine Synthetic

[0309] to 6-tributyl stannyl-2-(4 '-ethoxyl phenenyl) imidazo [1,2-a] methyl alcohol/methyl-sulphoxide (blending ratio: 9/1) mixing solutions (concentration: 1mg/mL) among the 60 μ L of pyridine, the 2mol/L hydrochloric acid that adds 90 μ L, the 1mmol/mL sodium iodide of 15 μ L, the 436MBq of 100 μ L [ ¹²³I] 10% (w/v) hydrogen peroxide of sodium iodide and 15 μ L.With this mixture after leaving standstill 10 minutes under 50 ℃, carry out HPLC under the following conditions, to obtain 2-(4 '-ethoxyl phenenyl)-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine utmost point branch.

[0310] HPLC condition:

Chromatographic column: Phenomenex Luna C18 (trade(brand)name; By the Phenomenex corporate system; Size: 4.6 x 150mm)

Moving phase: 0.1% trifluoroacetic acid/acetonitrile=20/80 → 0/100 (17 minutes)

Flow velocity: 1.0mL/ minute

Detector: the UV, visible light extinction photometer (detects wavelength: 282nm) and radioactive counter (Raytest company corporate system; Model: STEFFI)

[0311] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C8 Cartridges, the Waters corporate system; The loading level of filler: 145mg), so that this post absorptive collection 2-(4 '-ethoxyl phenenyl)-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.Water with 1mL washes this post, allows the ether of 1mL pass through then, with wash-out 2-(4 '-ethoxyl phenenyl)-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.When just having finished, the radioactive activity of the compound that is obtained is 88MBq synthetic.In addition, carry out TLC under the following conditions and analyze, the result, the radiochemical purity of this compound is 98%.

[0312] TLC analysis condition:

TLC plate: silica gel 60F ₂₅₄(trade(brand)name; By Merck ﹠ Co., Inc.'s system)

Launch phase: chloroform/methanol/triethylamine=100/1/2

Detector: Rita Star (trade(brand)name; By the Raytest corporate system)

[0313] Reference example II-1:[ ¹²³ I]-IMPY synthetic

[0314] according to following operation synthesize use in the comparative example of the property accumulated in the mensuration of research logP octanol and brain [ ¹²³I]-IMPY.

[0315] according in document (people such as Zhi-Ping Zhuang, J.Med.Chem, 2003,46, the p.237-243) method described in, synthetic 6-tributyl stannyl-2-[4 '-(N, the N-dimethylamino) phenyl] imidazo [1,2-a] pyridine, and be dissolved in methyl alcohol (concentration: 1mg/mL).In the gained solution of 53 μ L, add the 1mol/L hydrochloric acid of 75 μ L, the 224-253MBq of 60-70 μ L [ ¹²³I] sodium iodide, 10% (w/v) hydrogen peroxide of the 1mmol/L sodium iodide of 10 μ L and 15 μ L.With the solution of mixture after leaving standstill 10 minutes under 50 ℃, with this solution with the described identical condition of example II-3 under carry out HPLC, with obtain [ ¹²³I]-IMPY utmost point branch.

[0316] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) LightC8Cartridges, the Waters corporate system; The loading level of filler: 145mg), so that this post absorptive collection [ ¹²³I]-IMPY.Water with 1mL washes this post, allows the ether of 1mL pass through then, with wash-out [ ¹²³I]-IMPY.When just having finished, the radioactive activity of the compound that is obtained is 41-57MBq synthetic.In addition, with the described identical condition of example II-3 under carry out TLC and analyze, the result, the radiochemical purity of this compound is 93%.

[0317] Example II-7, Comparative Example I I-1 to II-3: with the affinity of amyloid Measure

By following external affinity in conjunction with experimental examination The compounds of this invention and amyloid.

[0318] (1) is with A β _1-42(with the pure pharmaceutical worker's industry of light corporate system) is dissolved in phosphate buffered saline buffer (pH7.4), and under 37 ℃, vibrated 72 hours, with the suspension of the aggegation A β that obtains 1mg/mL (below, be called amyloid in the present embodiment) (below, be called the amyloid suspension in the present embodiment).

[0319] (2) according to document (Naiki, people such as H., Laboratory Investigation, 74P.374-383 (1996)) described method, based on the spectrophotofluorimetry that uses thioflavin T (making) by Fluka, carry out the qualitative experiment of this amyloid suspension, to confirm that the aggegation A β that obtains is amyloid (condition determination: excitation wavelength 446nm, wavelength of fluorescence 490nm) in (1).

[0320] (3) are according to document (Wang, people such as Y., J.Labelled CompoundsRadiopharmaceut. 44, S239 (2001)) described in method, by the precursor 2-of mark (4 '-aminophenyl) benzothiazole preparation [ ¹²⁵I] 2-(3 '-iodo-4 '-aminophenyl) benzothiazole (below be called [ ¹²⁵I] 3 '-I-BTA-0), it is dissolved in the ethanol.With Congo red, thioflavin T and 6-methyl-2-[4 '-(N, N-dimethylamino) phenyl] benzothiazole (below be called 6-Me-BTA-2), directly weigh and use with the form of commercial reagent.

[0321] (4) synthesize IMPY according to the method described in the document (Zhuang, people such as Z.P., J.Med.Chem.46,237 (2003)).

[0322] (5) will respectively be used for the compound estimated or its ethanolic soln, above-mentioned (3) preparation [ ¹²⁵I] 3 '-ethanolic soln of I-BTA-0 and above-mentioned (1) in amyloid suspension of preparation be dissolved in the phosphate buffered saline buffer (pH 7.4) that comprises 0.1% bovine serum albumin, respectively the preparation compound that respectively is used to estimate, [ ¹²⁵I] 3 '-ultimate density of I-BTA-0 and amyloid is respectively the sample of the concentration shown in table 2-2.

[0323] ultimate density of table 2-2 each compound in sample solution

[0324] (6) are filled in each sample solution of preparation in above-mentioned (5) in each holes of 96 orifice plates (the about 0.3mL of volume).The microtest plate that is filled with sample solution was vibrated 3 hours down at 22 ℃ with command speed (400rpm).Allow the mixing solutions in each hole pass through glass fibre filter (trade(brand)name then; Mulutiscreen ^TM-FC is made by Millipore) filter, with from free [ ¹²⁵I] 3 '-isolate among the I-BTA-0 with the amyloid bonded [ ¹²⁵I] 3 '-I-BTA-0.

[0325] (7) are used to filter the glass fibre filter of each sample solution with phosphate buffered saline buffer (0.5mL * 5) washing that comprises 1% bovine serum albumin, use Autowell Gamma system (by the Aloka corporate system then, model: ARC-301B) radioactivity of measuring this glass fibre filter (below, the radioactive level of sample when A represents that the compound concentrations that respectively is used for estimating is zero (0), B represent that the compound concentrations that respectively is used for estimating is the 0.001nmol/L or the radioactive level of sample when higher).

[0326] (8) prepare the 6-Me-BTA-2 that comprises 15 μ mol/L in addition, 400pmol/L [ ¹²⁵I] 3 '-solution of I-BTA-0 and 1 μ mol/L amyloid, carry out measuring radioactive level with the same operation described in (7) and (8).The radioactive level of being measured is defined as the background radiation level, is used to calculate inhibiting rate (below be called BG).

[0327] (9) use the radioactive level of being measured in above-mentioned (7) and (8), determine inhibiting rate by following formula (2-1).

[0328] $\frac{B-\mathrm{BG}}{A-\mathrm{BG}}x100(\%)---(2-1)$

[0329] draws logarithmic with respect to institute's assessing compound concentration by the figure of the inhibiting rate that is obtained, to obtain proximate straight line by method of least squares by the value of probit transformation.Use this line, determine each compound estimated 50% inhibition concentration (below be called IC _50%Value).Use this value as indication, estimate and respectively be used to the compound estimated and the affinity of amyloid.

[0330] respectively is used to the IC of the compound estimated _50%Value is shown in table 2-3.Compound I I-3 has shown the IC less than 100 _50%Value knownly has the Congo red of affinity with amyloid and compares with thioflavin T with general, demonstrates to have higher and affinity amyloid.These results show that Compound I I-3 and IMPY are same, have good affinity with amyloid.

[0331] IC of table 2-3 compound of the present invention _50%Value

Experiment	The compound that is used to estimate	IC 50％Value (nmol/L)
			Comparative Example I I-1	Congo red	>1000
Comparative Example I I-2	Thioflavin T	>1000
			Comparative Example I I-3	IMPY	25.8
Example II-7	Compound I I-3	66.9

[0332] Example II-8 is to II-9, Comparative Example I I-4: based on the branch system of disposition of octanol extraction process The mensuration of number

[0333] measure partition ratio based on the octanol extraction process (below be called logP _Octanol), its general known be as the index of compound infiltration by hemato encephalic barrier (below be called BBB).

[0334] be diluted in the diethyl ether solution (example II-8) of the Compound I I-1 of preparation in the example II-3 respectively with the normal saline solution of xitix that comprises 10mg/mL, in example II-6 diethyl ether solution (example II-9) of the Compound I I-2 of preparation and in reference example II-1, prepare [ ¹²³I]-diethyl ether solution (Comparative Example I I-2) of IMPY, regulate radioactive concentration to 20-30MBq/ml.In the octanol of 2mL, add each prepared sample solution of 10 μ L respectively, add the 10mmol/L phosphate buffered saline buffer (pH 7.4) of 2mL again, stirred then 30 seconds.With behind low speed centrifuge (2000rpm x 60 minutes) this mixture of centrifugation, octanol layer and the water layer of the 1mL that takes a sample respectively, and with Autowell Gamma system (model: ARC-301B is made by Aloka) mensuration radiocounting.Use the radiocounting that is obtained, calculate logP according to formula (2-2) _Octanol

[0336] result is shown in table 2-4.The logP of all compound exhibits _OctanolValue is all between 1～3.Known porous is crossed the logP of the compound of BBB _OctanolValue between 1～3 (people such as DouglasD.Dischino, J.Nucl.Med., (1983), 24, p.1030-1038).Therefore show that these two kinds of compounds all have the BBB perviousness same with IMPY.

[0337] table 2-4: the logP of The compounds of this invention _OctanolValue

Experiment	Compound	logP OctanolValue
			Comparative Example I I-4	[ 123I]-IMPY	1.9
Example II-8	Compound I I-1	1.8
			Example II-9	Compound I I-2	2.1

[0338] Example II-10 is to II-11, Comparative Example I I-5: transitivity in brain and removing The mensuration of property

[0339] use Compound I I-1 (example II-10) and Compound I I-2 (example II-11), be determined at that radioactivity is accumulated in the male Wistar rat brain in (7 age in week) through the time variation.

[0340] be diluted in the diethyl ether solution (example II-10) of the Compound I I-1 of preparation in the example II-3 respectively with the normal saline solution of xitix that comprises 10mg/mL, in example II-6 diethyl ether solution (example II-11) of the Compound I I-2 of preparation and in reference example II-1, prepare [ ¹²³I]-diethyl ether solution (Comparative Example I I-5) of IMPY, to regulate radioactive concentration to 8-12MBq/ml.Under the condition of Thiopental Sodium anesthesia, the prepared sample solution that is respectively 0.05mL is expelled in the tail vein of rat.Injection 2,5, after 30 and 60 minutes by putting to death these rats from the abdominal aorta bloodletting, pipette brain, carry out the mensuration of brain quality, (detector models: SP-20 is by OHYO KOKEN KOGYO Co. to use the single passage analyser again, Ltd. make) measure the radioactivity (below, be called A in the present embodiment) of brain.In addition, measure the radioactivity (below, be called B in the present embodiment) of the remainder of whole health according to mode same as described above.Use these measurement results, according to the increased radioactivity (%ID/g) of following formula (2-3) calculating in the per unit brain quality of each time point.

Three each time points that animal is used to test.

[0342] result is shown in table 2-5.As show shown in the 2-5, at the back 2 minutes time point of injection, Compound I I-1 and II-2 shown with [ ¹²³I]-the same significant radioactivity of IMPY accumulates, and shown the trend of removing rapidly in 60 minutes then.These results enlightenment, Compound I I-1 and II-2 and [ ¹²³I]-IMPY is same, have good to brain transitivity and can from brain, remove rapidly.

[0343] table 2-5: after intravenous injection, the increased radioactivity (rat) of compound of the present invention in brain

[0344] Comparative Example I I-6: the rat of use amyloid injection model carries out [ ¹²³ I]-the stripped autoradiogram(ARGM) of IMPY

[0345] (1) is with A β _1-40(Co., Ltd.'s peptide institute system) is dissolved in phosphate buffered saline buffer (pH7.4), and 37 ℃ of down vibrations 72 hours, with the suspension of the aggegation A β that obtains 1mg/mL (below, be called the amyloid suspension in the present embodiment).

[0346] (2) are expelled to the amyloid suspension of 2.5 μ L (being equivalent to 25 μ g) in the amygdala of male Wistar rat (7 age in a week) side.In contrast, the phosphate buffered saline solution (pH 7.4) with 2.5 μ L is expelled in the amygdala of this rat opposite side.Check this rat after 1 day at injection amyloid suspension and phosphate buffered saline solution (pH 7.4).

[0347] (3) will [ ¹²³I]-IMPY is dissolved in the normal saline solution of the xitix that comprises 10mg/mL, obtains sample solution (in sample solution, radioactive concentration is 29MBq/mL).Under the condition of Thiopental Sodium anesthesia, with this solution by tail vein injection (dosage: 0.5mL, radioactive activity that gives: be equivalent to 14.5MBq) in rat.

[0348] (4) pipette brain in injection after 60 minutes, make the brain section of thickness 10 μ m with slicing machine (model: CM3050S is made by LEICA).This brain section was exposed on imaging plate 20 hours, then by using biology-image analyzer (model: BAS-2500; By Fuji Photo Film Co., Ltd.'s system) carry out image analysis.

[0349] (5) carry out pathology dyeing with thioflavin T after finishing image analysis with biology-image analyzer, by using fluorescent microscope (by NIKON's system; Model: TE2000-U type; Excitation wavelength: 400-440nm; Detect wavelength: 470nm) carry out video picture.Thereby proved that amyloid is deposited in section and goes up (Fig. 2-5b).

[0350] Fig. 2-5 has shown the autoradiogram(ARGM) and the painted image of thioflavin T of the brain section of the rat of injection amyloid in the brain.As shown in the drawing, in the amygdala of having injected amyloid suspension one side, observe tangible radioactivity and accumulate, but in the white matter of not injecting amyloid, also observed non-specific accumulating.

[0351] Example II-12: the proof of the image of amyloid in the brain

[0352] carries out following experiment and whether can make amyloid video picture in the brain with the compound of the present invention of upchecking.

[0353] (1) is with A β _1-42(with the pure pharmaceutical worker of light industry corporate system) is dissolved in phosphate buffered saline buffer (pH7.4), and 37 ℃ of vibrations 72 hours down, with the suspension of the aggegation A β that obtains 1mg/mL (below, be called the amyloid suspension in the present embodiment).

[0354] (2) are expelled to the amyloid suspension of 2.5 μ L (being equivalent to 25 μ g) in the amygdala of male Wistar rat (7 age in a week) side.In contrast, the phosphate buffered saline solution (pH 7.4) with 2.5 μ L is expelled in the amygdala of this rat opposite side.Check this rat after 1 day at injection amyloid suspension and phosphate buffered saline solution (pH 7.4).

[0355] (3) are dissolved in Compound I I-1 in the normal saline solution of the xitix that comprises 10mg/mL, obtain sample solution (in sample solution, radioactive concentration is 22MBq/mL).Under the condition of Thiopental Sodium anesthesia, with this solution by tail vein injection (dosage: 0.5mL, radioactive activity that gives: be equivalent to 11-13MBq) in rat.

[0356] (4) pipette brain in injection after 60 minutes, make the brain section of thickness 10 μ m with slicing machine (model: CM3050S is made by LEICA).This brain section was exposed on imaging plate 20 hours, then by using biology-image analyzer (model: BAS-2500; By Fuji Photo Film Co., Ltd.'s system) carry out image analysis.

[0357] (5) carry out pathology dyeing with thioflavin T after finishing image analysis with biology-image analyzer, by using fluorescent microscope (by NIKON's system; Model: TE2000-U type; Excitation wavelength: 400-440nm; Detect wavelength: 470nm) carry out video picture.Proved that thus amyloid is deposited in section and goes up (Fig. 2-6b).

[0358] Fig. 2-6 has shown autoradiogram(ARGM) and the painted image of thioflavin T by the brain section of the rat of injection amyloid in the brain.As shown in the drawing, in the amygdala of having injected amyloid suspension one side, observe tangible radioactivity and accumulate.On the other hand, compare, in the amygdala of injecting normal saline solution one side, do not observe significant radioactivity and accumulate with other sites.In addition, in autoradiogram(ARGM), on the site beyond the site of injection amyloid, almost do not observe radioactive accumulating.By the painted result of thioflavin T, proved to exist amyloid (Fig. 2-6b) in the site that radioactivity is accumulated.

[0359] therefore, Compound I I-1 shows that hardly radioactivity accumulates on the site beyond the site of injection amyloid, and [ ¹²³I]-non-specific binding with white matter also shown among the IMPY hardly.These result's enlightenments, Compound I I-1 has the good ability that makes the amyloid video picture in total autoradiogram(ARGM).These results also enlighten, and Compound I I-1 is a kind of compound that amyloid video picture in the brain is had high degree of specificity.

[0360] Example II-13: the image confirming of amyloid in the brain

[0361] carries out and the same operation of example II-12, except using the solution that Compound I I-2 is dissolved in the bad hematic acid solution of 10mg/mL and forms as sample solution (radioactive concentration of sample solution is 25MBq/mL).

[0362] Fig. 2-7 has shown autoradiogram(ARGM) and the painted image of thioflavin T by the brain section of the rat of injection amyloid in the brain.As shown in the drawing, in the amygdala of having injected amyloid suspension one side, observe tangible radioactivity and accumulate.Accumulate the painted result of thioflavin T in site by radioactivity, proved in this site to exist amyloid.On the other hand, compare, in the amygdala of injecting normal saline solution one side, do not observe significant radioactivity and accumulate with other sites.

[0363] site of Compound I I-2 beyond injection amyloid site shown that some radioactivity accumulate, but with [ ¹²³I]-IMPY compares, and this accumulating is subjected to very big inhibition.As a result, entire image demonstrates it and has the very high ability that makes the amyloid video picture.

These result's enlightenments, Compound I I-2 is a kind of compound that amyloid video picture in the brain is had high degree of specificity.

[0364] Example II-14:2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1,2-a] Synthesizing of pyridine (on-radiation iodate form)

[0365] the 50mL ethyl acetate is joined in the 8.60g cupric bromide of (being equivalent to 46.0mmol) obtains suspension, to the 50mL ethyl acetate solution that wherein adds 2.50g (being equivalent to 22.0mmol) 3 '-hydroxy acetophenone.Reflux gained mixture then.After 2 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=2/1) refining gained crude product, obtain the 2-bromo-3 of 4.42g (being equivalent to 20.6mmol) '-hydroxy acetophenone (Fig. 2-8, operation 1).

[0366] with the 2-bromo-3 of 987mg (being equivalent to 4.55mmol) '-2-amino-5-iodine pyridine of hydroxy acetophenone and 1.00g (being equivalent to 4.55mmol) is dissolved in the 50mL acetonitrile.Under 110 ℃, with gained solution reflux 2 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 10mL water and 10mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 10mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains the 927mg 2-of (being equivalent to 2.76mmol) (3 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 2-8, operation 2).

[0367] in addition, the ethylene bromohyrin of 2.50g (being equivalent to 20.0mmol) and the imidazoles of 2.72g (being equivalent to 40.0mmol) are dissolved in the dimethyl formamide (DMF) of 10mL, and are cooled to 0 ℃.Then, to wherein adding the 5.50g tert-butyl diphenyl chlorosilane of (being equivalent to 20.0mmol).After reaction mixture is at room temperature stirred 18 hours, add saturated nacl aqueous solution, use ethyl acetate extraction 3 times.With the ethyl acetate layer anhydrous sodium sulfate drying that merges, concentrating under reduced pressure.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=10/1) make with extra care the gained crude product, obtain 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane (Fig. 2-8, operation 3) of 7.04g (being equivalent to 19.4mmol).

[0368] the 300mg 2-of (being equivalent to 0.893mmol) (3 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine is dissolved in the dimethyl formamide of 5.0mL, to wherein adding the 370mg salt of wormwood of (being equivalent to 2.68mmol).Then to 1-bromo-2-(tert-butyl diphenyl siloxy-) ethane that wherein adds 357mg (being equivalent to 0.982mmol).In that reaction mixture after 2 hours, is added saturated nacl aqueous solution in stirring under 90 ℃, use ethyl acetate extraction 3 times.With the ethyl acetate layer anhydrous sodium sulfate drying that merges, concentrating under reduced pressure.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=3/1) refining gained crude product, obtain the 477mg 2-[3 ' of (being equivalent to 0.771mmol)-(2 ＂-tert-butyl diphenyl siloxy-oxyethyl group) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 2-8, operation 4).

[0369] with the 477mg 2-[3 ' of (being equivalent to 0.771mmol)-(2 ＂-tert-butyl diphenyl siloxy-oxyethyl group) phenyl]-6-iodine imidazo [1,2-a] pyridine is dissolved in the tetrahydrofuran (THF) of 0.98mL, to the 1.0mol/L tetrahydrofuran solution 0.93mL that wherein adds tetrabutyl ammonium fluoride.After reaction mixture is at room temperature stirred 15 minutes, add ammonium chloride solution, add 5.0mL water and 2.0mL acetonitrile then, the filtered and recycled precipitation.Water and acetonitrile be the precipitation behind the washing and filtering successively, obtains the 120mg 2-[3 ' of (being equivalent to 0.316mmol)-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 2-8, operation 5).

[0370] gained 2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-the NMR measurement result (internal standard substance: tetramethylsilane) as follows of 6-iodine imidazo [1,2-a] pyridine.

[0371] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: methyl-sulphoxide-d6, and resonant frequency: 500MHz): δ 8.91 (s, 1H), 8.35 (s, 1H), and 7.52-7.51 (m, 2H), 7.45 (s, 2H), 7.35 (t, J=8.2Hz, 1H), and 6.93-6.90 (m, 1H), 4.06 (t, J=4.6Hz, 2H), 3.75 (t, J=4.6Hz, 2H).

[0372] Example II-15:6-tributyl stannyl-2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl] Synthesizing of imidazo [1,2-a] pyridine

[0373] 2-[3 ' of the 70mg (being equivalent to 0.184mmol) that will in example II-14, obtain-(2 ＂-hydroxyl-oxethyl) phenyl]-6-iodine imidazo [1,2-a] pyridine is dissolved in the 4.0mL De diox, to the triethylamine that wherein adds 2.0mL.Then, to the tetrakis triphenylphosphine palladium of two (tributyl tins) that wherein add 0.20mL (being equivalent to 0.39mmol) and 14.0mg (catalytic amount).Descending stirring after 20 hours at 90 ℃ reaction mixture, underpressure distillation removes and desolvates.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=2/1) refining gained crude product, obtain 6-tributyl stannyl-2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl of 73.0mg (being equivalent to 0.134mmol)] imidazo [1,2-a] pyridine (Fig. 2-9, operation 1).

[0374] gained 6-tributyl stannyl-2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of imidazo [1,2-a] pyridine.

[0375] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, and resonant frequency: 500MHz): δ 7.99 (d, J=0.9Hz, 1H), 7.82 (s, 1H), and 7.64-7.50 (m, 3H), 7.34-7.31 (m, 1H), 7.18-7.17 (m, 1H), 6.90-6.87 (m, 1H), 4.20 (t, J=4.3Hz, 2H), 3.98 (t, J=4.3Hz, 2H), 1.69-1.48 (m, 6H), 1.39-1.32 (m, 6H), 1.19-1.05 (m, 6H), 0.91 (t, J=7.4Hz, 9H).

[0376] example II-16:2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³ I] the iodine imidazo Synthesizing of [1,2-a] pyridine

[0377] to 6-tributyl stannyl-2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl] imidazo [1,2-a] methyl alcohol/methyl-sulphoxide (blending ratio: 9/1) mixing solutions (concentration: 1mg/mL) among the 60 μ L of pyridine, the 1mol/L hydrochloric acid that adds 150 μ L, the 1mmol/mL sodium iodide of 15 μ L, the 274MBq of 250 μ L [ ¹²³I] 10% (w/v) hydrogen peroxide of sodium iodide and 15 μ L.With this mixture after leaving standstill 10 minutes under 50 ℃, carry out HPLC under the following conditions, to obtain 2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine utmost point branch.

[0378] HPLC condition:

Chromatographic column: Phenomenex Luna C18 (trade(brand)name; By the Phenomenex corporate system; Size: 4.6 x 150mm)

Moving phase: 0.1% trifluoroacetic acid/acetonitrile=20/80 → 0/100 (17 minutes)

Flow velocity: 1.0mL/ minute

Detector: the UV, visible light extinction photometer (detects wavelength: 282nm) and radioactive counter (Raytest company corporate system; Model: STEFFI)

[0379] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C8 Cartridges, the Waters corporate system; The loading level of filler: 145mg), so that this post absorptive collection 2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.Water with 1mL washes this post, allows the ether of 1mL pass through then, with wash-out 2-[3 '-(2 ＂-hydroxyl-oxethyl) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.When just having finished, the radioactive activity of the compound that is obtained is 112.9MBq synthetic.In addition, carry out TLC under the following conditions and analyze, the result, the radiochemical purity of this compound is 97%.

[0380] TLC analysis condition:

TLC plate: silica gel 60F ₂₅₄(trade(brand)name; By Merck ﹠ Co., Inc.'s system)

Launch phase: chloroform/methanol/triethylamine=100/1/2

Detector: Rita Star (trade(brand)name; By the Raytest corporate system)

[0381] Example II-17:2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl]-6-iodine imidazo [1,2-a] Synthesizing of pyridine (on-radiation iodate form)

[0382] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 2-10, operation 1).

[0383] with the 2-bromo-4 of 987mg (being equivalent to 4.55mmol) '-2-amino-5-iodine pyridine of hydroxy acetophenone and 1.00g (being equivalent to 4.55mmol) is dissolved in the 50mL acetonitrile.Under 110 ℃, with gained solution reflux 2 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 10mL water and 1mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 10mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains the 927mg 2-of (being equivalent to 2.76mmol) (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine (Fig. 2-10, operation 2).

[0384] in addition, the 2-bromopropyl alcohol of 7.0g (being equivalent to 50.4mmol) and the imidazoles of 6.86g (being equivalent to 101mmol) are dissolved in the dimethyl formamide of 50mL, and are cooled to 0 ℃.Then, to wherein adding the 7.59g TERT-BUTYL DIMETHYL CHLORO SILANE of (being equivalent to 50.4mmol).After reaction mixture is at room temperature stirred 24 hours, add saturated nacl aqueous solution, use extracted with diethyl ether 3 times.The ether layer that merges is dry on anhydrous magnesium sulfate, concentrating under reduced pressure.(100 ℃, 70mmHg) refining gained crude product obtains 1-bromo-3-(t-butyldimethylsilyloxy base) propane (Fig. 2-10, operation 3) of 7.23g (being equivalent to 30.2mmol) by underpressure distillation.

[0385] the 2.00g 2-of (being equivalent to 5.95mmol) (4 '-hydroxy phenyl)-6-iodine imidazo [1,2-a] pyridine is dissolved in the dimethyl formamide of 30.0mL, to wherein adding the 2.47g salt of wormwood of (being equivalent to 17.9mmol).Then to 1-bromo-3-(t-butyldimethylsilyloxy base) propane that wherein adds 1.51g (being equivalent to 5.95mmol).After reaction mixture is at room temperature stirred 8 days, replenish with saturated nacl aqueous solution, use ethyl acetate extraction 3 times.With the ethyl acetate layer anhydrous sodium sulfate drying that merges, concentrating under reduced pressure.By quick silica gel column chromatography (elutriant: hexane/ethyl acetate=1/1) refining gained crude product, obtain the 1.52g 2-[4 ' of (being equivalent to 2.99mmol)-(3 ＂-t-butyldimethylsilyloxy base propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 2-10, operation 4).

[0386] with the 1.52g 2-[4 ' of (being equivalent to 2.99mmol)-(3 ＂-t-butyldimethylsilyloxy base propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyridine is dissolved in the tetrahydrofuran (THF) of 5.0mL, to the 1.0mol/L tetrahydrofuran solution 2.99mL that wherein adds tetrabutyl ammonium fluoride.After reaction mixture is at room temperature stirred 30 minutes, add ammonium chloride solution, add the water of 10mL and 5.0mL acetonitrile then with filtering-depositing.Water and acetonitrile be the precipitation behind the washing and filtering successively, obtains the 1.03g 2-[4 ' of (being equivalent to 2.61mmol)-(3 ＂-hydroxyl propoxy-) phenyl]-6-iodine imidazo [1,2-a] pyridine (Fig. 2-10, operation 5).

[0387] gained 2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl]-the NMR measurement result (internal standard substance: tetramethylsilane) as follows of 6-iodine imidazo [1,2-a] pyridine.

[0388] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: methyl-sulphoxide-d6, resonant frequency: 500MHz): δ 8.96 (s, 1H), 8.33 (s, 1H), 7.98 (d, J=8.7Hz, 2H), 7.46 (s, 2H), 7.06 (d, J=8.7Hz, 2H), 4.63 (t, J=5.0Hz, 1H), 4.17 (t, J=6.0Hz, 2H), 3.72 (dt, J=5.0,6.0Hz, 2H), 1.98 (tt, J=6.0,6.0Hz, 2H).

[0389] Example II-18:6-tributyl stannyl-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl] Synthesizing of imidazo [1,2-a] pyridine

[0390] the 50mL ethyl acetate is joined in the 28.17g cupric bromide of (being equivalent to 126mmol) obtains suspension, to the mixing solutions of 50mL ethyl acetate that wherein adds 4 of 8.18g (being equivalent to 60.0mmol) '-hydroxy acetophenone and 50mL chloroform.Reflux gained mixture then.After 5 hours, reaction mixture is cooled to room temperature, and filters.Concentrating under reduced pressure gained filtrate.Residue is dissolved in ethyl acetate, and adds the gac operation of decolouring.Then, filter gained solution and concentrated.By quick silica gel column chromatography (elutriant: chloroform/methanol=20/1) refining gained crude product, obtain the 2-bromo-4 of 7.25g (being equivalent to 33.7mmol) '-hydroxy acetophenone (Fig. 2-11, operation 1).

[0391] with the 2-bromo-4 of 2.15g (being equivalent to 10.0mmol) '-2-amino-5-bromopyridine of hydroxy acetophenone and 1.74g (being equivalent to 10.0mmol) is dissolved in the 50mL acetonitrile.Under 105 ℃, with gained solution reflux 6 hours in oil bath.After reaction finishes, reaction mixture is cooled to room temperature, the filtered and recycled precipitation.With acetonitrile washing precipitation and drying under reduced pressure.The gained coarse crystal is suspended in the mixing solutions of 20mL water and 20mL methyl alcohol.Then, to the saturated sodium bicarbonate solution that wherein adds about 25mL, usefulness supersound washing device was with mixture supersound process 5 minutes.Filtered and recycled precipitation from the gained mixture, and water thorough washing, drying under reduced pressure obtains 6-bromo-2-(4 '-hydroxy phenyl) imidazo [1, the 2-a] pyridine (Fig. 2-11, operation 2) of 2.41g (being equivalent to 8.32mmol).

[0392] the dewatered 6-bromo-of 1.45g (being equivalent to 5.0mmol) thorough drying 2-(4 '-hydroxy phenyl) imidazo [1,2-a] pyridine is dissolved in the N of 50mL, in the dinethylformamide, to wherein adding the 2.07g salt of wormwood of (being equivalent to 15.0mmol).3-bromo-1-propyl alcohol with 680 μ L (being equivalent to 7.5mmol) replenishes this mixture, at room temperature stirs then 17 hours.After reaction finishes, reaction soln is poured in the water, use chloroform extraction 3 times.With the chloroform layer that the saturated nacl aqueous solution washing merges, use anhydrous sodium sulfate drying, filter and concentrate.Recrystallization gained crude product in methyl alcohol obtains 6-bromo-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl of 1.28g (being equivalent to 3.67mmol)] imidazo [1,2-a] pyridine (Fig. 2-11, operation 3).

[0393] with 6-bromo-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl of 100mg (being equivalent to 0.288mmol)] imidazo [1,2-a] pyridine is dissolved in the 4.0mL De diox, to the triethylamine that wherein adds 2.0mL.Then, to the tetrakis triphenylphosphine palladium of two (tributyl tins) that wherein add 0.22mL (being equivalent to 0.43mmol) and 22.0mg (catalytic amount).Descending stirring after 24 hours at 90 ℃ reaction mixture, underpressure distillation removes and desolvates, and by quick silica gel column chromatography (elutriant: hexane/ethyl acetate=3/1) refining residue, obtain 6-tributyl stannyl-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl of 68.0mg (being equivalent to 0.122mmol)] imidazo [1,2-a] pyridine (Fig. 2-11, operation 4).

[0394] gained 6-tributyl stannyl-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl] the NMR measurement result (internal standard substance: tetramethylsilane) as follows of imidazo [1,2-a] pyridine.

[0395] employed NMR device: JNM-ECP-500 (Jeol Ltd.'s system)

¹H-NMR (solvent: chloroform-d1, resonant frequency: 500MHz): δ 7.97 (s, 1H), 7.88 (d, J=8.3Hz, 2H), 7.74 (s, 1H), 7.58 (d, J=8.3Hz, 1H), 7.14 (d, J=8.7Hz, 1H), 6.98 (d, J=8.7Hz, 2H), 4.18 (t, J=6.0Hz, 2H), 3.89 (t, J=6.0Hz, 2H), 2.08 (tt, J=6.0,6.0Hz, 2H), 1.59-1.49 (m, 6H), 1.39-1.31 (m, 6H), 1.18-1.05 (m, 6H), 0.90 (t, J=7.3Hz, 9H).

[0396] Example II-19:2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl]-6-[ ¹²³ I] the iodine imidazo Synthesizing of [1,2-a] pyridine

[0397] to 6-tributyl stannyl-2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl] imidazo [1,2-a] methyl alcohol/methyl-sulphoxide (blending ratio: 9/1) mixing solutions (concentration: 1mg/mL) among the 100 μ L of pyridine, the 2mol/L hydrochloric acid that adds 80 μ L, the 1mmol/mL sodium iodide of 15 μ L, the 414MBq of 120 μ L [ ¹²³I] 10% (w/v) hydrogen peroxide of sodium iodide and 20 μ L.With this mixture after leaving standstill 10 minutes under 50 ℃, carry out HPLC under the following conditions, to obtain 2-[3 '-(4 ＂-hydroxyl propoxy-) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine utmost point branch.

[0398] HPLC condition:

Chromatographic column: Phenomenex Luna C18 (trade(brand)name; By the Phenomenex corporate system; Size: 4.6 x 150mm)

Moving phase: 0.1% trifluoroacetic acid/acetonitrile=20/80 → 0/100 (17 minutes)

Flow velocity: 1.0mL/ minute

Detector: the UV, visible light extinction photometer (detects wavelength: 282nm) and radioactive counter (Raytest company corporate system; Model: STEFFI)

[0399] water with 10mL joins in this utmost point branch.Allow gained solution by reversed-phase column (trade(brand)name; Sep-Pak (registered trademark) Light C8 Cartridges, the Waters corporate system; The loading level of filler: 145mg), so that this post absorptive collection 2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.Water with 1mL washes this post, allows the ether of 1mL pass through then, with wash-out 2-[4 '-(3 ＂-hydroxyl propoxy-) phenyl]-6-[ ¹²³I] iodine imidazo [1,2-a] pyridine.When just having finished, the radioactive activity of the compound that is obtained is 219MBq synthetic.In addition, carry out TLC under the following conditions and analyze, the result, the radiochemical purity of this compound is 97%.

[0400] TLC analysis condition:

TLC plate: silica gel 60F ₂₅₄(trade(brand)name; By Merck ﹠ Co., Inc.'s system)

Launch phase: chloroform/methanol/triethylamine=100/1/2

Detector: Rita Star (trade(brand)name; By the Raytest corporate system)

[0401] Example II-20 is to II-21, Comparative Example I I-7: based on the distribution of octanol extraction process The mensuration of coefficient

[0402] be diluted in the diethyl ether solution (example II-20) of the Compound I I-4 of preparation in the example II-16 respectively with the normal saline solution of xitix that comprises 10mg/mL, in example II-19 diethyl ether solution (example II-21) of the Compound I I-6 of preparation and [ ¹²³I]-diethyl ether solution (Comparative Example I I-7) of IMPY, regulate radioactive concentration to 20-30MBq/ml.In the octanol of 2mL, add the prepared various sample solutions of 10 μ L separately respectively, add the 10mmol/L phosphate buffered saline buffer (pH 7.4) of 2mL again, stirred then 30 seconds.With behind low speed centrifuge (2000rpm x 60 minutes) this mixture of centrifugation, octanol layer and the water layer of the 1mL that takes a sample respectively, and with Autowell Gamma system (model: ARC-301B is made by Aloka) mensuration radiocounting separately.Use the radiocounting that is obtained, calculate logP according to formula (2-4) _Octanol

[0404] result is shown in table 2-6.The logP of all compound exhibits _OctanolValue is all between 1～3.Known porous is crossed the logP of the compound of BBB _OctanolValue between 1～3 (people such as DouglasD.Dischino, J.Nucl.Med., (1983), 24, p.1030-1038).Above result shows that these two kinds of compounds all have the BBB perviousness suitable with IMPY.

[0405] table 2-6: the logP of compound of the present invention _OctanolValue

Experiment	Compound	logP OctanolValue
			Comparative Example I I-7	[ 123I]-IMPY	2.1
Example II-20	Compound I I-4	2.5
			Example II-21	Compound I I-6	2.1

[0406] Example II-22 is to II-23, Comparative Example I I-8: transitivity in brain and removing The mensuration of property

[0407] use Compound I I-4 and Compound I I-6, be determined at that radioactivity is accumulated in the male Wistar rat brain in (7 age in week) through the time change.

[0408] with the normal saline solution of the xitix that comprises 10mg/mL diluted compounds II-4 (example II-22) respectively, Compound I I-6 (example II-23) and in reference example II-1, prepare [ ¹²³I]-IMPY (Comparative Example I I-8), to prepare solution (radioactive concentration is 20-31MBq/ml) respectively.Under the condition of Thiopental Sodium anesthesia, respectively that 0.05mL is prepared sample solution is expelled in the Wistar rat tail vein in (7 age in week). Injection 2,5, after 30 and 60 minutes by putting to death these rats from the abdominal aorta bloodletting, pipette brain, carry out the mensuration of brain quality, (detector models: SP-20 is by OHYOKOKEN KOGYO Co. to use the single passage analyser again, Ltd. make) the mensuration radioactivity (below, be called A in the present embodiment).In addition, measure the radioactivity (below, be called B in the present embodiment) of the remainder of whole health according to mode same as described above.Use these measurement results, according to the increased radioactivity (%ID/g) of following formula (2-5) calculating in each time point per unit brain quality.

Three each time points that animal is used to test.

[0410] result is shown in table 2-7.As show shown in the 2-7, when the back 2 minutes time point of injection, Compound I I-4 and II-6 shown with [ ¹²³I]-the same significant radioactivity of IMPY accumulates, and shown the trend of removing rapidly in 60 minutes then.These results enlightenment, Compound I I-4 and II-6 and [ ¹²³I]-IMPY is same, and have very high transitivity and also can from brain, remove rapidly to brain.

[0411] table 2-7: after intravenous injection, the increased radioactivity (rat) of compound of the present invention in brain

[0412] Example II-24 arrives II-25: the image confirming of amyloid in the brain

[0413] (1) is with A β _1-42(with the pure pharmaceutical worker of light industry corporate system) is dissolved in phosphate buffered saline buffer (pH7.4), and 37 ℃ of vibrations 72 hours down, with the suspension of the aggegation A β that obtains 1mg/mL (below, be called the amyloid suspension in the present embodiment).

[0414] (2) are expelled to the amyloid suspension of 2.5 μ L (being equivalent to 25 μ g) in the amygdala of male Wistar rat (7 age in a week) side.In contrast, the phosphate buffered saline solution (pH 7.4) with 2.5 μ L is expelled in the amygdala of this rat opposite side.Check this rat after 1 day at injection amyloid suspension and phosphate buffered saline solution (pH 7.4).

[0415] (3) preparation Compound I I-4 is dissolved in the normal saline solution of the xitix that comprises 10mg/mL and the sample solution that obtains (radioactive concentration is 30MBq/mL, example II-24), the sample solution (radioactive concentration is 30MBq/mL, example II-25) that obtains with Compound I I-6 is dissolved in the normal saline solution of the xitix that comprises 10mg/mL.Under the condition of Thiopental Sodium anesthesia, with this solution by tail vein injection (dosage: 0.5mL, radioactive activity that gives: be equivalent to 11-15MBq) in rat.

[0416] (4) pipetted brain in back 60 minutes in injection, made the brain section of thickness 10 μ m with slicing machine (model: CM3050S is made by LEICA).This brain section was exposed on imaging plate 20 hours, then by using biology-image analyzer (model: BAS-2500; By Fuji Photo Film Co., Ltd.'s system) carry out image analysis.

[0417] (5) carry out pathology dyeing with thioflavin T after finishing image analysis with biology-image analyzer, by using fluorescent microscope (by NIKON's system; Model: TE2000-U type; Excitation wavelength: 400-440nm; Detect wavelength: 470nm) carry out video picture.Thereby proved that amyloid is deposited in section and goes up (Fig. 2-12 and Fig. 2-13).

[0418] Fig. 2-12 and Fig. 2-13 shown autoradiogram(ARGM) and the painted image of thioflavin T by the brain section of the rat of injection amyloid in the brain.As shown in these figures, used in the corpse or other object for laboratory examination and chemical testing of Compound I I-4 and II-6, in the amygdala of injection amyloid suspension one side, observed tangible radioactivity and accumulate.On the other hand, compare, in the amygdala of injecting normal saline solution one side, do not observe significant radioactivity and accumulate with other sites.On autoradiogram(ARGM), on the site beyond the site of injection amyloid, almost do not observe radioactive accumulating.By the painted result of thioflavin T, proved on the site that radioactivity is accumulated, to exist amyloid (Fig. 2-12 and Fig. 2-13).These result's enlightenments, Compound I I-4 and II-6 have the character of accumulating on the amyloid in brain, and have the ability that makes amyloid video picture in the brain.

Industrial applicability

[0419] compound of the present invention can use at diagnostic field.

Claims (25)

1. the compound or its salt shown in the following formula (1):

Wherein, A ₁, A ₂, A ₃And A ₄Represent carbon or nitrogen independently of one another,

R ¹Be halogenic substituent,

R ²Be halogenic substituent, and

M is the integer of 0-2,

Condition is R ¹And R ²In at least one be the radiohalogen substituting group, A ₁, A ₂, A ₃And A ₄In at least one the expression carbon, R ¹With A ₁, A ₂, A ₃Or A ₄Shown carbon links to each other.

2. the described compound or its salt of claim 1, wherein, A ₁, A ₂, A ₃And A ₄In at least three the expression carbon.

3. the described compound or its salt of claim 2, wherein, A ₁, A ₂, A ₃And A ₄All represent carbon.

4. each described compound or its salt of claim 1-3, wherein, R ¹Be selected from ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.

5. each described compound or its salt of claim 1-4, wherein, R ²Be selected from ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.

6. the compound or its salt shown in the following formula (2):

Wherein, A ₅, A ₆, A ₇And A ₈Represent carbon or nitrogen independently of one another,

R ³Be to be selected from non-radioactive halogen substituting group, nitro substituent, alkyl chain to have the trialkyl stannyl substituting group of 1-4 carbon atom and the group of triphenyl stannyl,

R ⁴Be be selected from non-radioactive halogen substituting group, mesyloxy substituting group, trifluoro-methanesulfonyl oxy substituting group or the substituent group of aromatic series sulfonyloxy and

N is the integer of 0-2,

Condition is A ₅, A ₆, A ₇And A ₈In at least one the expression carbon, R ³With A ₅, A ₆, A ₇Or A ₈Shown carbon links to each other.

7. the described compound or its salt of claim 6, wherein, A ₅, A ₆, A ₇And A ₈In at least three the expression carbon.

8. the described compound or its salt of claim 7, wherein, A ₅, A ₆, A ₇And A ₈All represent carbon.

9. each described compound or its salt of claim 6-8, wherein, R ³Be selected from chlorine, iodine, bromine, nitro substituent, trimethylammonium stannyl substituting group, tributyl stannyl substituting group and triphenyl stannyl substituting group.

10. the hypotoxicity diagnostic reagent of alzheimer's disease comprises the compound or its salt shown in the following formula (1):

Wherein, A ₁, A ₂, A ₃And A ₄Represent carbon or nitrogen independently of one another,

R ¹Be halogenic substituent,

R ²Be halogenic substituent, and

M is the integer of 0-2,

Condition is R ¹And R ²In at least one be the radiohalogen substituting group, A ₁, A ₂, A ₃And A ₄In at least one the expression carbon, R ¹With A ₁, A ₂, A ₃Or A ₄Shown carbon links to each other.

11. the hypotoxicity diagnostic reagent of the described alzheimer's disease of claim 10, wherein, A ₁, A ₂, A ₃And A ₄In at least three the expression carbon.

12. the hypotoxicity diagnostic reagent of the described alzheimer's disease of claim 11, wherein, A ₁, A ₂, A ₃And A ₄All represent carbon.

13. the hypotoxicity diagnostic reagent of each described alzheimer's disease of claim 10-12, wherein, R ¹Be selected from ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.

14. the hypotoxicity diagnostic reagent of each described alzheimer's disease of claim 10-13, wherein, R ²Be selected from ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.

15. the compound or its salt shown in the following formula (3):

Wherein, A ₉, A ₁₀, A ₁₁And A ₁₂Represent carbon or nitrogen independently of one another,

R ⁵Be the radiohalogen substituting group,

R ⁶Be to be selected from hydrogen, hydroxyl, methoxyl group, carboxyl, amino, N-methylamino, N, the group of N-dimethylamino and cyano group, and

P is the integer of 0-2,

Condition is A ₉, A ₁₀, A ₁₁And A ₁₂In at least one the expression carbon, R ⁵With A ₉, A ₁₀, A ₁₁Or A ₁₂Shown carbon links to each other.

16. the described compound or its salt of claim 15, wherein, A ₉, A ₁₀, A ₁₁And A ₁₂In at least three the expression carbon.

17. the described compound or its salt of claim 16, wherein, A ₉, A ₁₀, A ₁₁And A ₁₂All represent carbon.

18. each described compound or its salt of claim 15-17, wherein, R ⁵Be selected from ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.

19. the compound or its salt shown in the following formula (4):

Wherein, A ₁₃, A ₁₄, A ₁₅And A ₁₆Represent carbon or nitrogen independently of one another,

R ⁷Be to be selected from trialkyl ammonium group, the alkyl chain that non-radioactive halogen substituting group, nitro substituent, alkyl chain have 1-4 carbon atom to have the trialkyl stannyl substituting group of 1-4 carbon atom and the group of triphenyl stannyl,

R ⁸Be to be selected from hydrogen, hydroxyl, methoxyl group, carboxyl, amino, N-methylamino, N, the group of N-dimethylamino and cyano group, and

Q is the integer of 0-2,

Condition is A ₁₃, A ₁₄, A ₁₅And A ₁₆In at least one the expression carbon, R ⁷With A ₁₃, A ₁₄, A ₁₅Or A ₁₆Shown carbon links to each other.

20. the described compound or its salt of claim 19, wherein, A ₁₃, A ₁₄, A ₁₅And A ₁₆In at least three the expression carbon.

21. the described compound or its salt of claim 20, wherein, A ₁₃, A ₁₄, A ₁₅And A ₁₆All represent carbon.

22. the hypotoxicity diagnostic reagent of alzheimer's disease comprises the compound or its salt shown in the following formula (3):

Wherein, A ₉, A ₁₀, A ₁₁And A ₁₂Represent carbon or nitrogen independently of one another,

R ⁵Be the radiohalogen substituting group,

R ⁶Be to be selected from hydrogen, hydroxyl, methoxyl group, carboxyl, amino, N-methylamino, N, the group of N-dimethylamino and cyano group, and

P is the integer of 0-2,

Condition is A ₉, A ₁₀, A ₁₁And A ₁₂In at least one the expression carbon, R ⁵With A ₉, A ₁₀, A ₁₁Or A ₁₂Shown carbon links to each other.

23. the hypotoxicity diagnostic reagent of the described alzheimer's disease of claim 22, wherein, A ₉, A ₁₀, A ₁₁And A ₁₂In at least three the expression carbon.

24. the hypotoxicity diagnostic reagent of the described alzheimer's disease of claim 23, wherein, A ₉, A ₁₀, A ₁₁And A ₁₂All represent carbon.

25. the hypotoxicity diagnostic reagent of each described alzheimer's disease of claim 22-24, wherein, R ⁵Be selected from ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.

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