JP7449864B2 - エバンスブルー誘導体の化学結合体ならびに前立腺癌を標的とするための放射線療法および造影剤としてのその使用 - Google Patents
エバンスブルー誘導体の化学結合体ならびに前立腺癌を標的とするための放射線療法および造影剤としてのその使用 Download PDFInfo
- Publication number
- JP7449864B2 JP7449864B2 JP2020543529A JP2020543529A JP7449864B2 JP 7449864 B2 JP7449864 B2 JP 7449864B2 JP 2020543529 A JP2020543529 A JP 2020543529A JP 2020543529 A JP2020543529 A JP 2020543529A JP 7449864 B2 JP7449864 B2 JP 7449864B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- psma
- formula
- mcg
- acid
- 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.)
- Active
Links
- 206010060862 Prostate cancer Diseases 0.000 title claims description 22
- 208000000236 Prostatic Neoplasms Diseases 0.000 title claims description 22
- 238000001959 radiotherapy Methods 0.000 title description 19
- 239000000126 substance Substances 0.000 title description 19
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical class CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 title description 5
- 239000002872 contrast media Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 112
- 238000011282 treatment Methods 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 238000003745 diagnosis Methods 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229920000858 Cyclodextrin Polymers 0.000 claims description 3
- 150000003983 crown ethers Chemical class 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000004032 porphyrins Chemical class 0.000 claims description 3
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 2
- 229930012538 Paclitaxel Natural products 0.000 claims description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 2
- 229940120638 avastin Drugs 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 229940127093 camptothecin Drugs 0.000 claims description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 229940097362 cyclodextrins Drugs 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 claims description 2
- 229960004679 doxorubicin Drugs 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 229940082789 erbitux Drugs 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- 229940022353 herceptin Drugs 0.000 claims description 2
- 229960001592 paclitaxel Drugs 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 2
- 229960004964 temozolomide Drugs 0.000 claims description 2
- 239000003906 humectant Substances 0.000 claims 2
- 230000002335 preservative effect Effects 0.000 claims 1
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 53
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 52
- 206010028980 Neoplasm Diseases 0.000 description 40
- 239000000203 mixture Substances 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 23
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000000034 method Methods 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000003446 ligand Substances 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 241000699670 Mus sp. Species 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000007997 Tricine buffer Substances 0.000 description 12
- 239000013543 active substance Substances 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 125000005647 linker group Chemical group 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- -1 ester amide Chemical class 0.000 description 11
- 150000003384 small molecules Chemical class 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000014759 maintenance of location Effects 0.000 description 9
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 238000012636 positron electron tomography Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- RSTDSVVLNYFDHY-IOCOTODDSA-K 2-[4-[2-[[4-[[(2S)-1-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxypropyl]carbamoylamino]pentyl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]carbamoyl]cyclohexyl]methylamino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate lutetium-177(3+) Chemical compound [177Lu+3].OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CCC(CNC(=O)CN2CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC2)CC1)C(O)=O)C(O)=O RSTDSVVLNYFDHY-IOCOTODDSA-K 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 230000029142 excretion Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 108010037516 PSMA-617 Proteins 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000001045 blue dye Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000002738 chelating agent Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 231100000226 haematotoxicity Toxicity 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- JBHPLHATEXGMQR-LFWIOBPJSA-N vipivotide tetraxetan Chemical compound OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CC1=CC=C2C=CC=CC2=C1)NC(=O)[C@H]1CC[C@H](CNC(=O)CN2CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC2)CC1)C(O)=O)C(O)=O JBHPLHATEXGMQR-LFWIOBPJSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- JKHVDAUOODACDU-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCN1C(=O)C=CC1=O JKHVDAUOODACDU-UHFFFAOYSA-N 0.000 description 2
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 2
- XSVWFLQICKPQAA-UHFFFAOYSA-N 2-[4,10-bis(carboxymethyl)-7-[2-(2,5-dioxopyrrolidin-1-yl)oxy-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C1CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CCN1CC(=O)ON1C(=O)CCC1=O XSVWFLQICKPQAA-UHFFFAOYSA-N 0.000 description 2
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical group OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 description 2
- RXACEEPNTRHYBQ-UHFFFAOYSA-N 2-[[2-[[2-[(2-sulfanylacetyl)amino]acetyl]amino]acetyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)CNC(=O)CNC(=O)CS RXACEEPNTRHYBQ-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 description 2
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 2
- 238000012879 PET imaging Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical group OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 229940072107 ascorbate Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 206010013781 dry mouth Diseases 0.000 description 2
- 229960003699 evans blue Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 125000003827 glycol group Chemical group 0.000 description 2
- 238000011194 good manufacturing practice Methods 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 231100001252 long-term toxicity Toxicity 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- JOVLEOXYYWEEEW-UHFFFAOYSA-M sodium;1-amino-8-hydroxy-4-sulfonaphthalene-2-sulfonate Chemical compound [Na+].C1=CC(O)=C2C(N)=C(S([O-])(=O)=O)C=C(S(O)(=O)=O)C2=C1 JOVLEOXYYWEEEW-UHFFFAOYSA-M 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- FLCQLSRLQIPNLM-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-acetylsulfanylacetate Chemical compound CC(=O)SCC(=O)ON1C(=O)CCC1=O FLCQLSRLQIPNLM-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000005925 3-methylpentyloxy group Chemical group 0.000 description 1
- AECGEIVNZGQBJT-UHFFFAOYSA-N 3-tritylsulfanylpropanoic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(SCCC(=O)O)C1=CC=CC=C1 AECGEIVNZGQBJT-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- OPVPGKGADVGKTG-BQBZGAKWSA-N Ac-Asp-Glu Chemical compound CC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O OPVPGKGADVGKTG-BQBZGAKWSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 101100289888 Caenorhabditis elegans lys-5 gene Proteins 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 238000010824 Kaplan-Meier survival analysis Methods 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010070308 Refractory cancer Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- 229910009523 YCl3 Inorganic materials 0.000 description 1
- XYVNHPYNSPGYLI-UUOKFMHZSA-N [(2r,3s,4r,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-4-hydroxy-2-(phosphonooxymethyl)oxolan-3-yl] dihydrogen phosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H]1O XYVNHPYNSPGYLI-UUOKFMHZSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229940034605 capromab pendetide Drugs 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- AEDROEGYZIARPU-UHFFFAOYSA-K lutetium(iii) chloride Chemical compound Cl[Lu](Cl)Cl AEDROEGYZIARPU-UHFFFAOYSA-K 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 229940124633 peptidic drug Drugs 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011362 radionuclide therapy Methods 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000013042 tunel staining Methods 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- PCMOZDDGXKIOLL-UHFFFAOYSA-K yttrium chloride Chemical compound [Cl-].[Cl-].[Cl-].[Y+3] PCMOZDDGXKIOLL-UHFFFAOYSA-K 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B29/00—Monoazo dyes prepared by diazotising and coupling
- C09B29/0025—Monoazo dyes prepared by diazotising and coupling from diazotized amino heterocyclic compounds
- C09B29/0062—Monoazo dyes prepared by diazotising and coupling from diazotized amino heterocyclic compounds the heterocyclic ring containing nitrogen and oxygen as heteroatoms
- C09B29/007—Monoazo dyes prepared by diazotising and coupling from diazotized amino heterocyclic compounds the heterocyclic ring containing nitrogen and oxygen as heteroatoms containing a six-membered heterocyclic ring with nitrogen and oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B29/00—Monoazo dyes prepared by diazotising and coupling
- C09B29/24—Monoazo dyes prepared by diazotising and coupling from coupling components containing both hydroxyl and amino directing groups
- C09B29/28—Amino naphthols
- C09B29/30—Amino naphtholsulfonic acid
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本出願は、2018年2月22日に出願された米国仮出願第62/633,648号に対する優先権およびその利益を主張するものであり、その全体が参考として本出願中に取り入れられている。
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、およびR11は、水素、ハロゲン、ヒドロキシル、シアノ、C1~C6アルキル、C1~C6アルコキシ、C1~C6ハロアルキル、およびC1~C6ハロアルコキシから独立して選択され;
R12は、水素、C1~C6アルキル、またはC1~C6ハロアルキルであり;
L1は、-(CH2)m-であり、mは、0~12の整数であり、各々のCH2は、2つの隣り合うCH2基が置き換えられない限り、個々に-O-、-NH(CO)-または-(CO)-NH-で置き換えられ得;
L2は、-(CH2)n-であり、nは、0~12の整数であり、各々のCH2は、2つの隣り合うCH2基が置き換えられない限り、個々に-O-、-NH(CO)-または-(CO)-NH-で置き換えられ得;
L3は、-(CH2)p-であり、pは、0~12の整数であり、各々のCH2は、2つの隣り合うCH2基が置き換えられない限り、個々に-O-、-NH(CO)-または-(CO)-NH-で置き換えられ得;
L4は、C1~C60結合基であり、任意に-O-、-S-、-S(O)-、-S(O)2 -、-N(R)-、-C(=O)-、-C(=O)O-、-OC(=O)-、-N(R)C(=O)-、-C(=O)N(R)-、-OC(=O)O-、-N(R)C(=O)O-、または-OC(=O)N(R)-を含み、各々のRは、HまたはC1~C6アルキルであり;
R13は、キレート基であり;
R14は、前立腺特異的膜抗原(PSMA)に結合できる基である、
の化合物またはその薬学的に許容可能なエステル、アミド、溶媒和物もしくは塩、またはそのようなエステルもしくはアミドの塩、またはそのようなエステルアミドの溶媒和物、または塩を対象とする。
化合物は、標準命名法を用いて記載した。別に定義されない限り、本明細書で使用される全ての技術用語および科学用語は、本発明が属する当業者が一般的に理解するのと同じ意味を有する。
式Iおよび式IIの化合物は、立体中心、立体軸などの1つ以上の不斉元素、例えば不斉炭素原子を含んでいてもよく、その結果、当該化合物は種々の立体異性体形態で存在し得る。これらの化合物は、例えば、ラセミ体または光学活性形態であり得る。2つ以上の不斉元素を有する化合物の場合、これらの化合物は、さらにジアステレオマーの混合物であってもよい。不斉中心を有する化合物については、純粋な形態の全ての光学異性体およびそれらの混合物を、包含する。これらの状況では、単一の鏡像異性体、すなわち光学活性形態は、不斉合成、光学的に純粋な前駆体からの合成、またはラセミ体の分割によって得ることができる。ラセミ体の分割はまた、例えば、分割剤の存在下での結晶化のような従来の方法によって、または、例えばキラルHPLCカラムを使用するクロマトグラフィーによって達成することができる。それらを得るために使用される方法にかかわらず、全ての形態が本明細書で考えられる。
本発明の態様は、以下に示す式Iの化合物、または薬学的に許容可能なエステル、アミド、溶媒和物、またはその塩、あるいはかかるエステルもしくはアミドの塩、またはかかるエステルアミドもしくは塩の溶媒和物を有するエバンスブルー色素の化学結合体を包含する:
式への言及は、全ての下位式への言及を含み、例えば、式Iは、式IIの化合物を含む。本明細書中に開示される化合物は、そのままの化学物質として投与することができるが、好ましくは、医薬組成物として投与される。したがって、本発明は、式Iの化合物などの化合物または化合物の薬学的に許容される塩を少なくとも1つの薬学的に許容される担体と共に含む医薬組成物を包含する。医薬組成物は、唯一の活性剤として式Iの化合物または塩を含むことができるが、少なくとも1つの追加の活性剤を含むことが望ましい。特定の実施形態において、医薬組成物は、単位剤形中に約0.1mg~約2000mg、約10mg~約1000mg、約100mg~約800mg、または約200mg~約600mgの式Iの化合物、および任意に約0.1mg~約2000mg、約10mg~約1000mg、約100mg~約800mg、または約200mg~約600mgの追加の活性剤を含有する剤形である。医薬組成物はまた、式Iの化合物などの化合物、および追加の活性剤のモル比を含み得る。例えば、医薬組成物は、式Iの化合物に対する追加の活性剤の約0.5:1、約1:1、約2:1、約3:1または約1.5:1~約4:1のモル比を含むことができる。
式Iの化合物、ならびに当該化合物を含む医薬組成物は、癌などの疾患の診断または処置に有用である。本発明によれば、前立腺癌を処置する方法は、そのような処置を必要とする患者に、治療有効量の式Iの化合物を提供することを含む。一実施形態では、患者は哺乳動物であり、より具体的にはヒトである。当業者に理解されるであろうように、本発明はまた、コンパニオンアニマル、例えばネコ、イヌ、および家畜動物のような非ヒト患者を処置する方法も包含する。
Boc tert-ブトキシカルボニル
DIPEA ジイソプロピルエチルアミン
DMF N,N-ジメチルホルムアミド
DOTA 1,4,7,10-テトラアザシクロドデカン-1,4,7,10-四酢酸
Fmoc フルオレオキシカルボニルクロリド
HATU 1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム3-オキシドヘキサフルオロホスフェート
HPLC 高速液体クロマトグラフィー
LC-MS 液体クロマトグラフィー/質量分析
PET ポジトロン放出断層撮影
RT 室温
TFA トリフルオロ酢酸
Boc-リシン-Fmocアミノ酸は、AppTechから購入した。DOTA-NHSエステル)は、Macrocyclicsから購入した。その他の溶媒および化学物質はすべて、Sigma-AldrichまたはFisher Scientificから購入した。
ステップ1~2:トリシンLys-Bocの合成
ステップ1:エバンスブルーアミン(EB-NH2)の調製
2-トリシン(4.3g)および塩化メチレン(40ml)を含む100mlの丸底フラスコに、ジ-t-ブチルジカーボネート(4.4g)を加えた。混合物を、室温で一晩撹拌した。反応を濃縮し、残留物をシリカゲル上のクロマトグラフィーにより精製して、N-Boc-2-トリシン3.2gを得た。LC-MS:[MH]+=313.4135(m/z)、計算値:312.1838。
t-Bu-PSMA-617-アミンは、CS Bio Inc.から購入した。SATA(N-スクシンイミジルS-アセチルチオアセテート)は、ThermoFisher Scientificから購入した。PSMA-617は、以下のように3ステップで合成した。
MCG-SHは、Banerjee S.R.et al.“Synthesis and Evaluation of Techmetium-99m- and Rhenium-Labeled Inhibitors of the Prostate-Specific Membrane Antigen(PSMA),J.Med.Chem.2008,51(15),4504-4517に記載された手順に従って調製した。
JHUおよびDOTA-マレイミドからMCG-SHを用いてEB-MCGを合成した。LC-MS:[MH]-=1501.5(m/z)、749.5(m/2)。
EB-MCGは、JHUからのMCG-SHを使用して、EB-PSMA-617について上述したのと同じ方法で合成された。LC-MS:[MH]-=1501.5(m/z)、749.5(m/2)。
4~10μLの86YCl3、90YCl3または177LuCl3のいずれかを、0.5mlの0.4Mの酢酸アンモニウム、PH5.6で希釈した。次に、選択されたリガンド(EB-PSMA-617、EB-MCG、DOTA-PSMA-617またはDOTA-MCG)0.1mgを添加し、80℃で30分間反応を混合した。生成物の純度は、iTLCプレート(Fisher)および0.1Mのクエン酸、pH5を現像溶媒として用い、radio-TLC(AR-2000 Bioscanスキャナー)によりアッセイした。遊離の放射性同位体、約0.9のRf;所望の標識したリガンドのRfは、約0.1であった。
PSMA高レベルを発現するように操作したPSMA+ PC3 PIP細胞(ヒト転移性[骨]前立腺癌-Dr.Martin Pomer,JHUによって本発明者らに提供された)およびPSMA PC3(低いPSMAレベル)細胞を、10%のFBSおよびペニシリン/ストレプトマイシン(100U/mL/100μg/mL)を添加したRPMI 1640培地中で、5%のCO2中で空気中で37℃で培養した。
アッセイの24時間前に、105個のPC3-PIP細胞/ウェルを、24ウェルプレートに分布させた。細胞をPBSでX2洗浄し、次いで18.5KBq/ウェルの86Y-EB-PSMA-617または86Y-EB-MCGを、1%(w/v)ヒト血清アルブミン(HSA)を含有する培地0.5mL中に添加した。各示された時点で、細胞をPBSでX2洗浄し、0.1MのNaOHで溶解した。内在化は、0.5mLの酸性緩衝液(50mMのグリシン、100mMのNaCl、pH2.8)と共に1分間インキュベートし、X2洗浄し、溶解することにより、膜結合トレーサーを除去した後に測定した。細胞溶解物の放射能を、γ-カウンター(Perkin Elmer)で測定した。細胞取り込みおよび細胞内移行値は、加えた放射能のパーセントとして標準化した。各時点を、3つ1組で測定した。遮断試験のために、放射能と共に、10μgの標識していないリガンドを、ウェルに加えた。
上記の各群からの腫瘍組織を、種々の時点で採取し、Z-FIX(Anatec Ltd)で室温で凍結または保存した。厚さ10μmの切片を、クライオマイクロトームを用いてスライド上にマウントした。Ki-67、TUNELおよびH&E染色は、本発明者らの以前の研究に従って実施した(Chen et al.“Novel‘Add-On”Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to theranostic Agents”Journal of Nuclear Medicine 2017,58(4),590-597を参照)。Ki67陽性核の数を、スライド当たり5~6視野、各マウスについて5スライドおよび群当たり3マウスに関して視覚計数により分析した。定量は、Image Jソフトウェア(NIH)を用いて行った。
動物プロトコルは、NIH Clinical Center Animal Care and Use Committee(ACUC)により承認された。雄の無胸腺ヌード/ヌードマウス(5~6週)(Envigo)に、Matrigel(Sigma)1:1中のPC3-PIPまたはPC3細胞のいずれかの5×106個の細胞を右肩に接種した。
48時間の時点での最終スキャンの後、腫瘍、心臓、肺、肝臓、脾臓、胃、腸、膵臓、腎臓、筋肉、骨および血液を、安楽死させたマウスから採取し、秤量し、ガンマカウンターで測定した。結果は、組織1g当たりの注射した投与のパーセンテージ(%ID/g)として標準化される。
PETアッセイは、腫瘍体積が約200~350mm3に達したとき、腫瘍細胞接種後14~17日で実施された。マウスに、0.5nmol(高い比活性)の86Y-EB-PSMA-617(n=5、PC3-PIP;n=5、PC3)または86Y-EB-MCG(n=5、PC3-PIP;n=5、PC3)のいずれかを静脈内注射し、注射後1、4、24および48時間に10~20分間スキャンした(p.i.)。PET検査は、Nanoscan PET/CT(Mediso)およびInveon(Siemens)スキャナーで取得した。3D秩序化サブセット期待最大アルゴリズムを用いて画像を再構成し、ASIPRO(Siemens)を用いてROIを描出し、校正係数を乗じて、臓器(腫瘍および腎臓)における%注射用量/mL(平均値または最大値)を与えた。仮定では、1mLの密度は1gの組織(肺については除外)に等しい。
86Y-EB-MCG、86Y-EB-PSMA-617、および86Y-EB-MCGの腫瘍取り込みは、前述の例の86Y-EB-PSMA-617について記載されている手順に従って決定された。
PC3-PIP異種移植片において腫瘍治療試験を実施して、90Y-EB-PSMA-617、177Lu-EB-PSMA-617対生理食塩水および90Y-DOTA-PSMA-617または177Lu-DOTA-PSMA-617の静脈内注射(複数可)の治療効果を評価した。この試験は、Pc3-PIP異種移植片の接種7日後に開始され、その際全てのマウスは、約100~150mm3の腫瘍体積を有していた。マウスを、以下のようにいくつかのグループに分けた;(1)生理食塩水(n=4)、(2)7.4MBq 90Y-EB-PSMA-617(n=6)、(3)3.7MBq 90Y-EB-PSMA-617(n=6)、(3)18.5MBq 177Lu-EB-PSMA-617(n=6)、(4)7.4MBq 177Lu-EB-PSMA-617(n=6)、(5)7.4MBq 90Y-DOTA-PSMA-617(n=6)および18.5MBq 177Lu-DOTA-PSMA-617(n=6)。マウスには、0日目(処置の開始)に単回注射を行った。すべての生きているマウスを、50日間モニターした。マウスの体重および腫瘍体積を、実験を通して3~7日ごとにモニターした。腫瘍体積の計算に用いた式は、V=幅2×長さ/2であった。
EB-MCG/DOTA-MCG誘導体を用いた実験は、前の実施例で述べた手順と同様に行った。
Claims (16)
- 式I
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、およびR11は、水素、ハロゲン、ヒドロキシル、シアノ、C1~C6アルキル、C1~C6アルコキシ、C1~C6ハロアルキル、およびC1~C6ハロアルコキシから独立して選択され;
R12は、水素、C1~C6アルキル、またはC1~C6ハロアルキルであり;
L1は、-(CH2)m-であり、mは、0~12の整数であり、各々のCH2は、2つの隣り合うCH2基が置き換えられない限り、個々に-O-、-NH(CO)-または-(CO)-NH-で置き換えられ得;
L2は、-(CH2)n-であり、nは、0~12の整数であり、各々のCH2は、2つの隣り合うCH2基が置き換えられない限り、個々に-O-、-NH(CO)-または-(CO)-NH-で置き換えられ得;
L3は、-(CH2)p-であり、pは、0~12の整数であり、各々のCH2は、2つの隣り合うCH2基が置き換えられない限り、個々に-O-、-NH(CO)-または-(CO)-NH-で置き換えられ得;
L4は、-(CH2)q-であり、qは、0~12の整数であり、各々のCH2は、2つの隣り合うCH2基が置き換えられない限り、個々に-O-、-NH(CO)-または-(CO)-NH-で置き換えられ得;
R13は、
R14は、
の化合物またはその薬学的に許容可能な溶媒和物もしくは塩、またはそのような塩の溶媒和物。 - L1が-NH(CO)-であり、R1およびR4がそれぞれメチルであり、R2、R3、R5、R6、R7、R8、R9、R10、R11およびR12がそれぞれ水素である、請求項1に記載の化合物。
- R14が放射性核種をさらに含む、請求項1に記載の化合物。
- 前記放射性核種が18F、76Br、124I、125I、または131Iである、請求項4に記載の化合物。
- R13が放射性核種をさらに含む、請求項1に記載の化合物。
- 前記放射性核種が64Cu、67Cu、90Y、86Y、111In、186Re、188Re、89Zr、99Tc、153Sm、213Bi、225Ac、177Luまたは223Raである、請求項7に記載の化合物。
- 前記放射性核種が86Y、90Y、または177Luである、請求項8に記載の化合物。
- 請求項1に記載の化合物を薬学的に許容される担体と共に含む、医薬組成物。
- 前記薬学的に許容される担体が、結合剤、緩衝剤、着色剤、希釈剤、崩壊剤、乳化剤、香味剤、流動促進剤、滑沢剤、保存剤、安定剤、界面活性剤、錠剤化剤、および湿潤剤、ならびにそれらの組み合わせからなる群より選択される、請求項13に記載の医薬組成物。
- 哺乳動物における前立腺癌の処置または診断に使用するための、任意に1つ以上の追加の活性成分と組み合わせた、請求項13または14に記載の医薬組成物。
- 前記1つ以上の追加の活性成分が、ドキソルビシン、パクリタキセル、ドセタキセル、シスプラチン、カンプトテシン、テモゾロミド、アバスチン、ハーセプチン、アービタックス、およびそれらの組み合わせを含む、請求項15に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862633648P | 2018-02-22 | 2018-02-22 | |
US62/633,648 | 2018-02-22 | ||
PCT/US2019/019140 WO2019165200A1 (en) | 2018-02-22 | 2019-02-22 | Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents for targeting prostate cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021513979A JP2021513979A (ja) | 2021-06-03 |
JP7449864B2 true JP7449864B2 (ja) | 2024-03-14 |
Family
ID=67687409
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020543529A Active JP7449864B2 (ja) | 2018-02-22 | 2019-02-22 | エバンスブルー誘導体の化学結合体ならびに前立腺癌を標的とするための放射線療法および造影剤としてのその使用 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20210008232A1 (ja) |
EP (1) | EP3755321A4 (ja) |
JP (1) | JP7449864B2 (ja) |
KR (1) | KR20200124706A (ja) |
AU (1) | AU2019225154A1 (ja) |
CA (1) | CA3090812A1 (ja) |
IL (1) | IL276653A (ja) |
WO (1) | WO2019165200A1 (ja) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3495355A1 (en) | 2013-10-18 | 2019-06-12 | Deutsches Krebsforschungszentrum | Labeled inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer |
EP3310758A1 (en) | 2015-06-22 | 2018-04-25 | The U.S.A. As Represented By The Secretary, Department Of Health And Human Services | Chemical conjugates of evans blue derivatives and their use in the production of long-acting therapeutics |
JP6946342B2 (ja) | 2016-05-09 | 2021-10-06 | ザ ユナイテッド ステイツ オブ アメリカ, アズ リプレゼンテッド バイ ザ セクレタリー, デパートメント オブ ヘルス アンド ヒューマン サービシーズ | エバンスブルー誘導体の化学的コンジュゲート、ならびに放射線治療剤およびイメージング剤としてのそれらの使用 |
EP3692032B1 (en) | 2017-10-03 | 2024-06-19 | The U.S.A. as represented by the Secretary, Department of Health and Human Services | Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents |
CN110898233B (zh) * | 2019-12-12 | 2022-04-05 | 北京肿瘤医院(北京大学肿瘤医院) | 三模态***癌靶向纳米粒子显像剂及其制备方法 |
EP4227300A4 (en) * | 2021-02-10 | 2024-04-24 | Yantai Lannacheng Biotechnology Co Ltd | ASTRIDGED EVANS BLUE MODIFIED FIBROBLAST ACTIVATION PROTEIN INHIBITOR, METHOD OF PREPARING THE SAME AND USE THEREOF |
CN113004371A (zh) | 2021-03-01 | 2021-06-22 | 上海蓝纳成生物技术有限公司 | 一种长循环半衰期的***特异性膜抗原靶向化合物及其制备方法和应用 |
WO2023240135A2 (en) | 2022-06-07 | 2023-12-14 | Actinium Pharmaceuticals, Inc. | Bifunctional chelators and conjugates |
CN115850367B (zh) * | 2023-03-02 | 2023-05-23 | 北京先通国际医药科技股份有限公司 | Psma抑制剂的纯化方法及其用途 |
CN115947775B (zh) * | 2023-03-13 | 2023-06-09 | 北京先通国际医药科技股份有限公司 | 一种制备化合物(i)的方法和化合物(i)及其用途 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010045598A2 (en) | 2008-10-17 | 2010-04-22 | Purdue Research Foundation | Psma binding ligand-linker conjugates and methods for using |
JP2014051442A (ja) | 2012-09-05 | 2014-03-20 | Kyoto Univ | 前立腺がんを診断可能な核医学イメージングプローブ |
CN104650217A (zh) | 2015-01-26 | 2015-05-27 | 汇佳生物科技(上海)有限公司 | 伊文氏蓝或其衍生物修饰的Exendin-4及其制备方法和应用 |
WO2016209795A1 (en) | 2015-06-22 | 2016-12-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chemical conjugates of evans blue derivatives and their use in the production of long-acting therapeutics |
WO2017192874A1 (en) | 2016-05-04 | 2017-11-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Albumin-binding immunomodulatory compositions and methods of use thereof |
WO2017196806A1 (en) | 2016-05-09 | 2017-11-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents |
WO2019070236A1 (en) | 2017-10-03 | 2019-04-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | CHEMICAL CONJUGATES OF EVANS BLUE DERIVATIVES AND THEIR USE AS RADIATION THERAPY AND IMAGING AGENTS |
-
2019
- 2019-02-22 US US16/969,673 patent/US20210008232A1/en active Pending
- 2019-02-22 CA CA3090812A patent/CA3090812A1/en active Pending
- 2019-02-22 EP EP19756548.4A patent/EP3755321A4/en active Pending
- 2019-02-22 KR KR1020207027109A patent/KR20200124706A/ko not_active Application Discontinuation
- 2019-02-22 WO PCT/US2019/019140 patent/WO2019165200A1/en unknown
- 2019-02-22 AU AU2019225154A patent/AU2019225154A1/en active Pending
- 2019-02-22 JP JP2020543529A patent/JP7449864B2/ja active Active
-
2020
- 2020-08-11 IL IL276653A patent/IL276653A/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010045598A2 (en) | 2008-10-17 | 2010-04-22 | Purdue Research Foundation | Psma binding ligand-linker conjugates and methods for using |
JP2014051442A (ja) | 2012-09-05 | 2014-03-20 | Kyoto Univ | 前立腺がんを診断可能な核医学イメージングプローブ |
CN104650217A (zh) | 2015-01-26 | 2015-05-27 | 汇佳生物科技(上海)有限公司 | 伊文氏蓝或其衍生物修饰的Exendin-4及其制备方法和应用 |
WO2016209795A1 (en) | 2015-06-22 | 2016-12-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chemical conjugates of evans blue derivatives and their use in the production of long-acting therapeutics |
WO2017192874A1 (en) | 2016-05-04 | 2017-11-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Albumin-binding immunomodulatory compositions and methods of use thereof |
WO2017196806A1 (en) | 2016-05-09 | 2017-11-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents |
WO2019070236A1 (en) | 2017-10-03 | 2019-04-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | CHEMICAL CONJUGATES OF EVANS BLUE DERIVATIVES AND THEIR USE AS RADIATION THERAPY AND IMAGING AGENTS |
Non-Patent Citations (4)
Title |
---|
Cindy J. Choy et al.,177Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice,Theranostics ,2017年,7(7),1928-1939,DOI: 10.7150/thno.18719 |
Martina Benesova et al.,Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer,Journal of Nuclear Medicine ,2015年,56(6),914-920,DOI: 10.2967/jnumed.114.147413 |
Zhantong Wang et al.,Radioligand Therapy of Prostate Cancer with a Long-Lasting Prostate-Specific Membrane Antigen Targeting Agent 90Y-DOTA-EB-MCG,Bioconjugate Chemistry ,2018年,29(7),2309-2315,DOI: 10.1021/acs.bioconjchem.8b00292 |
Zhantong Wang et al.,Single Low-Dose Injection of Evans Blue Modified PSMA-617 Radioligand Therapy Eliminates Prostate-Specific Membrane Antigen Positive Tumors,Bioconjugate Chemistry ,2018年,29(9),3213-3221,DOI: 10.1021/acs.bioconjchem.8b00556 |
Also Published As
Publication number | Publication date |
---|---|
KR20200124706A (ko) | 2020-11-03 |
AU2019225154A1 (en) | 2020-09-10 |
EP3755321A4 (en) | 2021-11-24 |
IL276653A (en) | 2020-09-30 |
WO2019165200A1 (en) | 2019-08-29 |
CA3090812A1 (en) | 2019-08-29 |
JP2021513979A (ja) | 2021-06-03 |
EP3755321A1 (en) | 2020-12-30 |
US20210008232A1 (en) | 2021-01-14 |
CN111741751A (zh) | 2020-10-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7449864B2 (ja) | エバンスブルー誘導体の化学結合体ならびに前立腺癌を標的とするための放射線療法および造影剤としてのその使用 | |
EP3455206B1 (en) | Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents | |
TWI657827B (zh) | 用於正子斷層掃描之化合物 | |
EP2170075B1 (en) | Labeled inhibitors of prostate specific membrane antigen (psma), biological evaluation, and use as imaging agents | |
CN106660943B (zh) | 用于psma靶向的成像和放射疗法的金属/放射性金属标记的psma抑制物 | |
EP3692032B1 (en) | Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents | |
EP3209336B1 (en) | 18f-tagged inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer | |
CA2996330A1 (en) | 18f-tagged inhibitors of prostate specific membrane antigen (psma) and their use as imaging agents for prostate cancer | |
JP2022548749A (ja) | 画像化及び治療用組成物 | |
AU2015203742A1 (en) | Labeled inhibitors of prostate specific membrane antigen (psma), biological evaluation, and use as imaging agents | |
CN111741751B (zh) | 伊文思蓝衍生物的化学缀合物及其作为靶向***癌的放射疗法和显像剂的用途 | |
JP2023554079A (ja) | リガンド及びそれらの使用 | |
US20220402951A1 (en) | Radioisotope labeled compound for imaging or treatment of prostate cancer | |
CN116217505A (zh) | 用于诊断或治疗表达***特异性膜抗原癌症的新型标记靶向剂 | |
KR20230082178A (ko) | Her2-발현 암의 광역동 치료용 조성물 및 이의 용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211228 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20221215 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230207 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230508 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230529 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230620 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230920 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231024 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240122 |
|
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: 20240206 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240304 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7449864 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |