JP2019064986A - MOLECULE PROBE FOR Bcr-Abl PROTEIN IMAGING - Google Patents
MOLECULE PROBE FOR Bcr-Abl PROTEIN IMAGING Download PDFInfo
- Publication number
- JP2019064986A JP2019064986A JP2017194584A JP2017194584A JP2019064986A JP 2019064986 A JP2019064986 A JP 2019064986A JP 2017194584 A JP2017194584 A JP 2017194584A JP 2017194584 A JP2017194584 A JP 2017194584A JP 2019064986 A JP2019064986 A JP 2019064986A
- Authority
- JP
- Japan
- Prior art keywords
- group
- tumor
- bcr
- pon
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 238000010377 protein imaging Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 230000002285 radioactive effect Effects 0.000 claims abstract description 47
- 238000003384 imaging method Methods 0.000 claims abstract description 39
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 38
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000002243 precursor Substances 0.000 claims description 32
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 24
- 239000003068 molecular probe Substances 0.000 claims description 15
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical group [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000005492 nosylate group Chemical group 0.000 claims description 9
- 125000005490 tosylate group Chemical group 0.000 claims description 9
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 238000000163 radioactive labelling Methods 0.000 claims description 8
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical group FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 description 121
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 229910052739 hydrogen Inorganic materials 0.000 description 54
- 210000000056 organ Anatomy 0.000 description 39
- 210000004369 blood Anatomy 0.000 description 37
- 239000008280 blood Substances 0.000 description 37
- 210000003205 muscle Anatomy 0.000 description 36
- 210000000988 bone and bone Anatomy 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- 241000699670 Mus sp. Species 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- 102100022824 Serum paraoxonase/arylesterase 2 Human genes 0.000 description 25
- 101710180998 Serum paraoxonase/arylesterase 2 Proteins 0.000 description 25
- 230000035508 accumulation Effects 0.000 description 23
- 238000009825 accumulation Methods 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 17
- 102100035476 Serum paraoxonase/arylesterase 1 Human genes 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 101710180981 Serum paraoxonase/arylesterase 1 Proteins 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000011156 evaluation Methods 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- 241000581650 Ivesia Species 0.000 description 8
- 210000002216 heart Anatomy 0.000 description 8
- 238000010253 intravenous injection Methods 0.000 description 8
- 210000003734 kidney Anatomy 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 210000004072 lung Anatomy 0.000 description 8
- 210000000496 pancreas Anatomy 0.000 description 8
- 230000005855 radiation Effects 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000002603 single-photon emission computed tomography Methods 0.000 description 8
- 210000000813 small intestine Anatomy 0.000 description 8
- 210000000952 spleen Anatomy 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 8
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 8
- -1 inorganic acid salts Chemical class 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 5
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 238000009206 nuclear medicine Methods 0.000 description 4
- 238000002600 positron emission tomography Methods 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 4
- 210000000349 chromosome Anatomy 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000013170 computed tomography imaging Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 3
- IXYWNRNRQJPZDO-UHFFFAOYSA-N 3-bromo-4-[(4-methylpiperazin-1-yl)methyl]aniline Chemical compound C1CN(C)CCN1CC1=CC=C(N)C=C1Br IXYWNRNRQJPZDO-UHFFFAOYSA-N 0.000 description 2
- VYOHSFQVMLAURO-UHFFFAOYSA-N 3-ethynylimidazo[1,2-b]pyridazine Chemical compound C1=CC=NN2C(C#C)=CN=C21 VYOHSFQVMLAURO-UHFFFAOYSA-N 0.000 description 2
- DYBHNIBYSFQVTN-UHFFFAOYSA-N 4-[(4-methylpiperidin-1-yl)methyl]-3-(trifluoromethyl)aniline Chemical compound C1CC(C)CCN1CC1=CC=C(N)C=C1C(F)(F)F DYBHNIBYSFQVTN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229940124290 BCR-ABL tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WNDOGLDEEHULSK-UHFFFAOYSA-N 1-[(2-iodo-4-nitrophenyl)methyl]-4-methylpiperazine Chemical compound IC1=C(CN2CCN(CC2)C)C=CC(=C1)[N+](=O)[O-] WNDOGLDEEHULSK-UHFFFAOYSA-N 0.000 description 1
- COYJKQBJEGGZSD-UHFFFAOYSA-N 3,5-dibromo-4-methylbenzoyl chloride Chemical compound CC1=C(Br)C=C(C(Cl)=O)C=C1Br COYJKQBJEGGZSD-UHFFFAOYSA-N 0.000 description 1
- NDLCOZKAMPPKQH-UHFFFAOYSA-N 3,5-diiodo-4-methylbenzoic acid Chemical compound CC1=C(I)C=C(C(O)=O)C=C1I NDLCOZKAMPPKQH-UHFFFAOYSA-N 0.000 description 1
- MYIJMKUZTMTYRI-UHFFFAOYSA-N 3,5-diiodo-4-methylbenzoyl chloride Chemical compound CC1=C(C=C(C=C1I)C(=O)Cl)I MYIJMKUZTMTYRI-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- ADVGQOHDBWPMRV-UHFFFAOYSA-N 3-iodo-4-[(4-methylpiperazin-1-yl)methyl]aniline Chemical compound IC=1C=C(C=CC1CN1CCN(CC1)C)N ADVGQOHDBWPMRV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 150000004926 Imatinib derivatives Chemical class 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000036326 tumor accumulation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Abstract
Description
本開示は、Bcr-Ablタンパク質に結合可能な化合物及び該化合物を含むBcr-Ablタンパク質イメージング用分子プローブに関する。 The present disclosure relates to a compound capable of binding to Bcr-Abl protein and a molecular probe for imaging Bcr-Abl protein comprising the compound.
Bcr-Abl遺伝子及びそれから産生されるBcr-Ablタンパク質は、慢性骨髄性白血病(CML)の治療効果の評価や寛解の判断の指標の一つとされている(非特許文献1及び2)。なぜなら、CMLは、9番目の染色体と22番目の染色体の相互転座が生じることによりフィラデルフィア染色体が形成され、その染色体上で形成されたBcr−Abl遺伝子産生するBcr-Ablタンパク質が白血球細胞の無制限な増殖を引き起こすことにより発症するとされているからである。 The Bcr-Abl gene and the Bcr-Abl protein produced therefrom are considered as one of the indices for evaluation of the therapeutic effect of chronic myelogenous leukemia (CML) and judgment of remission (Non-patent Documents 1 and 2). This is because CML forms a Philadelphia chromosome by the occurrence of reciprocal translocation between the 9th chromosome and the 22nd chromosome, and the Bcr-Abl protein produced by the Bcr-Abl gene formed on that chromosome is a leukocyte cell of It is believed to be caused by causing unlimited proliferation.
一方、イマチニブ等のチロシンキナーゼ阻害剤(Bcr-Abl TKI)はCML治療においてもっとも有効性が高いとされているが、これらによる治療が有効ではない患者も中にはいる。このため、例えば、チロシンキナーゼ阻害剤耐性によりBcr-Abl TKIによる治療が失敗する可能性を回避するために、核医学診断用放射性イメージングプローブの検討が行われている(非特許文献3及び4)。 On the other hand, tyrosine kinase inhibitors such as imatinib (Bcr-Abl TKI) are considered to be the most effective in CML treatment, but some patients for which these treatments are not effective. For this reason, for example, in order to avoid the possibility that treatment with Bcr-Abl TKI may fail due to tyrosine kinase inhibitor resistance, examination of radioactive imaging probes for nuclear medicine diagnosis has been conducted (Non-patent Documents 3 and 4) .
しかしながら、Bcr-Ablタンパク質を鮮明にイメージング可能な放射性化合物は未だ開発されていない。そこで、本開示は、Bcr-Ablタンパク質をイメージング可能な新たな放射性化合物を提供する。 However, radioactive compounds capable of clearly imaging Bcr-Abl protein have not been developed yet. Thus, the present disclosure provides a novel radioactive compound capable of imaging Bcr-Abl protein.
本開示は、一態様において、下記式(I)で表される化合物又はその製薬上許容される塩(以下、「本開示の放射性化合物」ともいう)に関する。
Xは、−C(=O)−NH−又は−NH−C(=O)−であり、
R1は、
R2及びR3は、それぞれ独立して、水素原子、放射性ハロゲン原子、及びフッ化メチル基であり、R2及びR3の一方は、放射性ハロゲン原子である。
The present disclosure relates, in one aspect, to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as “a radioactive compound of the present disclosure”).
X is -C (= O) -NH- or -NH-C (= O)-,
R 1 is
R 2 and R 3 are each independently a hydrogen atom, a radioactive halogen atom, and a methyl fluoride group, and one of R 2 and R 3 is a radioactive halogen atom.
本開示は、一態様において、式(I)で表される化合物又はその製薬上許容される塩を含む、Bcr-Ablタンパク質イメージング用分子プローブに関する。 The present disclosure relates, in one aspect, to a molecular probe for imaging Bcr-Abl protein, which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
本開示は、一態様において、下記式(II)で表される化合物又はその製薬上許容される塩を含む、放射性標識のための前駆体組成物に関する。
Xは、−C(=O)−NH−又は−NH−C(=O)−であり、
R1は、
R4及びR5は、それぞれ独立して、水素原子、ハロゲン原子、トリアルキルスタニル基、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基であり、R4及びR5の一方は、ハロゲン原子、トリアルキルスタニル基、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基である。
The present disclosure relates, in one aspect, to a precursor composition for radioactive labeling, which comprises a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.
X is -C (= O) -NH- or -NH-C (= O)-,
R 1 is
R 4 and R 5 each independently represent a hydrogen atom, a halogen atom, a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group, and R 4 and R 5 One of them is a halogen atom, a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group.
本開示は、一態様において、Bcr-Ablチロシンキナーゼ阻害剤と、上記式(I)で表される化合物、その製薬上許容される塩又は上記分子プローブとが投与された被検体から前記化合物の放射性シグナルを検出することを含むイメージング方法に関する。 The present disclosure provides, in one aspect, a compound of the present invention from a subject to which a Bcr-Abl tyrosine kinase inhibitor and a compound represented by the above formula (I), a pharmaceutically acceptable salt thereof or the above molecular probe are administered The invention relates to an imaging method comprising detecting a radioactive signal.
本開示は、一態様において、Bcr-Ablタンパク質をイメージング可能な新たな放射性化合物を提供できる。 The present disclosure can provide, in one aspect, a novel radioactive compound capable of imaging Bcr-Abl protein.
本開示は、下記の放射性標識された化合物が、Bcr-Abl negative細胞であるA431細胞と比較して、Bcr-Abl positive細胞であるK562細胞及びBcr-Abl変異細胞であるBa/F Bcr-AblT315Iに特異的に結合するという知見に基づく。中でも、[125I]PON-2は、K562細胞により構成された腫瘍をSPECTによって鮮明にイメージングできる、という知見に基づく。
本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質に高い親和性を有し、かつ優れた腫瘍/血液比及び腫瘍/筋肉比を示すことができるという効果を奏しうる。このため、本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質の発現を非侵襲的に検出することができうるという効果を奏しうる。本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質が過剰に発現した腫瘍を非侵襲的に画像化、好ましくは定量できうるという効果を奏しうる。 The radioactive compound of the present disclosure can exhibit the effect of having high affinity to Bcr-Abl protein and capable of exhibiting excellent tumor / blood ratio and tumor / muscle ratio in one or more embodiments. For this reason, the radioactive compound of the present disclosure can exhibit an effect that the expression of Bcr-Abl protein can be detected noninvasively in one or more embodiments. The radioactive compound of the present disclosure can exhibit the effect of being able to noninvasively image, preferably quantify, a tumor in which Bcr-Abl protein is overexpressed, in one or more embodiments.
本開示の放射性化合物は、一又は複数の実施形態において、野生型Bcr-Ablタンパク質及び薬剤耐性変異型Bcr-Ablタンパク質(例えば、T315I変異型Bcr-Ablタンパク質)のいずれにも特異的に結合することができる。本開示の放射性化合物によれば、Bcr-Abl依存性耐性の被検体においても、Bcr-Ablタンパク質の発現を非侵襲的に検出することができる。 The radioactive compounds of the present disclosure, in one or more embodiments, specifically bind to both wild-type Bcr-Abl proteins and drug resistant mutant Bcr-Abl proteins (eg, T315I mutant Bcr-Abl proteins) be able to. According to the radioactive compound of the present disclosure, the expression of Bcr-Abl protein can be detected noninvasively even in a Bcr-Abl dependent resistant subject.
本開示において「Bcr-Ablタンパク質イメージング用分子プローブ」とは、可視化するための放射性同位元素を含み、標的となるBcr-Ablタンパク質を認識することができる分子をいう。イメージング用分子プローブは、一又は複数の実施形態において、陽電子断層撮影(PET)又は単光子断層撮影(SPECT)に用いることができる。 In the present disclosure, “a molecular probe for imaging Bcr-Abl protein” refers to a molecule that includes a radioactive isotope for visualization and can recognize a target Bcr-Abl protein. Molecular probes for imaging can be used in positron emission tomography (PET) or single photon emission tomography (SPECT) in one or more embodiments.
本明細書において「製薬上許容される塩」とは、薬理上及び/又は医薬上許容される塩を含有し、例えば、無機酸塩、有機酸塩、無機塩基塩、有機塩基塩、酸性又は塩基性アミノ酸塩等が挙げられる。本開示において「化合物の塩」には、化合物が大気中に放置されることにより、水分を吸収して形成されうる水和物が包含され得る。また、本開示において「化合物の塩」には、化合物が他のある種の溶媒を吸収して形成されうる溶媒和物も包含され得る。 As used herein, the term "pharmaceutically acceptable salt" includes pharmacologically and / or pharmaceutically acceptable salts, such as inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acid or acid salts. Basic amino acid salts and the like can be mentioned. In the present disclosure, the “salt of compound” may include a hydrate that can be formed by absorbing water when the compound is left in the air. In the present disclosure, the "salt of compound" may also include a solvate which may be formed by the compound absorbing some other solvent.
本明細書において「放射性ハロゲン原子」とは、ハロゲン原子の放射性同位体をいう。放射性ハロゲン原子としては、18F、123I、124I、125I、131I、75Br、76Br、及び77Brが挙げられる。本明細書において「ハロゲン原子」とは、ハロゲン原子の非放射性同位体をいう。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子又はヨウ素原子が挙げられる。 As used herein, the term "radioactive halogen atom" refers to a radioactive isotope of a halogen atom. The radioactive halogen atoms include 18 F, 123 I, 124 I, 125 I, 131 I, 75 Br, 76 Br and 77 Br. As used herein, the term "halogen atom" refers to non-radioactive isotopes of halogen atoms. As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom is mentioned.
[式(I)で表される化合物]
本開示は、一又は複数の実施形態において、下記式(I)で表される化合物又はその製薬上許容される塩に関する。
Xは、−C(=O)−NH−又は−NH−C(=O)−であり、
R1は、
R2及びR3は、それぞれ独立して、水素原子、放射性ハロゲン原子、及びフッ化メチル基であり、R2及びR3の一方は、放射性ハロゲン原子である。R1において、波線を付した結合手は、式(I)との結合部分を示す。フッ化メチル基としては、トリフルオロメチル基が挙げられる。式(I)において、薬剤耐性変異型Bcr-Ablタンパク質(中でもT315I変異型Bcr-Ablタンパク質)に対する結合親和性の向上の点からは、R3が放射性ハロゲン原子であることが好ましい。
[Compound represented by formula (I)]
The present disclosure relates, in one or more embodiments, to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
X is -C (= O) -NH- or -NH-C (= O)-,
R 1 is
R 2 and R 3 are each independently a hydrogen atom, a radioactive halogen atom, and a methyl fluoride group, and one of R 2 and R 3 is a radioactive halogen atom. In R 1 , the wavy bond represents a bonding portion to the formula (I). As a methyl fluoride group, a trifluoromethyl group is mentioned. In the formula (I), it is preferable that R 3 is a radioactive halogen atom from the viewpoint of improvement in binding affinity to a drug-resistant mutant Bcr-Abl protein (particularly, T315I mutant Bcr-Abl protein).
式(I)で表される化合物としては、一又は複数の実施形態において、下記式(1)〜(4)で表される化合物が挙げられる。
式(I)で表される化合物としては、薬剤耐性変異型Bcr-Ablタンパク質(中でもT315I変異型Bcr-Ablタンパク質)に対する結合親和性の向上の点からは、式(2)〜(4)で表される化合物が好ましい。
As a compound represented by Formula (I), the compound represented by following formula (1)-(4) in one or several embodiment is mentioned.
As the compound represented by the formula (I), from the viewpoint of the improvement of the binding affinity to a drug resistant mutant Bcr-Abl protein (especially T315I mutant Bcr-Abl protein), the compounds represented by the formulas (2) to (4) The compounds represented are preferred.
本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Ablタンパク質のイメージングに用いることができる。本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Abl陽性腫瘍のイメージングに用いることができる。イメージングとしては、一又は複数の実施形態において、PETやSPECT等のインビボ核医学イメージングが挙げられる。その他には、本開示の放射性化合物は、一又は複数の実施形態において、CMLと診断された被検体におけるBcr-Abl阻害作用を有するチロシンキナーゼ阻害剤による治療効果の有効性の評価を行うための情報を得ることを目的としたイメージングに用いることができる。よって、本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Abl阻害作用を有するチロシンキナーゼ阻害剤のコンパニオン診断薬として使用することができる。さらにその他には、本開示の放射性化合物は、一又は複数の実施形態において、Bcr-Abl TKIが標的とする又は結合するタンパク質のイメージングに用いることができる。 The radioactive compounds of the present disclosure can be used for imaging Bcr-Abl protein in one or more embodiments. The radioactive compounds of the present disclosure can be used to image Bcr-Abl positive tumors in one or more embodiments. Imaging, in one or more embodiments, includes in vivo nuclear medicine imaging such as PET or SPECT. In addition, the radioactive compound of the present disclosure, in one or more embodiments, is for evaluating the efficacy of a therapeutic effect of a tyrosine kinase inhibitor having Bcr-Abl inhibitory activity in a subject diagnosed with CML. It can be used for imaging for the purpose of obtaining information. Thus, the radioactive compound of the present disclosure can be used as a companion diagnostic agent for a tyrosine kinase inhibitor having Bcr-Abl inhibitory activity in one or more embodiments. Still further, the radioactive compounds of the present disclosure can be used, in one or more embodiments, for imaging of proteins targeted or bound by Bcr-Abl TKI.
本開示の放射性化合物は、一又は複数の実施形態において、薬剤耐性変異型Bcr-Ablタンパク質(例えば、T315I変異型Bcr-Ablタンパク質)に結合し、該タンパク質をイメージングすることができる。したがって、本開示の放射性化合物は、一又は複数の実施形態において、野生型Bcr-Ablタンパク質(T315I変異を含まないBcr-Ablタンパク質)に特異的な分子プローブ(すなわち、野生型Bcr-Ablタンパク質に対して親和性が優位に高く、かつT315I変異型Bcr-Ablタンパク質に対して親和性が優位に低い分子プローブ)と併用することにより、Bcr-Abl TKI投与後の被検体におけるT315I変異発生の評価を行うための情報を得ることを目的としたイメージングに用いることができる。 The radioactive compounds of the present disclosure, in one or more embodiments, can bind to and image a drug resistant mutant Bcr-Abl protein (eg, T315I mutant Bcr-Abl protein). Thus, the radioactive compound of the present disclosure, in one or more embodiments, is a molecular probe specific for wild-type Bcr-Abl protein (Bcr-Abl protein not containing T315I mutation) (ie, wild-type Bcr-Abl protein) Evaluation of T315I mutation generation in a subject after Bcr-Abl TKI administration by using in combination with a molecular probe which has a predominantly high affinity for T and a low affinity to T315I mutant Bcr-Abl protein Can be used for imaging aimed at obtaining information for performing
したがって、本開示は、一又は複数の実施形態において、本開示の放射性化合物を含む、Bcr-Ablタンパク質イメージング用分子プローブ又はイメージング用組成物に関する。本開示において、イメージング用分子プローブ及びイメージング用組成物の形態は、特に限定されるものではないが、一又は複数の実施形態において、溶液又は粉末が挙げられる。これらは、担体等の医薬品添加物を含んでいてもよい。 Thus, the present disclosure relates, in one or more embodiments, to a molecular probe or composition for imaging Bcr-Abl protein, comprising a radioactive compound of the present disclosure. In the present disclosure, the forms of the imaging molecular probe and the imaging composition are not particularly limited, but in one or more embodiments, solutions or powders may be mentioned. These may contain pharmaceutical additives such as carriers.
[式(I)で表される化合物の製造方法]
本開示の放射性化合物は、一又は複数の実施形態において、下記式(II)で表される化合物又はその製薬上許容される塩を放射性標識することにより製造できる。したがって、本開示は、一又は複数の実施形態において、式(II)で表される化合物又はその製薬上許容される塩を放射性標識することを含む、放射性化合物の製造方法に関する。
Xは、−C(=O)−NH−又は−NH−C(=O)−であり、
R1は、
R4及びR5は、それぞれ独立して、水素原子、ハロゲン原子、フッ化メチル基、トリアルキルスタニル基、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基であり、R4及びR5の一方は、ハロゲン原子、トリアルキルスタニル基、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基である。R1において、波線を付した結合手は、式(II)との結合部分を示す。
[Method for Producing Compound Represented by Formula (I)]
The radioactive compound of the present disclosure can be produced by radioactively labeling a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof in one or more embodiments. Thus, the present disclosure relates, in one or more embodiments, to a method of producing a radioactive compound comprising radiolabeling a compound of formula (II) or a pharmaceutically acceptable salt thereof.
X is -C (= O) -NH- or -NH-C (= O)-,
R 1 is
R 4 and R 5 each independently represent a hydrogen atom, a halogen atom, a methyl fluoride group, a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group, One of R 4 and R 5 is a halogen atom, a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group. The wavy bond in R 1 represents a bonding site to the formula (II).
式(II)において、薬剤耐性変異型Bcr-Ablタンパク質(中でもT315I変異型Bcr-Ablタンパク質)に対する結合親和性の高い分子プローブが得られる点からは、R4が水素原子であり、R5がハロゲン原子、トリアルキルスタニル基、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基であることが好ましい。 In the formula (II), R 4 is a hydrogen atom and R 5 is a hydrogen atom in that a molecular probe having high binding affinity to a drug-resistant mutant Bcr-Abl protein (especially T315I mutant Bcr-Abl protein) can be obtained. A halogen atom, trialkylstannyl group, nitro group, tosylate group, mesylate group, triflate group, nosylate group or brosylate group is preferable.
式(II)で表される化合物としては、一又は複数の実施形態において、下記式(5)〜(8)で表される化合物が挙げられる。
式(II)で表される化合物としては、薬剤耐性変異型Bcr-Ablタンパク質(中でもT315I変異型Bcr-Ablタンパク質)に対する結合親和性の高い分子プローブが得られる点からは、式(6)〜(8)で表される化合物であることが好ましい。
As a compound represented by Formula (II), the compound represented by following formula (5)-(8) in one or several embodiment is mentioned.
As the compound represented by the formula (II), from the viewpoint that a molecular probe having high binding affinity to a drug resistant mutant Bcr-Abl protein (especially, T315I mutant Bcr-Abl protein) can be obtained, It is preferable that it is a compound represented by (8).
本開示は、一又は複数の実施形態において、式(5)で表される化合物を放射性標識することを含む、式(1)で表される化合物の製造方法に関する。本開示は、一又は複数の実施形態において、式(6)で表される化合物を放射性標識することを含む、式(2)で表される化合物の製造方法に関する。本開示は、一又は複数の実施形態において、式(6)で表される化合物を放射性標識することを含む、式(3)で表される化合物の製造方法に関する。本開示は、一又は複数の実施形態において、式(7)で表される化合物を放射性標識することを含む、式(4)で表される化合物の製造方法に関する。 The present disclosure relates, in one or more embodiments, to a method of producing a compound represented by Formula (1), which comprises radiolabeling a compound represented by Formula (5). The present disclosure relates, in one or more embodiments, to a method of producing a compound represented by Formula (2), which comprises radiolabeling a compound represented by Formula (6). The present disclosure relates, in one or more embodiments, to a method of producing a compound represented by Formula (3), which comprises radiolabeling a compound represented by Formula (6). The present disclosure relates, in one or more embodiments, to a method of producing a compound represented by Formula (4), which comprises radiolabeling a compound represented by Formula (7).
放射性標識は、一又は複数の実施形態において、[123/124/125I]NaI等を用いて直接標識法により行うことができる。 Radioactive labeling can be performed by direct labeling in one or more embodiments using [ 123/124/125 I] NaI or the like.
式(II)で表される化合物又はその製薬上許容される塩は、上述のとおり、標識前駆体として使用することができる。したがって、本開示は、一又は複数の実施形態において、式(II)で表される化合物又はその製薬上許容される塩(以下、「本開示の標識前駆体化合物」という)に関する。また、本開示は、一又は複数の実施形態において、本開示の放射性化合物を合成するための標識前駆体として使用する本開示の標識前駆体化合物を含む組成物に関する。また、本開示は、一又は複数の実施形態において、本開示の標識前駆体化合物を含む本開示の放射性化合物を調製するためのキットに関する。本開示のキットは、一又は複数の実施形態において、放射性ハロゲン原子を含む標識試薬をさらに含んでいてもよい。 The compound represented by the formula (II) or a pharmaceutically acceptable salt thereof can be used as a labeled precursor as described above. Accordingly, the present disclosure relates, in one or more embodiments, to a compound represented by Formula (II) or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the labeled precursor compound of the present disclosure”). The present disclosure also relates, in one or more embodiments, to a composition comprising a labeled precursor compound of the present disclosure for use as a labeled precursor for synthesizing a radioactive compound of the present disclosure. The present disclosure also relates, in one or more embodiments, to a kit for preparing a radioactive compound of the present disclosure that includes a labeled precursor compound of the present disclosure. The kit of the present disclosure may further include a labeling reagent containing a radioactive halogen atom in one or more embodiments.
[イメージング方法]
本開示は、一態様において、本開示の放射性化合物又は本開示の分子プローブが投与された被検体から前記化合物の放射性シグナルを検出することを含むイメージング方法(以下、「本開示のイメージング方法」ともいう)に関する。被検体は、特に限定されないが、一又は複数の実施形態において、ヒト、ヒト以外の哺乳類、培養細胞、又はBcr-Ablが発現している可能性のある対象等が挙げられる。
[Imaging method]
In one aspect, the present disclosure provides an imaging method (hereinafter referred to as “the imaging method of the present disclosure”) which comprises detecting the radioactive signal of the compound from the subject to which the radioactive compound of the present disclosure or the molecular probe of the present disclosure has been administered. Say). The subject is not particularly limited, and in one or more embodiments, a human, a non-human mammal, a cultured cell, a subject in which Bcr-Abl may be expressed, and the like can be mentioned.
本開示は、その他の態様において、Bcr-Ablチロシンキナーゼ阻害剤と、本開示の放射性化合物又は本開示の分子プローブとが投与された被検体から前記化合物の放射性シグナルを検出することを含むイメージング方法に関する。 The disclosure relates, in another aspect, to an imaging method comprising detecting a radioactive signal of the compound from a subject to which a Bcr-Abl tyrosine kinase inhibitor and a radioactive compound of the disclosure or a molecular probe of the disclosure have been administered. About.
本開示のイメージング方法は、一又は複数の実施形態において、Bcr-Ablの発現レベルの測定、Bcr-Abl陽性腫瘍のイメージング、及びCMLと診断された被検体におけるBcr-Abl阻害作用を有するチロシンキナーゼ阻害剤による治療効果の有効性の評価等の用途に用いることができる。 The imaging method of the present disclosure, in one or more embodiments, measures the expression level of Bcr-Abl, imaging Bcr-Abl positive tumors, and tyrosine kinases having Bcr-Abl inhibitory activity in a subject diagnosed with CML It can be used for applications such as evaluation of the efficacy of therapeutic effects by inhibitors.
シグナルの検出は、一又は複数の実施形態において、使用する本開示の化合物に含まれる放射性同位元素の種類に応じて適宜決定でき、例えば、PET及びSPECT等を用いて行うことができる。 The detection of the signal can be appropriately determined according to the type of radioactive isotope contained in the compound of the present disclosure to be used in one or more embodiments, and can be performed using, for example, PET and SPECT.
以下に実施例を用いて本開示をさらに説明するが、これらは例示的なものであって、本開示は以下の実施例に限定して解釈されるものではない。 The present disclosure will be further described by way of the following examples, which are illustrative, and the present disclosure should not be construed as being limited to the following examples.
[機器及び試薬]
1H(400 MHz or 500 MHz) NMRスペクトルはLNM-AL 400又は500(日本電子株式会社)にて測定し、内部標準物質としてテトラメチルシランを用いた。
逆相HPLCはLC-20AD(株式会社 島津製作所)を用い、検出器としてSPD-20A UV(株式会社 島津製作所)とサーベイメーター NDW-351(日立アロカメディカル株式会社)を使用した。
逆相HPLC用カラムにはCOSMOSIL C18-AR-II(10 x 250 mm)(ナカライテスク株式会社)を用い、移動相には(A) 0.1% TFA水溶液及び (B) 0.1% TFAアセトニトリル溶液を使用した。TLCにはsilica gel 60 F254(メルク株式会社)を用いた。
カラムクロマトグラフィーによる精製には中圧カラムW-Prep 2XY(株式会社 山善)を用い、シリカゲルはHi Flash silica gel 40 mm, 60Å(株式会社 山善)を使用した。
[125I]NaIは、PerkinElmer社より購入し、[123I]NH4Iは、日本メジフィジックス社より購入した。体内動態評価における放射能は、オートウェルガンマカウンターWallac 1480 WIARD 3(PerkinElmer社)を用いて測定した。
SPECT/CTによる画像収集は、GMI FX-3300 Pre-Clinical Imaging Systemを用い、データ解析には3D OSEMを使用した。
[Devices and Reagents]
1 H (400 MHz or 500 MHz) NMR spectra were measured by LNM-AL 400 or 500 (JEOL Ltd.), and tetramethylsilane was used as an internal standard substance.
The reverse phase HPLC used LC-20AD (Shimadzu Corporation), and used SPD-20A UV (Shimadzu Corporation) and the survey meter NDW-351 (Hitachi Aloka Medical Co., Ltd.) as a detector.
Use of COSMOSIL C18-AR-II (10 x 250 mm) (Nacalai Tesque, Inc.) for reverse phase HPLC column and (A) 0.1% aqueous TFA and (B) 0.1% TFA acetonitrile solution for mobile phase did. For TLC, silica gel 60 F 254 (Merck Corporation) was used.
For purification by column chromatography, medium pressure column W-Prep 2XY (Yamazen Co., Ltd.) was used, and for the silica gel, Hi Flash silica gel 40 mm, 60 Å (Yamazen Co., Ltd.) was used.
[ 125 I] NaI was purchased from PerkinElmer, and [ 123 I] NH 4 I was purchased from Japan Medi-Physics. Radioactivity in the pharmacokinetic evaluation was measured using an autowell gamma counter Wallac 1480 WIARD 3 (PerkinElmer).
Image acquisition by SPECT / CT used GMI FX-3300 Pre-Clinical Imaging System and 3D OSEM for data analysis.
(製造例1)
下記スキームに従って下記式で表されるPON-1を製造した。
PON-1 represented by the following formula was produced according to the following scheme.
3,5-Diiodo-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-benzamide(化合物1)
3,5-Diiodo-4-methylbenzoic acid (194.0 mg, 0.5 mmol)にSOCl2 (0.73 mL, 10 mmol)加え、DMFを触媒量滴下し、室温で20時間攪拌した。溶液を減圧乾燥させ、中間体 (3,5-Diiodo-4-methyl-benzoyl chloride) (178.9mg, 0.44 mmol, 88%, white solid)を得た。
4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)-benzenamine (94.6 mg, 0.35 mmol)、N,N-Diisopropylethylamine (73 μL, 0.42 mmol)、DMAP (1.2 mg, 0.01 mmol)をTHF (2.4 mL)に溶解させ、そこへ中間体 (170.7 mg, 0.42 mmol)を加え、室温で2時間攪拌した。水を加え酢酸エチルで抽出し、エバポレーターで減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 10 : 1) により精製し化合物1 (180.0 mg, 0.28 mmol, 80%, pale yellow solid)を得た。
1H NMR (500 MHz, CDCl3) δ 8.30 (2H, s), 8.04 (1H, s), 7.89 (1H, d, J=8.0Hz), 7.86 (1H, s), 7.76 (1H, d, J=8.0Hz), 3.65 (2H, s), 2.81 (3H, s), 2.72-2.42 (8H, m), 2.38 (3H, s).
3,5-Diiodo-4-methyl-N- [4-[(4-methyl-1-piperidinyl) methyl] -3- (trifluoromethyl) phenyl] -benzamide (Compound 1)
SOCl 2 (0.73 mL, 10 mmol) was added to 3,5-Diiodo-4-methylbenzoic acid (194.0 mg, 0.5 mmol), a catalytic amount of DMF was added dropwise, and the mixture was stirred at room temperature for 20 hours. The solution was dried under reduced pressure to give an intermediate (3,5-Diiodo-4-methyl-benzoyl chloride) (178.9 mg, 0.44 mmol, 88%, white solid).
4-[(4-Methyl-1-piperidinyl) methyl] -3- (trifluoromethyl) -benzenamine (94.6 mg, 0.35 mmol), N, N-Diisopropylethylamine (73 μL, 0.42 mmol), DMAP (1.2 mg, 0.01 mmol) ) Was dissolved in THF (2.4 mL), and the intermediate (170.7 mg, 0.42 mmol) was added thereto, and stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate and concentrated with an evaporator under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain Compound 1 (180.0 mg, 0.28 mmol, 80%, pale yellow solid).
1 H NMR (500 MHz, CDCl 3 ) δ 8.30 (2 H, s), 8.04 (1 H, s), 7. 89 (1 H, d, J = 8.0 Hz), 7.86 (1 H, s), 7. 76 (1 H, d, J) J = 8.0 Hz), 3.65 (2H, s), 2.81 (3H, s), 2.72–2. 42 (8H, m), 2.38 (3H, s).
PON-1
3-Ethynyl-imidazo[1,2-b]pyridazine (30.5 mg, 2.0 mmol)、Pd(PPh3)4 (11.6 mg, 0.01 mmol)、CuI (3.05 mg, 0.016 mmol)、化合物1 (137.0 mg, 0.21 mmol)をDMF (1.6 mL)に溶解させ、そこへN,N-Diisopropylethylamine (55.8 μL, 0.32 mmol)を加え、室温で2.5時間攪拌した。水を加え、酢酸エチルで抽出し、エバポレーターで減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 5 : 1) により精製しPON-1 (33.3 mg, 0.051 mmol, 24%, pale yellow solid)を得た。
1H NMR (500 MHz, CDCl3) δ 8.50 (1H, dd, J=4.5, 1.0Hz), 8.34 (1H, d, J=1.5Hz), 8.09 (1H, s), 8.04 (1H, d, J=1.5Hz), 8.01 (1H, dd, J=9.0, 1.0Hz), 7.91 (1H, dd, J=8.0, 2.5Hz), 7.88 (1H, d, J=2.5Hz), 7.77 (1H, d, J=8.0Hz), 7.16 (1H, dd, J=9.0, 4.5Hz), 3.67 (2H, s), 2.81 (3H, s), 2.70-2.48 (8H, m), 2.40 (3H, s).
PON-1
3-Ethynyl-imidazo [1,2- b] pyridazine (30.5 mg, 2.0 mmol), Pd (PPh 3) 4 (11.6 mg, 0.01 mmol), CuI (3.05 mg, 0.016 mmol), Compound 1 (137.0 mg, 0.21 mmol) was dissolved in DMF (1.6 mL), N, N-Diisopropylethylamine (55.8 μL, 0.32 mmol) was added thereto, and stirred at room temperature for 2.5 hours. Water was added, extracted with ethyl acetate, and concentrated under reduced pressure with an evaporator. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain PON-1 (33.3 mg, 0.051 mmol, 24%, pale yellow solid).
1 H NMR (500 MHz, CDCl 3 ) δ 8.50 (1 H, dd, J = 4.5, 1.0 Hz), 8.34 (1 H, d, J = 1.5 Hz), 8.09 (1 H, s), 8.04 (1 H, d, J = 1.5 Hz), 8.01 (1 H, dd, J = 9.0, 1.0 Hz), 7.91 (1 H, dd, J = 8.0, 2.5 Hz), 7.88 (1 H, d, J = 2.5 Hz), 7.77 (1 H, d, J = 8.0 Hz), 7.16 (1H, dd, J = 9.0, 4.5 Hz), 3.67 (2H, s), 2.81 (3H, s), 2.70-2.48 (8H, m), 2.40 (3H, s) ).
(製造例2)
下記スキームに従って下記式で表されるPON-2を製造した。
PON-2 represented by the following formula was produced according to the following scheme.
1-[(2-iodo-4-aminophenyl)methyl]-4-methyl-Piperazine(化合物2)
1-[(2-iodo-4-nitrophenyl)methyl]-4-methyl-Piperazine (638.2 mg, 1.77 mmol)、Na2S2O4 (3.08 g, 17.7 mmol)をAcetone / H2O = 1 : 1 (8.8 mL)に溶解させ75 ℃で24時間加熱攪拌した。エバポレーターで濃縮し、酢酸エチルを加え、水、sat-NaHCO3 aq.で洗浄、硫酸マグネシウムで脱水し、ろ過した後、エバポレーターで溶媒を留去し、化合物2 (145 mg, 0.44 mmol, 25%, pale yellow solid)を得た。
1H NMR (500 MHz, CDCl3) δ 7.19 (1H, d, J=2.0Hz), 7.11 (1H, d, J=8.0Hz), 6.63 (1H, dd, J=8.0, 2.0Hz), 3.61 (2H, br), 3.43 (2H, s), 2.70-2.25 (8H, m), 2.29 (3H, s).
1-[(2-iodo-4-aminophenyl) methyl] -4-methyl-piperazine (compound 2)
Acetone / H 2 O = 1: 1-[(2-iodo-4-nitrophenyl) methyl] -4-methyl-piperazine (638.2 mg, 1.77 mmol), Na 2 S 2 O 4 (3.08 g, 17.7 mmol) It was dissolved in 1 (8.8 mL) and heated and stirred at 75 ° C. for 24 hours. After concentration with an evaporator, addition of ethyl acetate, washing with water, sat-NaHCO 3 aq., Drying over magnesium sulfate, filtration and evaporation of the solvent with an evaporator, compound 2 (145 mg, 0.44 mmol, 25% , pale yellow solid).
1 H NMR (500 MHz, CDCl 3) δ 7.19 ( 1 H, d, J = 2.0 Hz), 7.11 (1 H, d, J = 8.0 Hz), 6.63 (1 H, dd, J = 8.0, 2.0 Hz), 3.61 ( 2H, br), 3.43 (2H, s), 2.70-2.25 (8H, m), 2.29 (3H, s).
PON-2
Methyl 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-benzoate (156.0 mg, 0.54 mmol)をH2O (251 μL)、濃塩酸 (771.8 μL)に溶解させ100℃で1.5時間加熱還流した。その後、溶媒を減圧留去し乾固した。そこへ塩化チオニル(622.6 μL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶媒を減圧留去し乾固した。得られた中間体(142.5 mg, 0.48 mmol)をTHF (7.5 mL)に溶解させ、化合物2 (145.0 mg, 0.44 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (83.6 μL, 0.48 mmol)を加え室温にて17時間攪拌した。水と酢酸エチルを加え、飽和NaHCO3溶液、水で洗浄後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 5 : 1) により精製しPON-2 (133.4 mg, 0.23 mmol, 53%, pale yellow solid)を得た。
1H NMR (500 MHz, CDCl3) δ 8.50 (dd, J = 4.3, 1.4 Hz, 1H), 8.16 (d, J = 2.0 Hz 1H), 8.08−8.00 (m, 3H), 7.82 − 7.77 (m, 2H), 7.66 (dd, J = 8.3, 2.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.15 (dd, J = 9.2, 4.6 Hz, 1H), 3.52 (s, 2H), 2.66 − 2.28 (m, 14H).
PON-2
Dissolve Methyl 3- (2-imidazo [1,2-b] pyridazin-3-ylthynyl) -4-methyl-benzoate (156.0 mg, 0.54 mmol) in H 2 O (251 μL) and concentrated hydrochloric acid (771.8 μL) The mixture was heated to reflux at 100.degree. C. for 1.5 hours. After that, the solvent was evaporated under reduced pressure to dryness. The thionyl chloride (622.6 microliters) and DMF (3 drops) were added there, and it stirred at room temperature for 17 hours. After that, the solvent was evaporated under reduced pressure to dryness. The obtained intermediate (142.5 mg, 0.48 mmol) was dissolved in THF (7.5 mL), compound 2 (145.0 mg, 0.44 mmol), DMAP (1.2 mg, 0.01 mmol), N, N-diisopropylethylamine (83.6 μL, 0.48 mmol) was added and stirred at room temperature for 17 hours. Water and ethyl acetate were added, and after washing with saturated NaHCO 3 solution and water, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain PON-2 (133.4 mg, 0.23 mmol, 53%, pale yellow solid).
1 H NMR (500 MHz, CDCl 3 ) δ 8.50 (dd, J = 4.3, 1.4 Hz, 1 H), 8.16 (d, J = 2.0 Hz 1 H), 8.08-8.00 (m, 3 H), 7.82-7.77 (m , 2H), 7.66 (dd, J = 8.3, 2.0 Hz, 1 H), 7. 40 (t, J = 8.0 Hz, 2 H), 7. 15 (dd, J = 9.2, 4.6 Hz, 1 H), 3.52 (s, 2 H) , 2.66-2.28 (m, 14H).
(製造例3)
下記スキームに従って下記式で表されるPON-3を製造した。
Methyl 3-iodo-4-((4-methylpiperazin-1-yl)methyl)benzoate (237.0 mg, 0.63 mmol)をH2O (296.6 μL)、濃塩酸 (953.0 μL)に溶解させ100℃で4時間加熱還流した。その後、溶媒を減圧留去し乾固した。そこへ塩化チオニル(904 μL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶媒を減圧留去し乾固した。得られた中間体(90.9 mg, 0.24 mmol)をTHF (3.8 mL)で溶解させ、3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylaniline (54.6 mg, 0.22 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (41.7 μL, 0.24 mmol)を加え室温にて2時間攪拌した。水と酢酸エチルを加え、飽和NaHCO3溶液、水で洗浄後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 10 : 1) により精製しPON-3 (80.4 mg, 0.13 mmol, 60%, white solid)を得た。
1H NMR (500 MHz, CDCl3) δ 8.48 (1H, dd, J=4.0, 2.0Hz), 8.32 (1H, d, J=2.0Hz), 8.05 (1H, s), 8.00 (1H, dd, J=9.0, 2.0Hz), 7.83 (1H, d, J=2.0Hz), 7.82 (1H, dd, J=8.0, 2.0Hz), 7.73 (1H, br), 7.62 (1H, dd, J=8.0, 2.0Hz), 7.55 (1H, d, J=8.0Hz), 7.28 (1H, d, J=8.0Hz), 7.13 (1H, dd, J=9.0, 4.0Hz), 3.57 (2H, s), 2.57 (3H, s), 2.56-2.40 (8H, m), 2.31 (3H, s).
(Production Example 3)
PON-3 represented by the following formula was produced according to the following scheme.
Methyl 3-iodo-4-((4-methylpiperazin-1-yl) methyl) benzoate (237.0 mg, 0.63 mmol) was dissolved in H 2 O (296.6 μL), concentrated hydrochloric acid (953.0 μL), and dissolved at 100 ° C for 4 hours Heated to reflux. After that, the solvent was evaporated under reduced pressure to dryness. The thionyl chloride (904 microliters) and DMF (3 drops) were added there, and it stirred at room temperature for 17 hours. After that, the solvent was evaporated under reduced pressure to dryness. The obtained intermediate (90.9 mg, 0.24 mmol) was dissolved in THF (3.8 mL) to give 3- (Imidazo [1,2-b] pyridazin-3-ylthynyl) -4-methylaniline (54.6 mg, 0.22 mmol) Then, DMAP (1.2 mg, 0.01 mmol) and N, N-diisopropylethylamine (41.7 μL, 0.24 mmol) were added and stirred at room temperature for 2 hours. Water and ethyl acetate were added, and after washing with saturated NaHCO 3 solution and water, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain PON-3 (80.4 mg, 0.13 mmol, 60%, white solid).
1 H NMR (500 MHz, CDCl 3 ) δ 8.48 (1 H, dd, J = 4.0, 2.0 Hz), 8.32 (1 H, d, J = 2.0 Hz), 8.05 (1 H, s), 8.00 (1 H, dd, J = 9.0, 2.0 Hz), 7.83 (1 H, d, J = 2.0 Hz), 7.82 (1 H, dd, J = 8.0, 2.0 Hz), 7.73 (1 H, br), 7.62 (1 H, dd, J = 8.0) , 2.0 Hz), 7.55 (1 H, d, J = 8.0 Hz), 7. 28 (1 H, d, J = 8.0 Hz), 7. 13 (1 H, dd, J = 9.0, 4.0 Hz), 3.57 (2 H, s), 2.57 (3H, s), 2.56-2.40 (8H, m), 2.31 (3H, s).
(製造例4)
下記スキームに従って下記式で表されるPON-4を製造した。
Methyl 3-(2-imidazo[1,2-a]pyridazin-3-ylethynyl)-4-methyl-benzoate (50.0 mg, 0.17 mmol)をH2O (80 μL)、濃塩酸 (245 μL)に溶解させ100℃で2時間加熱還流した。その後、溶媒を減圧留去し乾固した。そこへ塩化チオニル(243 μL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶媒を減圧留去し乾固した。得られた中間体をTHF (2.5 mL)に溶解させ、化合物2 (49.7 mg, 0.15 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (26 μL, 0.15 mmol)を加え室温にて2.5時間攪拌した。水と酢酸エチルを加え、飽和NaHCO3溶液、水で洗浄後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 5 : 1) により精製しPON-4 (77.3 mg, 0.13 mmol, 87%, off white solid)を得た。
1H NMR (500 MHz, DMSO-d6) δ 10.36 (1H, s), 9.21 (1H, s), 8.69 (1H, d, J=4.5Hz), 8.35 (1H, s), 8.31-8.25 (2H, m), 8.14 (1H, d, J=4.5Hz), 7.93 (1H, d, J=8.0Hz), 7.80 (1H, d, J=8.0Hz), 7.55 (1H, d, J=8.0Hz), 7.34 (1H, d, J=8.0Hz), 3.42 (2H, s), 2.61 (3H, s), 2.50-2.20 (8H, m), 2.15 (3H, s).
(Production Example 4)
PON-4 represented by the following formula was produced according to the following scheme.
Dissolve methyl 3- (2-imidazo [1,2-a] pyridazin-3-ylthynyl) -4-methyl-benzoate (50.0 mg, 0.17 mmol) in H 2 O (80 μL) and concentrated hydrochloric acid (245 μL) The mixture was heated to reflux at 100.degree. C. for 2 hours. After that, the solvent was evaporated under reduced pressure to dryness. The thionyl chloride (243 microliters) and DMF (3 drops) were added there, and it stirred at room temperature for 17 hours. After that, the solvent was evaporated under reduced pressure to dryness. The obtained intermediate was dissolved in THF (2.5 mL), compound 2 (49.7 mg, 0.15 mmol), DMAP (1.2 mg, 0.01 mmol), N, N-diisopropylethylamine (26 μL, 0.15 mmol) was added, and the mixture was brought to room temperature. The mixture was stirred for 2.5 hours. Water and ethyl acetate were added, and after washing with saturated NaHCO 3 solution and water, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain PON-4 (77.3 mg, 0.13 mmol, 87%, off white solid).
1 H NMR (500 MHz, DMSO-d 6 ) δ 10.36 (1 H, s), 9.21 (1 H, s), 8. 69 (1 H, d, J = 4.5 Hz), 8.35 (1 H, s), 8.31-8.25 ( 2H, m), 8.14 (1 H, d, J = 4.5 Hz), 7. 93 (1 H, d, J = 8.0 Hz), 7. 80 (1 H, d, J = 8.0 Hz), 7.55 (1 H, d, J = 8.0) Hz), 7.34 (1 H, d, J = 8.0 Hz), 3.42 (2 H, s), 2.61 (3 H, s), 2.50-2.20 (8 H, m), 2.15 (3 H, s).
[標識前駆体合成]
標識前駆体となるPON-1 precursor、PON-2 precursor、PON-3 precursor、及びPON-4 precursorを合成した。
[Labeled precursor synthesis]
The PON-1 precursor, PON-2 precursor, PON-3 precursor, and PON-4 precursor, which serve as labeling precursors, were synthesized.
(製造例5)
下記スキームに従って下記式で表されるPON-1 precursorを製造した。
A PON-1 precursor represented by the following formula was produced according to the following scheme.
3,5-Dibromo-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-benzamide(化合物3)
4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)-benzenamine (360 mg, 1.33 mmol)、N,N-Diisopropylethylamine (273 μL, 1.60 mmol)、DMAP (1.2 mg, 0.01 mmol)をTHF (5.0 mL)に溶解させ、3,5-Dibromo-4-methyl-benzoyl chloride (500 mg, 1.6 mmol)を加え、室温で2時間攪拌した。水を加え酢酸エチルで抽出し、エバポレーターで減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 10 : 1) により精製し化合物3 (540.0 mg, 0.98 mmol, 73.8%, pale yellow solid)を得た。
1H NMR (500 MHz, CDCl3) δ 9.00 (1H, br), 7.97 (2H, s), 7.92 (1H, d, J=8.5Hz), 7.89 (1H, s), 7.68 (1H, d, J=8.5Hz), 3.63 (2H, s), 2.76-2.46 (11H, m), 2.42 (3H, s).
3,5-Dibromo-4-methyl-N- [4-[(4-methyl-1-piperidinyl) methyl] -3- (trifluoromethyl) phenyl] -benzamide (compound 3)
4-[(4-Methyl-1-piperidinyl) methyl] -3- (trifluoromethyl) -benzenamine (360 mg, 1.33 mmol), N, N-Diisopropylethylamine (273 μL, 1.60 mmol), DMAP (1.2 mg, 0.01 mmol) ) Was dissolved in THF (5.0 mL), 3,5-Dibromo-4-methyl-benzoyl chloride (500 mg, 1.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate and concentrated with an evaporator under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain compound 3 (540.0 mg, 0.98 mmol, 73.8%, pale yellow solid).
1 H NMR (500 MHz, CDCl 3 ) δ 9.00 (1 H, br), 7. 97 (2 H, s), 7. 92 (1 H, d, J = 8.5 Hz), 7. 89 (1 H, s), 7. 68 (1 H, d, J) J = 8.5 Hz), 3.63 (2H, s), 2.76-2.46 (11 H, m), 2.42 (3 H, s).
PON-1 precursor
化合物3 (265.0 mg, 0.48 mmol)、3-Ethynyl-imidazo[1,2-b]pyridazine (116.0 mg, 0.81 mmol)、Pd(PPh3)4 (56.8 mg, 0.05 mmol)、CuI (9.4 mg, 0.05 mmol)をDMF (2.5 mL)に溶解させ、そこへN,N-Diisopropylethylamine (130 μL, 0.75 mmol)を加え、室温で4時間攪拌した。水を加え、クロロホルムで抽出し、エバポレーターで減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 5 : 1) により精製しPON-1 precursor (77.0 mg, 0.144 mmol, 30%, pale yellow solid)を得た。
1H NMR (500 MHz, CDCl3) δ 8.60 (1H, br), 8.48 (1H, dd, J=4.5, 2.0Hz), 8.11 (1H, s), 8.09 (1H, d, J=2.0Hz), 7.99 (1H, d, J=2.0Hz), 7.97-7.90 (3H, m), 7.78 (1H, d, J=8.0Hz), 7.14 (1H, dd, J=9.0, 4.5Hz), 3.64 (2H, s), 2.71 (3H, s), 2.65-2.35 (8H, m), 2.32 (3H, s).
PON-1 precursor
Compound 3 (265.0 mg, 0.48 mmol) , 3-Ethynyl-imidazo [1,2-b] pyridazine (116.0 mg, 0.81 mmol), Pd (PPh 3) 4 (56.8 mg, 0.05 mmol), CuI (9.4 mg, 0.05 mmol) was dissolved in DMF (2.5 mL), N, N-Diisopropylethylamine (130 μL, 0.75 mmol) was added thereto, and the mixture was stirred at room temperature for 4 hours. Water was added, extracted with chloroform, and concentrated under reduced pressure with an evaporator. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain PON-1 precursor (77.0 mg, 0.144 mmol, 30%, pale yellow solid).
1 H NMR (500 MHz, CDCl 3 ) δ 8.60 (1 H, br), 8. 48 (1 H, dd, J = 4.5, 2.0 Hz), 8.11 (1 H, s), 8.09 (1 H, d, J = 2.0 Hz) , 7.99 (1H, d, J = 2.0 Hz), 7.97-7.90 (3H, m), 7.78 (1 H, d, J = 8.0 Hz), 7.14 (1 H, dd, J = 9.0, 4.5 Hz), 3.64 (3 2H, s), 2.71 (3H, s), 2.65-2.35 (8H, m), 2.32 (3H, s).
(製造例6)
下記スキームに従って下記式で表されるPON−2 precursorを製造した。
Methyl 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-benzoate (127.0 mg, 0.44 mmol)をH2O (217 μL)、濃塩酸 (222 μL)に溶解させ100℃で2時間加熱還流した。その後、溶媒を減圧留去し乾固した。そこへ塩化チオニル(622.6 μL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶媒を減圧留去し乾固した。得られた中間体(100.5 mg, 0.34 mmol)をTHF (5.3 mL)に溶解させ1-[(2-bromo-4-aminophenyl)methyl]-4-methyl-Piperazine (86.8 mg, 0.31 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (59.3 μL, 0.34 mmol)を加え室温にて2.5時間攪拌した。水と酢酸エチルを加え、飽和NaHCO3溶液、水で洗浄後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 5 : 1) により精製しPON-2 precursor (108.1 mg, 0.20 mmol, 64%, white solid)を得た。
1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 4.0 Hz, 1H), 8.10 - 8.08 (m, 2H), 8.04 (d, J = 1.7 Hz, 1H), 8.0 − 7.95 (m, 2H), 7.81 (dd, J = 7.7, 2.0 Hz, 1H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), , 7.14 (dd, J = 9.2, 4.6 Hz, 1H), 3.59 (s, 2H), 2.64−2.28 (m, 14H).
(Production Example 6)
PON-2 precursor represented by the following formula was manufactured according to the following scheme.
Dissolve Methyl 3- (2-imidazo [1,2-b] pyridazin-3-ylthynyl) -4-methyl-benzoate (127.0 mg, 0.44 mmol) in H 2 O (217 μL), concentrated hydrochloric acid (222 μL) The mixture was heated to reflux at 100.degree. C. for 2 hours. After that, the solvent was evaporated under reduced pressure to dryness. The thionyl chloride (622.6 microliters) and DMF (3 drops) were added there, and it stirred at room temperature for 17 hours. After that, the solvent was evaporated under reduced pressure to dryness. The obtained intermediate (100.5 mg, 0.34 mmol) was dissolved in THF (5.3 mL) to give 1-[(2-bromo-4-aminophenyl) methyl] -4-methyl-piperazine (86.8 mg, 0.31 mmol), DMAP (1.2 mg, 0.01 mmol) and N, N-diisopropylethylamine (59.3 μL, 0.34 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. Water and ethyl acetate were added, and after washing with saturated NaHCO 3 solution and water, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain PON-2 precursor (108.1 mg, 0.20 mmol, 64%, white solid).
1 H NMR (500 MHz, CDCl 3 ) δ 8.49 (d, J = 4.0 Hz, 1 H), 8.10-8.08 (m, 2 H), 8.04 (d, J = 1.7 Hz, 1 H), 8.0-7.95 (m, 2H), 7.81 (dd, J = 7.7, 2.0 Hz, 1 H), 7. 60 (dd, J = 8.3, 2.0 Hz, 1 H), 7.46 (d, J = 8.6 Hz, 1 H), 7. 39 (d, J = 8.0) Hz, 1 H),, 7.14 (dd, J = 9.2, 4.6 Hz, 1 H), 3.59 (s, 2 H), 2.64-2.28 (m, 14 H).
(製造例7)
下記スキームに従って下記式で表されるPON-2 precursor(スズ化合物)を製造した。
1H NMR (500 MHz, CDCl3) δ 7.00 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2.5H), 6.57 (dd, J = 2.5, 8.0 Hz, 1H), 3.59 (s, 1H), 3.34 (s, 1H), 2.41 (brs, 6H), 2.28 (s, 3H), 1.62 (brs, 2H), 0.26 (s, 9H).
(Production Example 7)
According to the following scheme, PON-2 precursor (tin compound) represented by the following formula was produced.
1 H NMR (500 MHz, CDCl 3 ) δ 7.00 (d, J = 8.0 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 2.5 H), 6.57 (dd, J = 2.5, 8.0 Hz, 1 H), 3.59 (s, 1 H), 3.34 (s, 1 H), 2.41 (brs, 6 H), 2. 28 (s, 3 H), 1.62 (brs, 2 H), 0.26 (s, 9 H).
化合物D (58.9 mg)とMethyl 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl) -4-methyl- -benzoic acid hydrocloride(50 mg)をCH2Cl2 (1.5 mL)に溶解させ、N,N-ジイソプロピルアミン (84 μL)、N,N−ジメチル-4-アミノピリジン (3.9 mg)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩 (36.8 mg)を加え室温で撹拌させた。一晩撹拌後、飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、硫酸ナトリウムで脱水しろ過した。得られたろ液を減圧留去し、シリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 95 : 5→9:1) により精製し (60.0 mg,淡黄色固体)を得た。
δ 8.50 (dd, J = 2.0, 5.0 Hz, 1H), 8.10 - 8.05 (m, 2H), 8.00(dd, J = 2.0, 9.0 Hz, 1H), 7.92 (s, 1H), 7.83 (dd, J = 2.0, 8.0 Hz, 1H), 7.73 (dd, J = 2.5, 8.0 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.14 (dd, J = 5.0, 9.0 Hz, 1H), 3.45 (s, 2H), 2.65 (s, 3H), 2.43 (brs, 6H), 2.29 (s, 3H), 1.67 (s, 2H), 0.31 (s, 9H).
Compound D (58.9 mg) and Methyl 3- (2-imidazo [1,2-b] pyridazin-3-ylthynyl) -4-methyl-benzoic acid hydrochloride (50 mg) in CH 2 Cl 2 (1.5 mL) Dissolve, N, N-diisopropylamine (84 μL), N, N-dimethyl-4-aminopyridine (3.9 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (36.8 mg) The addition was allowed to stir at room temperature. After stirring overnight, it was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate and filtered. The obtained filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5 → 9: 1) to obtain (60.0 mg, pale yellow solid).
δ 8.50 (dd, J = 2.0, 5.0 Hz, 1 H), 8. 10-8.05 (m, 2 H), 8.00 (dd, J = 2.0, 9.0 Hz, 1 H), 7. 92 (s, 1 H), 7. 83 (dd, J = 2.0, 8.0 Hz, 1 H), 7.73 (dd, J = 2.5, 8.0 Hz, 1 H), 7. 60 (d, J = 2.5 Hz, 1 H), 7. 40 (d, J = 8.0 Hz, 1 H), 7. 25 (s , 1H), 7.14 (dd, J = 5.0, 9.0 Hz, 1H), 3.45 (s, 2H), 2.65 (s, 3H), 2.43 (brs, 6H), 2.29 (s, 3H), 1.67 (s, 2H), 0.31 (s, 9H).
(製造例7)
下記スキームに従って下記式で表されるPON-3 precursorを製造した。
Methyl 3-bromo-4-((4-methylpiperazin-1-yl)methyl)benzoate (150.0 mg, 0.46 mmol)をH2O (214.6 μL)、濃塩酸 (659.5 μL)に溶解させ100℃で2時間加熱還流した。その後、溶媒を減圧留去し乾固した。そこへ塩化チオニル(654 μL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶媒を減圧留去し乾固した。そこへTHF (2.9 mL)で溶解させ、3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylaniline (42.2 mg, 0.17 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (33.0 μL, 0.19 mmol)を加え室温にて2.5時間攪拌した。水と酢酸エチルを加え、飽和NaHCO3溶液、水で洗浄後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 10 : 1) により精製しPON-3 precursor (46.2 mg, 0.085 mmol, 60%, pale yellow solid)を得た。
1H NMR (500 MHz, CDCl3) δ 8.48 (1H, dd, J=4.5, 2.0Hz), 8.05 (1H, d, J=2.0Hz), 8.04 (1H, s), 8.00 (1H, dd, J=9.0, 2.0Hz), 7.83 (1H, d, J=2.0Hz), 7.78 (1H, dd, J=8.0, 2.0Hz), 7.75 (1H, br), 7.63 (1H, d, J=8.0Hz), 7.61 (1H, dd, J=8.0, 2.0Hz), 7.28 (1H, d, J=8.0Hz), 7.13 (1H, dd, J=9.0, 4.5Hz), 3.65 (2H, s), 2.65-2.40 (11H, m), 2.32 (3H, s).
(Production Example 7)
According to the following scheme, PON-3 precursor represented by the following formula was manufactured.
Methyl 3-bromo-4-((4-methylpiperazin-1-yl) methyl) benzoate (150.0 mg, 0.46 mmol) is dissolved in H 2 O (214.6 μL) and concentrated hydrochloric acid (659.5 μL) Heated to reflux. After that, the solvent was evaporated under reduced pressure to dryness. The thionyl chloride (654 microliters) and DMF (3 drops) were added there, and it stirred at room temperature for 17 hours. After that, the solvent was evaporated under reduced pressure to dryness. The product was dissolved in THF (2.9 mL), 3- (Imidazo [1,2-b] pyridazin-3-ylthynyl) -4-methylaniline (42.2 mg, 0.17 mmol), DMAP (1.2 mg, 0.01 mmol), N , N-Diisopropylethylamine (33.0 μL, 0.19 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Water and ethyl acetate were added, and after washing with saturated NaHCO 3 solution and water, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain PON-3 precursor (46.2 mg, 0.085 mmol, 60%, pale yellow solid).
1 H NMR (500 MHz, CDCl 3 ) δ 8.48 (1 H, dd, J = 4.5, 2.0 Hz), 8.05 (1 H, d, J = 2.0 Hz), 8.04 (1 H, s), 8.00 (1 H, dd, J = 9.0, 2.0 Hz), 7.83 (1 H, d, J = 2.0 Hz), 7. 78 (1 H, dd, J = 8.0, 2.0 Hz), 7.75 (1 H, br), 7.63 (1 H, d, J = 8.0) Hz), 7.61 (1H, dd, J = 8.0, 2.0 Hz), 7.28 (1 H, d, J = 8.0 Hz), 7.13 (1 H, dd, J = 9.0, 4.5 Hz), 3.65 (2 H, s), 2.65-2.40 (11 H, m), 2.32 (3 H, s).
(製造例8)
下記スキームに従って下記式で表されるPON-4 precursorを製造した。
Methyl 3-(2-imidazo[1,2-a]pyridazin-3-ylethynyl)-4-methyl-benzoate (77.0 mg, 0.26 mmol)をH2O (124 μL)、濃塩酸 (380 μL)に溶解させ100℃で2時間加熱還流した。その後、溶媒を減圧留去し乾固した。そこへ塩化チオニル(377 μL)、DMF (3 drops)を加え室温にて17時間攪拌した。その後、溶媒を減圧留去し乾固した。そこへTHF (4.1 mL)に溶解させ1-[(2-bromo-4-aminophenyl)methyl]-4-methyl-Piperazine (68.2 mg, 0.24 mmol)、DMAP (1.2 mg, 0.01 mmol)、N,N-Diisopropylethylamine (42 μL, 0.24 mmol)を加え室温にて2.5時間攪拌した。水と酢酸エチルを加え、飽和NaHCO3溶液、水で洗浄後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム : メタノール = 10 : 1) により精製しPON-4 precursor (92.9 mg, 0.17 mmol, 70%, pale yellow solid)を得た。
1H NMR (500 MHz, DMSO-d6) δ 9.21 (1H, s), 8.68 (1H, d, J=5.0Hz), 8.30 (1H, s), 8.28-8.25 (2H, m), 8.15-8.12 (2H, m), 7.93 (1H, dd, J=8.0, 2.0Hz), 7.75 (1H, dd, J=8.0, 2.0Hz), 7.55 (1H, d, J=8.0Hz), 7.42 (1H, d, J=8.0Hz), 3.49 (2H, s), 2.61 (3H, s), 2.50-2.25 (8H, m), 2.15 (3H, s).
Production Example 8
A PON-4 precursor represented by the following formula was produced according to the following scheme.
Dissolve Methyl 3- (2-imidazo [1,2-a] pyridazin-3-ylthynyl) -4-methyl-benzoate (77.0 mg, 0.26 mmol) in H 2 O (124 μL) and concentrated hydrochloric acid (380 μL) The mixture was heated to reflux at 100.degree. C. for 2 hours. After that, the solvent was evaporated under reduced pressure to dryness. Thionyl chloride (377 μL) and DMF (3 drops) were added thereto, and the mixture was stirred at room temperature for 17 hours. After that, the solvent was evaporated under reduced pressure to dryness. There, it was dissolved in THF (4.1 mL), 1-[(2-bromo-4-aminophenyl) methyl] -4-methyl-piperazine (68.2 mg, 0.24 mmol), DMAP (1.2 mg, 0.01 mmol), N, N -Diisopropylethylamine (42 μL, 0.24 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Water and ethyl acetate were added, and after washing with saturated NaHCO 3 solution and water, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain PON-4 precursor (92.9 mg, 0.17 mmol, 70%, pale yellow solid).
1 H NMR (500 MHz, DMSO-d 6 ) δ 9.21 (1 H, s), 8.68 (1 H, d, J = 5.0 Hz), 8.30 (1 H, s), 8.28-8.25 (2 H, m), 8.15 8.12 (2 H, m), 7. 93 (1 H, dd, J = 8.0, 2.0 Hz), 7. 75 (1 H, dd, J = 8.0, 2.0 Hz), 7.55 (1 H, d, J = 8.0 Hz), 7.42 (1 H , d, J = 8.0 Hz), 3.49 (2H, s), 2.61 (3H, s), 2.50-2.25 (8H, m), 2.15 (3H, s).
[放射化学合成]
放射性標識化合物である[125I]PON-1、[123/125I]PON-2、[125I]PON-3、及び[125I]PON-4を下記スキームに従って合成した。
Radiolabeled compounds [ 125 I] PON-1, [ 123/125 I] PON-2, [ 125 I] PON-3, and [ 125 I] PON-4 were synthesized according to the following scheme.
(製造例9)
[ 125 I]PON-1
PON-1 precursor (6.6 mg)、CuSO4・5H2O (7.25 mg)、(NH4)2SO4 (6.41 mg)を反応バイアルへ入れ、MeOH (200 μL)、H2O (200 μL)に懸濁させ、[125I]NaI (237 μCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (200 μL)、MeOH (200 μL)で反応物を洗浄した後、MeCN (200 μL)、H2O (200 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 50% (A) and (B), flow rate 1.0 mL/min, λ = 220, 254 nm, Rt = 32.25-34.75 min)にて精製し、[125I]PON-1を放射化学的収率10%、放射化学的純度>99%で得た。
Production Example 9
[ 125 I] PON-1
PON-1 precursor (6.6 mg) , CuSO 4 · 5H 2 O (7.25 mg), (NH 4) 2 SO 4 and (6.41 mg) were placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) And after adding [ 125 I] NaI (237 μCi), heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction with MeCN (200 μL), MeOH (200 μL), MeCN (200 μL), H 2 O (200 μL) is added and the solution is passed through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR -II, 10 x 250 mm, eluent 50% (A) and (B), flow rate 1.0 mL / min, λ = 220, 254 nm, Rt = 32.25-24.75 min), [ 125 I] PON -1 was obtained in a radiochemical yield of 10%, radiochemical purity> 99%.
(製造例10)
[ 125 I]PON-2
PON-2 precursor (2.2 mg)、CuSO4・5H2O (2.8 mg)、(NH4)2SO4 (3.2 mg)を反応バイアルへ入れ、MeOH (200 μL)、H2O (200 μL)に懸濁させ、[125I]NaI (252 μCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (200 μL)、MeOH (200 μL)で反応物を洗浄した後、MeCN (800 μL)、H2O (800 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 65% (A) and 35% (B), flow rate 2.0 mL/min, λ = 220, 254 nm, Rt = 14.5-16.5 min)にて精製し、[125I]PON-2を放射化学的収率50%、放射化学的純度>99%で得た。
Production Example 10
[ 125 I] PON-2
PON-2 precursor (2.2 mg) , CuSO 4 · 5H 2 O (2.8 mg), (NH 4) 2 SO 4 a (3.2 mg) was placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) The mixture was suspended in water, added with [ 125 I] NaI (252 μCi), and then heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction with MeCN (200 μL), MeOH (200 μL), MeCN (800 μL), H 2 O (800 μL) is added and the solution is passed through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR -II, 10 x 250 mm, and purified by eluent 65% (A) and 35 % (B), flow rate 2.0 mL / min, λ = 220, 254 nm, Rt = 14.5-16.5 min), [125 I PON-2 was obtained in a radiochemical yield of 50%, radiochemical purity> 99%.
(製造例11)
[ 125 I]PON-3
PON-3 precursor (1.54 mg)、CuSO4・5H2O (2.51 mg)、(NH4)2SO4 (2.62 mg)を反応バイアルへ入れ、MeOH (200 μL)、H2O (200 μL)に懸濁させ、[125I]NaI (251 μCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (200 μL)、MeOH (200 μL)、MeOH/H2O=1/1 (400 μL) で反応物を洗浄した後、MeCN (200 μL)、H2O (200 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 60% (A) and 40% (B), flow rate 1.0 mL/min, λ = 220, 254 nm, Rt = 26.5-28.0 min)にて精製し、[125I]PON-3を放射化学的収率38%、放射化学的純度>99%で得た。
(Production Example 11)
[ 125 I] PON-3
PON-3 precursor (1.54 mg) , CuSO 4 · 5H 2 O (2.51 mg), (NH 4) 2 SO 4 and (2.62 mg) were placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) And after adding [ 125 I] NaI (251 μCi), heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction product with MeCN (200 μL), MeOH (200 μL), MeOH / H 2 O = 1/1 (400 μL), MeCN (200 μL), H 2 O (200 μL) is added, and the solution is added. Through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 60% (A) and 40% (B), flow rate 1.0 mL / min, λ = 220, 254 nm, Rt (26.5-28.0 min) to obtain [ 125 I] PON-3 in a radiochemical yield of 38%, radiochemical purity> 99%.
(製造例12)
[ 125 I]PON-4
PON-4 precursor (3.1 mg)、CuSO4・5H2O (5.3 mg)、(NH4)2SO4 (4.3 mg)を反応バイアルへ入れ、MeOH (200 μL)、H2O (200 μL)に懸濁させ、[125I]NaI (383 μCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (200 μL)、MeOH (200 μL)、MeOH/H2O=1/1 (400 μL)で反応物を洗浄した後、MeCN (600 μL)、H2O (600 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 65% (A) and 35% (B), flow rate 1.0 mL/min, λ = 220, 254 nm, Rt = 31.0-32.0 min)にて精製し、[125I]PON-3を放射化学的収率33%、放射化学的純度>99%で得た。
Production Example 12
[ 125 I] PON-4
PON-4 precursor (3.1 mg) , CuSO 4 · 5H 2 O (5.3 mg), (NH 4) 2 SO 4 a (4.3 mg) was placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) And after adding [ 125 I] NaI (383 μCi), heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction with MeCN (200 μL), MeOH (200 μL), MeOH / H 2 O = 1/1 (400 μL), MeCN (600 μL), H 2 O (600 μL) is added, and the solution is added. Through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 65% (A) and 35% (B), flow rate 1.0 mL / min, λ = 220, 254 nm, Rt It refine | purified in = 31.0-32.0 min), and obtained [< 125 > I] PON-3 with radiochemical yield 33% and radiochemical purity> 99%.
(製造例13)
[ 123 I]PON-2
PON-2 precursor (1.71 mg)、CuSO4・5H2O (2.61 mg)、(NH4)2SO4 (2.62 mg)を反応バイアルへ入れ、MeOH (200 μL)、H2O (200 μL)に懸濁させ、[123I]NH4I (29.1 mCi)を加えた後、封緘中150℃で加熱した。10分後から反応バイアルへ26Gの注射針、ルアーアダプタ、輸液ポンプ用延長チューブを経由し溶媒を留去しながら、50分間加熱した。MeCN (400 μL)、MeOH (400 μL)、MeOH/H2O=1/1 (400 μL)で反応物を洗浄した後、MeCN (400 μL)、H2O (400 μL)を加え、溶液をCosmonicefilter Sを通し、逆相HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 65% (A) and 35% (B), flow rate 1.0 mL/min, λ = 220, 254 nm, Rt = 30.0-32.0 min)にて精製し、[123I]PON-2を放射化学的収率37%、放射化学的純度>99%で得た。
Production Example 13
[ 123 I] PON-2
PON-2 precursor (1.71 mg) , CuSO 4 · 5H 2 O (2.61 mg), (NH 4) 2 SO 4 and (2.62 mg) were placed into a reaction vial, MeOH (200 μL), H 2 O (200 μL) The mixture was suspended in water, added with [ 123 I] NH 4 I (29.1 mCi), and then heated at 150 ° C. in a sealed vessel. After 10 minutes, the reaction vial was heated for 50 minutes while distilling the solvent through a 26G injection needle, a luer adapter, and an infusion pump extension tube. After washing the reaction product with MeCN (400 μL), MeOH (400 μL), MeOH / H 2 O = 1/1 (400 μL), MeCN (400 μL), H 2 O (400 μL) is added, and the solution is added. Through Cosmonicefilter S, reverse phase HPLC (COSMOSIL 5C18-AR-II, 10 x 250 mm, eluent 65% (A) and 35% (B), flow rate 1.0 mL / min, λ = 220, 254 nm, Rt Purification at 30.0 to 32.0 min) gave [ 123 I] PON-2 in a radiochemical yield of 37%, radiochemical purity> 99%.
[細胞増殖抑制活性の測定]
96ウェルプレート上にK562細胞(3.0×103 cells/well)またはBa/F3 Bcr-AblT315細胞(3.0×103 cells/well)を播種し、10% Fetal Bovine Serum含有RPMI1640培地中にて1晩培養した。各ウェルにPON-1, -2, -3, -4を終濃度が0.03-1000 nMになるように添加し、CO2インキュベーター中で72時間インキュベートした。72時間後、Cell Counting Kit-8(同仁科学株式会社)を用いて生存細胞数をカウントし、各濃度のカウント数から各化合物のIC50値を算出した。
[Measurement of cell growth inhibitory activity]
K562 cells (3.0 × 10 3 cells / well) or Ba / F 3 Bcr-Abl T315 cells (3.0 × 10 3 cells / well) are seeded on a 96-well plate, and 1 in RPMI 1640 medium containing 10% Fetal Bovine Serum. It was cultured overnight. To each well, PON-1, -2, -3, -4 were added to a final concentration of 0.03 to 1000 nM and incubated for 72 hours in a CO 2 incubator. After 72 hours, the number of viable cells was counted using Cell Counting Kit-8 (Dohito Science Co., Ltd.), and the IC50 value of each compound was calculated from the count number of each concentration.
表1に示すように、PON-1, -2, -3, -4はBcr-Abl positive細胞であるK562細胞に対して結合親和性を示した。また、PON -2, -3, -4はBcr-Abl変異細胞であるBa/F Bcr-AblT315Iに対して結合親和性を示した。 As shown in Table 1, PON-1, -2, -3, -4 showed binding affinity to K562 cells which are Bcr-Abl positive cells. In addition, PON -2, -3, -4 showed binding affinity to Ba / F Bcr-AblT315I which is a Bcr-Abl mutant cell.
[K562担がんマウスを用いた[125I]PON-1体内動態評価]
Bcr-Abl positive細胞であるK562担がんマウスへ[125I]PON-1(18.5 kBq/100 μL)をマウス尾静注より投与した。投与後60、120、180、240分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果を図1及び3に示す。図1は、血液、骨、腫瘍及び筋肉における集積量の経時変化を示すグラフである。図2は、左から順に腫瘍/血液比、腫瘍/筋肉比及び腫瘍/骨比の経時変化を示すグラフである。図1に示すように、投与後240分において、腫瘍への集積は2.3 ID%/gであった。また、図2に示すように、画像化に重要な臓器比は腫瘍/血液比13.8、腫瘍/筋肉比3.1、腫瘍/骨比4.1と高い臓器比が得られた。
[ 125 I] PON-1 pharmacokinetics evaluation using K562 tumor-bearing mice]
[ 125 I] PON-1 (18.5 kBq / 100 μL) was administered by intravenous injection from a mouse tail to K562 tumor-bearing mice that are Bcr-Abl positive cells. Each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed 60, 120, 180, 240 minutes after administration. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. The results are shown in FIGS. 1 and 3. FIG. 1 is a graph showing the time course of accumulation in blood, bone, tumor and muscle. FIG. 2 is a graph showing the time course of the tumor / blood ratio, the tumor / muscle ratio and the tumor / bone ratio in order from the left. As shown in FIG. 1, at 240 minutes after administration, accumulation in the tumor was 2.3 ID% / g. In addition, as shown in FIG. 2, as for organ ratios important for imaging, a high organ ratio was obtained with a tumor / blood ratio of 13.8, a tumor / muscle ratio of 3.1, and a tumor / bone ratio of 4.1.
[K562担がんマウスを用いた[125I]PON-2体内動態評価]
Bcr-Abl positive細胞であるK562担がんマウスへ[125I]PON-2(18.5 kBq/100 μL)をマウス尾静注より投与した。投与後60、120、180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果を図3及び4に示す。図3は、血液、骨、腫瘍及び筋肉における集積量の経時変化を示すグラフである。図4は、左から順に腫瘍/血液比、腫瘍/筋肉比及び腫瘍/骨比の経時変化を示すグラフである。図3に示すように、投与後180分において、腫瘍への集積は4.1 ID%/gであった。また、図4に示すように、画像化に重要な臓器比は腫瘍/血液比9.6、腫瘍/筋肉比4.6、腫瘍/骨比3.7と高い臓器比が得られた。
[ 125 I] PON-2 pharmacokinetics evaluation using K562 tumor-bearing mice]
[ 125 I] PON-2 (18.5 kBq / 100 μL) was administered by intravenous injection from a mouse tail to K562 tumor-bearing mice that are Bcr-Abl positive cells. Each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed 60, 120, 180 minutes after administration. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. The results are shown in FIGS. FIG. 3 is a graph showing the time course of accumulation in blood, bone, tumor and muscle. FIG. 4 is a graph showing the time course of the tumor / blood ratio, the tumor / muscle ratio and the tumor / bone ratio in order from the left. As shown in FIG. 3, at 180 minutes after administration, accumulation in the tumor was 4.1 ID% / g. In addition, as shown in FIG. 4, the organ ratio important for imaging was a tumor / blood ratio of 9.6, a tumor / muscle ratio of 4.6, and a tumor / bone ratio of 3.7, which were high.
[A431担がんマウスを用いた[125I]PON-2体内動態評価]
Bcr-Abl negative細胞であるA431担がんマウスへ[125I]PON-2(18.5 kBq/100 μL)をマウス尾静注より投与した。投与後180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。投与後180分において、腫瘍への集積は0.6 ID%/gであり、画像化に重要な臓器比は腫瘍/血液比2.9、腫瘍/筋肉比1.3、腫瘍/骨比0.9と低い臓器比が認められた。
[ 125I ] PON-2 pharmacokinetics evaluation using A431 tumor-bearing mice]
[ .Sup.125 I] PON-2 (18.5 kBq / 100 .mu.L) was administered to A431 tumor-bearing mice, which are Bcr-Abl negative cells, by intravenous injection from the mouse tail. 180 minutes after administration, each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. At 180 minutes after administration, accumulation in the tumor was 0.6 ID% / g, and organ ratios important for imaging were a tumor / blood ratio of 2.9, a tumor / muscle ratio of 1.3, a tumor / bone ratio of 0.9 and a low organ ratio. It was done.
[K562担がんマウスを用いた[125I]PON-3体内動態評価]
Bcr-Abl positive細胞であるK562担がんマウスへ[125I]PON-3(18.5 kBq/100 μL)をマウス尾静注より投与した。投与後60、120、180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果を図5及び7に示す。図5は、血液、骨、腫瘍及び筋肉における集積量の経時変化を示すグラフである。図6は、左から順に腫瘍/血液比、腫瘍/筋肉比及び腫瘍/骨比の経時変化を示すグラフである。図5に示すように、投与後180分において、腫瘍への集積は1.3 ID%/gであった。また、図6に示すように、画像化に重要な臓器比は腫瘍/血液比5.8、腫瘍/筋肉比7.2、腫瘍/骨比1.6と高い臓器比が得られた。
[ 125 I] PON-3 pharmacokinetics evaluation using K562 tumor-bearing mice]
[ 125 I] PON-3 (18.5 kBq / 100 μL) was administered to the K562 tumor-bearing mice, which are Bcr-Abl positive cells, by intravenous injection from the mouse tail. Each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed 60, 120, 180 minutes after administration. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. The results are shown in FIGS. FIG. 5 is a graph showing the time course of accumulation in blood, bone, tumor and muscle. FIG. 6 is a graph showing the time course of the tumor / blood ratio, tumor / muscle ratio and tumor / bone ratio in order from the left. As shown in FIG. 5, at 180 minutes after administration, accumulation in the tumor was 1.3 ID% / g. In addition, as shown in FIG. 6, as for the organ ratio important for imaging, a high organ ratio was obtained with a tumor / blood ratio of 5.8, a tumor / muscle ratio of 7.2, and a tumor / bone ratio of 1.6.
[A431担がんマウスを用いた[125I]PON-3体内動態評価]
Bcr-Abl negative細胞であるA431担がんマウスへ[125I]PON-3(18.5 kBq/100 μL)をマウス尾静注より投与した。投与後180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果、投与後180分において、腫瘍への集積は0.3 ID%/gであり、画像化に重要な臓器比は腫瘍/血液比2.1、腫瘍/筋肉比4.4、腫瘍/骨比1.8と低い臓器比が認められた。
[ 125I ] PON-3 pharmacokinetics evaluation using A431 tumor-bearing mice]
[ 125I ] PON-3 (18.5 kBq / 100 μL) was administered to A431 tumor-bearing mice, which are Bcr-Abl negative cells, by intravenous injection from the mouse tail. 180 minutes after administration, each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. As a result, at 180 minutes after administration, accumulation in the tumor was 0.3 ID% / g, and organ ratios important for imaging were tumor / blood ratio 2.1, tumor / muscle ratio 4.4, and tumor / bone ratio 1.8 as low as organ. A ratio was noted.
[K562担がんマウスを用いた[125I]PON-4体内動態評価]
Bcr-Abl positive細胞であるK562担がんマウスへ[125I]PON-4(18.5 kBq/100 μL)をマウス尾静注より投与した。投与後60、120、180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果を図7及び8に示す。図7は、血液、骨、腫瘍及び筋肉における集積量の経時変化を示すグラフである。図8は、左から順に腫瘍/血液比、腫瘍/筋肉比及び腫瘍/骨比の経時変化を示すグラフである。図8に示すように、投与後180分において、腫瘍への集積は1.5 ID%/gであった。また、図8に示すように、画像化に重要な臓器比は腫瘍/血液比10.2、腫瘍/筋肉比3.9、腫瘍/骨比3.9と高い臓器比が得られた。
[ 125 I] PON-4 pharmacokinetics evaluation using K562 tumor-bearing mice]
[ 125 I] PON-4 (18.5 kBq / 100 μL) was administered from a mouse tail intravenous injection to K562 tumor-bearing mice that are Bcr-Abl positive cells. Each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed 60, 120, 180 minutes after administration. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. The results are shown in FIGS. 7 and 8. FIG. 7 is a graph showing the time course of accumulation in blood, bone, tumor and muscle. FIG. 8 is a graph showing the time course of the tumor / blood ratio, the tumor / muscle ratio and the tumor / bone ratio sequentially from the left. As shown in FIG. 8, at 180 minutes after administration, accumulation in the tumor was 1.5 ID% / g. In addition, as shown in FIG. 8, as for organ ratios important for imaging, a high organ ratio was obtained with a tumor / blood ratio of 10.2, a tumor / muscle ratio of 3.9, and a tumor / bone ratio of 3.9.
[A431担がんマウスを用いた[125I]PON-4体内動態評価]
Bcr-Abl negative細胞であるA431担がんマウスへ[125I]PON-4(18.5 kBq/100 μL)をマウス尾静注より投与した。投与後180分に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果、投与後180分において、腫瘍への集積は0.3 ID%/gであり、画像化に重要な臓器比は腫瘍/血液比1.5、腫瘍/筋肉1.9、腫瘍/骨比1.2と低い臓器比が認められた。
[ 125I ] PON-4 pharmacokinetics evaluation using A431 tumor-bearing mice]
[ .Sup.125 I] PON-4 (18.5 kBq / 100 .mu.L) was administered to A431 tumor-bearing mice, which are Bcr-Abl negative cells, by intravenous injection from the mouse tail. 180 minutes after administration, each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. As a result, at 180 minutes after administration, the accumulation in the tumor is 0.3 ID% / g, and the organ ratio important for imaging is a tumor / blood ratio of 1.5, a tumor / muscle of 1.9, a tumor / bone ratio of 1.2 and a low organ ratio Was recognized.
[Ba/F Bcr-AblT315I担がんマウスを用いた[125I]PON-2体内動態評価]
Bcr-Abl変異細胞であるBa/F Bcr-AblT315I担がんマウスへ[125I]PON-2(18.5 kBq/100 μL)をマウス尾静注より投与した。投与後1、3、24時間に各臓器(腫瘍、血液、心臓、肺、肝臓、膵臓、胃、小腸、脾臓、腎臓、筋肉、骨)を摘出した。各臓器の重量と放射能を測定し、単位重量あたりの放射能から放射集積量(ID%/g)を算出した。その結果を図9に示す。図9は、左から順に腫瘍/血液比、腫瘍/筋肉比及び腫瘍/骨比の経時変化を示すグラフである。投与後3時間の時点において、腫瘍への集積は1.7 ID%/gであった。また、図9に示すように、投与後24時間において画像化に重要な臓器比は腫瘍/血液比7.5、腫瘍/筋肉比6.2、腫瘍/骨比2.9と高い臓器比が得られた。
[ 125 I] PON-2 pharmacokinetics evaluation using Ba / F Bcr-AblT 315I tumor-bearing mice
[ 125 I] PON-2 (18.5 kBq / 100 μL) was administered to the Bcr-Abl mutant cells Ba / F Bcr-AblT 315I tumor-bearing mice through intravenous injection of mouse tail. At 1, 3 and 24 hours after administration, each organ (tumor, blood, heart, lung, liver, pancreas, stomach, small intestine, spleen, kidney, muscle, bone) was removed. The weight and radioactivity of each organ were measured, and the radiation accumulation amount (ID% / g) was calculated from the radioactivity per unit weight. The results are shown in FIG. FIG. 9 is a graph showing the time course of the tumor / blood ratio, the tumor / muscle ratio and the tumor / bone ratio sequentially from the left. At 3 hours post dose, tumor accumulation was 1.7 ID% / g. Also, as shown in FIG. 9, organ ratios important for imaging at 24 hours after administration were a tumor / blood ratio of 7.5, a tumor / muscle ratio of 6.2, and a tumor / bone ratio of 2.9, a high organ ratio.
[SPECT/CT撮像]
K562担がんマウスへ[123I]PON-2(87.3 MBq/100 μL)をマウス尾静脈より投与した。投与後1074分からイソフルラン(2.0%)吸引麻酔し投与後1084分からSPECT/CT装置(FX-3300)を用いて48分間撮像した。その後、CT撮像(60 kV, 320 μA)を行った。画像再構成は、3D-OSEMを用いて行った。得られた画像を図10に示す。図10に示すように、移植したK562細胞で構成された腫瘍をイメージングできた。撮像終了後、屠殺し各臓器を摘出し、各臓器の重量と放射能を測定し、単位重量あたりの放射能から集積量(%ID/g)を算出した。その結果、腫瘍/血液比12.1、腫瘍/筋肉比7.4、腫瘍/骨比10.5と高い近接臓器比が認められた。
[SPECT / CT imaging]
[ 123 I] PON-2 (87.3 MBq / 100 μL) was administered to K562 tumor-bearing mice from the tail vein of the mouse. Isoflurane (2.0%) was anaesthetized at 1074 minutes after administration, and imaging was performed for 48 minutes using a SPECT / CT apparatus (FX-3300) after 1084 minutes after administration. Thereafter, CT imaging (60 kV, 320 μA) was performed. Image reconstruction was performed using 3D-OSEM. The obtained image is shown in FIG. As shown in FIG. 10, a tumor composed of the transplanted K562 cells could be imaged. After the end of imaging, each animal was sacrificed, each organ was extracted, the weight and radioactivity of each organ were measured, and the accumulated amount (% ID / g) was calculated from the radioactivity per unit weight. As a result, a tumor / blood ratio 12.1, a tumor / muscle ratio 7.4, and a tumor / bone ratio 10.5, a high adjacent organ ratio were recognized.
Claims (7)
Xは、−C(=O)−NH−又は−NH−C(=O)−であり、
R1は、
R2及びR3は、それぞれ独立して、水素原子、放射性ハロゲン原子、及びフッ化メチル基であり、R2及びR3の一方は、放射性ハロゲン原子である。] The compound represented by following formula (I), or its pharmaceutically acceptable salt.
X is -C (= O) -NH- or -NH-C (= O)-,
R 1 is
R 2 and R 3 are each independently a hydrogen atom, a radioactive halogen atom, and a methyl fluoride group, and one of R 2 and R 3 is a radioactive halogen atom. ]
Xは、−C(=O)−NH−又は−NH−C(=O)−であり、
R1は、
R4及びR5は、それぞれ独立して、水素原子、ハロゲン原子、フッ化メチル基、トリアルキルスタニル基、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基であり、R4及びR5の一方は、ハロゲン原子、トリアルキルスタニル基、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基である。] A precursor composition for radioactive labeling, which comprises a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof.
X is -C (= O) -NH- or -NH-C (= O)-,
R 1 is
R 4 and R 5 each independently represent a hydrogen atom, a halogen atom, a methyl fluoride group, a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group, One of R 4 and R 5 is a halogen atom, a trialkylstannyl group, a nitro group, a tosylate group, a mesylate group, a triflate group, a nosylate group or a brosylate group. ]
[式(5)中のR4及び式(6)〜(8)中のR4は、ハロゲン原子、トリアルキルスタニル基、ニトロ基、トシレート基、メシレート基、トリフレート基、ノシレート基又はブロシレート基である。] The precursor composition according to claim 5, wherein the compound represented by the formula (II) is a compound represented by any one of the following formulas (5) to (8).
[R 4 in the formula (5) R 4 and Equation (6) to (8) in a halogen atom, a trialkyl stannyl group, a nitro group, a tosylate group, mesylate group, triflate group, nosylate group or brosylate It is a group. ]
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017194584A JP7024960B2 (en) | 2017-10-04 | 2017-10-04 | Molecular probe for Bcr-Abl protein imaging |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017194584A JP7024960B2 (en) | 2017-10-04 | 2017-10-04 | Molecular probe for Bcr-Abl protein imaging |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019064986A true JP2019064986A (en) | 2019-04-25 |
JP7024960B2 JP7024960B2 (en) | 2022-02-24 |
Family
ID=66339043
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017194584A Active JP7024960B2 (en) | 2017-10-04 | 2017-10-04 | Molecular probe for Bcr-Abl protein imaging |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP7024960B2 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009521462A (en) * | 2005-12-23 | 2009-06-04 | アリアド・ファーマシューティカルズ・インコーポレイテッド | Bicyclic heteroaryl compounds |
WO2012121285A1 (en) * | 2011-03-07 | 2012-09-13 | 国立大学法人京都大学 | Labeling precursor compound, radioactively labeling compound, and processes for producing those compounds |
-
2017
- 2017-10-04 JP JP2017194584A patent/JP7024960B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009521462A (en) * | 2005-12-23 | 2009-06-04 | アリアド・ファーマシューティカルズ・インコーポレイテッド | Bicyclic heteroaryl compounds |
WO2012121285A1 (en) * | 2011-03-07 | 2012-09-13 | 国立大学法人京都大学 | Labeling precursor compound, radioactively labeling compound, and processes for producing those compounds |
Non-Patent Citations (2)
Title |
---|
YE, YIHUA E.; WOODWARD, CAROLINE N.; NARASIMHAN, NARAYANA I.: "Absorption, metabolism, and excretion of [14C]ponatinib after a single oral dose in humans", CANCER CHEMOTHERAPY AND PHARMACOLOGY, vol. Vol.79(3), JPN6021030586, 2017, pages 507 - 518, ISSN: 0004666159 * |
渡邊裕之ら: "放射性ヨウ素標識BODIPYの開発とその生体分子イメージングへの応用", JSMI REPORT, vol. Vol.10(2), JPN6021030584, 2017, pages 166, ISSN: 0004666160 * |
Also Published As
Publication number | Publication date |
---|---|
JP7024960B2 (en) | 2022-02-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR20190030727A (en) | Radioligand for imaging IDO1 enzyme | |
AU2017226878B2 (en) | Radiolabeled macrocyclic EGFR inhibitor | |
JP2023184564A (en) | Novel compound | |
JP2005501830A (en) | Radiolabeled neuropeptide YY5 receptor antagonist | |
JP6994715B2 (en) | Molecular probe for Bcr-Abl protein imaging | |
JP7024960B2 (en) | Molecular probe for Bcr-Abl protein imaging | |
US10865195B2 (en) | Pet imaging agents | |
EP2657213A1 (en) | Labelled quinoxaline derivatives as multimodal radiopharmaceuticals and their precursors | |
JP6709552B2 (en) | Nuclear medicine diagnostic imaging agent | |
KR102044480B1 (en) | A novel radioactive compound for diagnosing malignant melanoma and use thereof | |
EP3111960B1 (en) | Nuclear medicine diagnostic imaging agent | |
JP2009132701A (en) | Diagnostic drug for nuclear medicine | |
JP6609868B2 (en) | Radioactive halogen-labeled pyrido [1,2-a] benzimidazole derivative compound | |
US20180064742A1 (en) | Pet imaging tracer for imaging prostate cancer | |
JP7054134B2 (en) | Benzo [b] carbazole compound and imaging using it | |
JP6739987B2 (en) | Nuclear medicine diagnostic imaging agent | |
US20200123104A1 (en) | Pharmaceutical agent that binds the p2x7 receptor | |
JP2014218455A (en) | Styrylpyridine derivative compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200818 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20210719 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210817 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210903 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210930 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211118 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20211221 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220117 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20220201 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20220202 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7024960 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |