MXPA98002107A - Biotin derivatives marked radiactivame - Google Patents
Biotin derivatives marked radiactivameInfo
- Publication number
- MXPA98002107A MXPA98002107A MXPA/A/1998/002107A MX9802107A MXPA98002107A MX PA98002107 A MXPA98002107 A MX PA98002107A MX 9802107 A MX9802107 A MX 9802107A MX PA98002107 A MXPA98002107 A MX PA98002107A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- composition
- labeled
- biotin
- living
- Prior art date
Links
- 125000004057 biotinyl group Chemical class [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 title description 2
- 229960002685 biotin Drugs 0.000 claims abstract description 81
- 235000020958 biotin Nutrition 0.000 claims abstract description 81
- 239000011616 biotin Substances 0.000 claims abstract description 81
- -1 biotin compound Chemical class 0.000 claims abstract description 78
- 239000000203 mixture Substances 0.000 claims abstract description 58
- 229910052751 metal Inorganic materials 0.000 claims abstract description 41
- 239000002184 metal Substances 0.000 claims abstract description 41
- 125000004429 atoms Chemical group 0.000 claims abstract description 32
- 239000002738 chelating agent Substances 0.000 claims abstract description 30
- 230000002285 radioactive Effects 0.000 claims abstract description 9
- 230000005298 paramagnetic Effects 0.000 claims abstract description 8
- 229910052692 Dysprosium Inorganic materials 0.000 claims abstract description 7
- 229910052691 Erbium Inorganic materials 0.000 claims abstract description 7
- 229910052688 Gadolinium Inorganic materials 0.000 claims abstract description 7
- 229910052689 Holmium Inorganic materials 0.000 claims abstract description 7
- 229910052779 Neodymium Inorganic materials 0.000 claims abstract description 7
- 229910052777 Praseodymium Inorganic materials 0.000 claims abstract description 7
- 229910052772 Samarium Inorganic materials 0.000 claims abstract description 7
- 229910052771 Terbium Inorganic materials 0.000 claims abstract description 7
- 229910052769 Ytterbium Inorganic materials 0.000 claims abstract description 7
- 229910052804 chromium Inorganic materials 0.000 claims abstract description 7
- 229910052803 cobalt Inorganic materials 0.000 claims abstract description 7
- 229910052802 copper Inorganic materials 0.000 claims abstract description 7
- 229910052742 iron Inorganic materials 0.000 claims abstract description 7
- 229910052748 manganese Inorganic materials 0.000 claims abstract description 7
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 7
- 239000012217 radiopharmaceutical Substances 0.000 claims abstract description 6
- 230000002799 radiopharmaceutical Effects 0.000 claims abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
- 238000003745 diagnosis Methods 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 24
- 108090001008 Avidin Proteins 0.000 claims description 21
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 21
- 229920001184 polypeptide Polymers 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 17
- 239000004615 ingredient Substances 0.000 claims description 11
- 238000001514 detection method Methods 0.000 claims description 10
- 239000003638 reducing agent Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 7
- 239000000523 sample Substances 0.000 claims description 7
- 210000004369 Blood Anatomy 0.000 claims description 6
- 108010090804 Streptavidin Proteins 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- 230000000240 adjuvant Effects 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- FXUHHSACBOWLSP-UHFFFAOYSA-N oxido(trioxo)technetium Chemical class [O-][Tc](=O)(=O)=O FXUHHSACBOWLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000969 carrier Substances 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 238000005755 formation reaction Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 230000001225 therapeutic Effects 0.000 claims description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical class CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims description 3
- NKIJBSVPDYIEAT-UHFFFAOYSA-N 1,4,7,10-tetrazacyclododec-10-ene Chemical compound C1CNCCN=CCNCCN1 NKIJBSVPDYIEAT-UHFFFAOYSA-N 0.000 claims description 2
- MRLKMCJVGAIGGE-UHFFFAOYSA-N 1,4,8,11-tetrazacyclotetradec-10-ene Chemical compound C1CNCCNCCCN=CCNC1 MRLKMCJVGAIGGE-UHFFFAOYSA-N 0.000 claims description 2
- GRUVVLWKPGIYEG-UHFFFAOYSA-N 2-[2-[carboxymethyl-[(2-hydroxyphenyl)methyl]amino]ethyl-[(2-hydroxyphenyl)methyl]amino]acetic acid Chemical compound C=1C=CC=C(O)C=1CN(CC(=O)O)CCN(CC(O)=O)CC1=CC=CC=C1O GRUVVLWKPGIYEG-UHFFFAOYSA-N 0.000 claims description 2
- WTHDJYYROCOPPR-UHFFFAOYSA-N 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclotridec-1-yl]acetic acid Chemical compound OC(=O)CN1CCCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WTHDJYYROCOPPR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 229960000958 Deferoxamine Drugs 0.000 claims description 2
- 229940022766 EGTA Drugs 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 241000406221 Hypostomus robinii Species 0.000 claims description 2
- JVHROZDXPAUZFK-UHFFFAOYSA-N TETA Chemical compound OC(=O)CN1CCCN(CC(O)=O)CCN(CC(O)=O)CCCN(CC(O)=O)CC1 JVHROZDXPAUZFK-UHFFFAOYSA-N 0.000 claims description 2
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000001588 bifunctional Effects 0.000 claims description 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 2
- 230000005251 gamma ray Effects 0.000 claims 3
- RAEOEMDZDMCHJA-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-[2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]ethyl]amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CCN(CC(O)=O)CC(O)=O)CC(O)=O RAEOEMDZDMCHJA-UHFFFAOYSA-N 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 125000005647 linker group Chemical class 0.000 claims 1
- 229910052709 silver Inorganic materials 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- 150000001615 biotins Chemical class 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 229960003330 Pentetic Acid Drugs 0.000 description 4
- 210000002966 Serum Anatomy 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- KCSKCIQYNAOBNQ-YBSFLMRUSA-N biotin sulfoxide Chemical compound N1C(=O)N[C@H]2CS(=O)[C@@H](CCCCC(=O)O)[C@H]21 KCSKCIQYNAOBNQ-YBSFLMRUSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VJSYOIXZCBUUJP-RJNKSYOCSA-N C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@H]12)(=O)S(=O)C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@H]12)=O Chemical compound C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@H]12)(=O)S(=O)C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@H]12)=O VJSYOIXZCBUUJP-RJNKSYOCSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
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- 239000008079 hexane Substances 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 229960000060 monoclonal antibodies Drugs 0.000 description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
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- 210000001519 tissues Anatomy 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N Gentisic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
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- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
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- HNKJADCVZUBCPG-UHFFFAOYSA-N methylsulfanylbenzene Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
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- PVMDAMXGKHIMSQ-YDHLFZDLSA-N 4-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC(=O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1 PVMDAMXGKHIMSQ-YDHLFZDLSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesions Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- NJRWNWYFPOFDFN-UHFFFAOYSA-L phosphonate(2-) Chemical compound [O-][P]([O-])=O NJRWNWYFPOFDFN-UHFFFAOYSA-L 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate dihydrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 1
- FJFIOAKCGFEILW-UHFFFAOYSA-N thian-2-imine Chemical class N=C1CCCCS1 FJFIOAKCGFEILW-UHFFFAOYSA-N 0.000 description 1
- CNHYKKNIIGEXAY-UHFFFAOYSA-N thiolan-2-imine Chemical class N=C1CCCS1 CNHYKKNIIGEXAY-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
The invention relates to a labeled biotin compound, wherein said biotin compound is represented by the general formula (I): wherein: n is 1 or 2, R is a chelator group for chelating a metal atom, and Sp is a spacer group having at least 4 atoms that separate NH from R, and wherein said biotin compound is labeled with a metal atom selected from a) the group consisting of the radioactive isotopes 99mTc, 203Pb, 66Ga, 67Ga, 68Ga, 72As, 111In, 113mN, 114mN, 97Ru, 62Ru, 62Cu, 64Cu, 52Fe, 52mMn, 51Cr, 186Re, 188Re, 77As, 90Y, 67Cu, 169Er, 117mSn, 121Sn, 127Te, 142Pr, 143Pr, 198Au, 199Au, 149Tb, 161Tb, 109Pd, 165Dy, 149Pm, 151Pm, 153Sm, 157Gd, 166Ho, 172Tm, 169Yb, 177Lu, 105Rh and 111Ag or b) the group consisting of the paramagnetic metal atoms Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Yb, Gd, Tb, Dy, Ho and Er, said metal atom being fixed to the biotin compound by means of said chelator group, the invention also refers to a composition farm which comprises the labeled biotin compound, the use of said composition for diagnosis and therapy, and a device for preparing a radiopharmaceutical composition.
Description
BIOTIN DERIVATIVES RADIATELY MARKED
DESCRIPTIVE MEMORY
The present invention relates to labeled biotin compounds, to a method for preparing these compounds, to a pharmaceutical composition comprising these compounds, to the use of this composition for diagnosis and therapy and to a device for preparing a radiopharmaceutical composition. It is well known in the art that various polypeptides or proteins such as monoclonal antibodies (MAb's), bind with high affinity to antigens associated with tumors. Consequently, radiolabelled monoclonal antibodies (MAb * 's) have been used successfully for the ijn localization of tumors in nuclear medicine. One of the main disadvantages in the use of MAb * 's is its prolonged blood purification. As a result, deficient tumor / background ratios are usually achieved and the radiation dose to normal tissues is high. A promising development in the application of MAb * 's in nuclear diagnostics is the pre-identification approach. According to this method, administration of the tumor specific protein (antibody) and radioactivity takes place at separate time points. This methodology is possible through the use of an avidin / biotin system. There are two different basic protocols that can be used for tumor localization with this avidin / biotin pre-identification system (Paganelli et al., Nucí, Med.Com.12, 1991, 211-234), namely, the Two-step and three-step approach. In the two-step approach, a conjugate prepared in. (strept) avidin and the tumor-seeking prolypeptide, e.g., the antibody, is injected first, followed two or three days later by injection with radiolabeled biotin. Using the three-step pre-identification approach, biotinylated MAb (first step), streptavidin (second step) and radiolabeled biotin (third step) are injected successively (at time intervals of approximately 24 hours) to the patient. The first steps, as well as the first step in the two-step approach, result in the avidinidation of the tumor. In addition, biotinylated MAbs, which have not been located in the tumor but still circulate in the blood, are macroaggregated by excess avidin. These avidin / high molecular weight MAb adducts are rapidly assimilated and catabolized by the liver. The third step includes the in vivo administration of radiolabeled biotin. Due to the rapid clearance of blood from the biotin derivative not bound to the tumor, it is expected to quickly achieve adequate tumor / fundus relationships. For the visualization of tumors, biotin labeled with a radionuclide, preferably a metal radionuclide, or with a paramagnetic metal ion is required. Since biotin lacks functional groups suitable for a stable metal bond, a bifunctional ligand suitable for biotin has to be coupled to make possible the labeling with the desired metal atom. Biotin derivatives labeled with radioactive metal are described in the literature, e.g., in the U.S. patent. No. 5,283,342, in WO 93/25240, and by Koch and Mácke (Angew. Chemie, Int. Ed. 31, 1992, 1507-1509). Vizzi et al. (J. Nucí.
Med. 32, 1991, 920-Proc. 39th Ann. Mt., no. 403) who have evaluated 12 different biotin derivatives labeled with technetium-99m. The conclusion of these authors is that biotin derivatives labeled with Tc-99m show instability in vivo, as a consequence of which high levels of Tc-99m are found in normal tissues. The aim of the present invention is to provide a labeled biotin compound having a high affinity to avidin, comparable to that of biotin itself, and having improved in vivo stability, i.e., improved resistance to enzymatic cleavage, for allow its proper use in diagnosis and therapy. This objective can be achieved by means of a labeled biotin compound, wherein said biotin compound is represented by the general formula
CD wherein: n is 1 or 2, R is a chelator group for chelating a metal atom, and Sp is a spacer group having at least 4 atoms that separate NH from R; and wherein said biotin compound is labeled with a metal atom selected from (a) the group consisting of the radioactive isotopes 9 m "rc, 203Pb," Ga, 6? Ga, 68Ga,? 2AS. min, 113-? in, ?? «« ln, 9? Ru, «CU, ** CU, S2pe, 52« "Mn, sicr, ißßRe,
188Re,? 7As > 90Y > 67 U, 169Er, l "» Sn, 121Sn, 127Te 142pr> l * 3pr> 198Au> 199Au> 149Tb, 61Tb, l ° 9Pd, 16 * Dy, 149p |? L, 15lpm> 153Sm, 157Gd , 166H0,? 2Tm, 69Yb, 175? B, 177Lu> 105Rh and 111 Ag or (b) the group consisting of the paramagnetic metal atoms Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm , Yb, Gd, Tb, Dy, Ho and Er, said metal atom is fixed to the biotin compound by means of said chelating group The separating group Sp defined above is preferably a group of the general formula
wherein A is a biradical of the formula -NH- (CH2) - or -NH-C (= X) - (CH-2) xY- (CH2) mC (C02H) H- where x and y are each independently 0 or 1; m is an integer from 1 to 4; p is an integer from 0 to 4; X is 0 or S; and Y is NH, CO or S. The chelator group R defined above is preferably selected from the group consisting of Nt PS (4-tq) tetradentation chelating agents, wherein t + q = 2-4, or groups derived from Ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), cyclohexyl acid
1,2-diaminotetracetic acid (CDTA), ethylene glycol-0,0 '-bis (2-aminoethyl) -N, N, N', N '-tetraacetic acid (EGTA), N, N-bis (hydroxybenzyl) ethylenediamine- N, N'-diacetic (HBED), triethylenetetraaminehexaacetic acid (TTHA), 1,4,7,10-tetraazacyclododecane-N, N ', N ", N' '' -tri- and tetraacetic acid (D03A and
DOTA), l, 4,7,10-tetraazacyclotidecane-N, N ', N ", N"' -tri- and tetraacetic acid (TRI3A and TRITA), hydroxyethyldiaminotriacetic acid (HEDTA), acid 1,4,8,11 -tetra-azacyclotetradecane-N, N ', N ", N"' -tetraacetic (TETA), substituted DTPA, substituted EDTA, or from deferoxamine
(deferrioxamine) or a compound of the general formula
wherein Ri is an optionally substituted, branched or unbranched hydrocarbyl radical, which may be interrupted by one or more heterogeneous atoms selected from N, 0 and S and / or by one or more NH groups, and Q is a group that is capable of reacting with an amino group of the peptide and which is preferably selected from the group consisting of carbonyl, carbimidoyl, N-alkylcarbimidoyl of Ci-C, N-hydroxycarbimidoyl and N-alkoxycarbimidoyl of Ci-Ce. Suitable examples of NtPqS tetradentate chelating agents (A-t-q) are selected from
* (VIID (IX) 00
wherein: R6-R20 are each individually hydrogen atoms or C1-C4 alkyl groups, with the proviso that at least one of Ce to C9 is the symbol Y; R21 is a hydrogen atom or a CO2 alkyl group of Ci-C4; R22 and R23 are each individually alkylcarbonyl groups of Ci-C, benzoyl or benzyl; v is 0 or 1; s is 2 or 3; R24 is CH2COOH or a functional derivative thereof; A is C 1 -C 4 alkylene, if desired substituted with C 1 alkyl, CH 2 C 0 alkyl, CONH 2, CONHCH 2 CO 2 alkyl; phenylene, phenylene substituted by C02alkyl, wherein the alkyl groups have 1 to 4 carbon atoms; G is NH or S; And it is a union of valence or a functional group capable of linking with the separating group; and Z is S u 0.
If Y is a functional group, Y preferably comprises isocyanato, isothiocyanato, formyl, o-halógenonitrofenilo, diazonium, epoxy, trichloro-s-thiazinyl, ethyleneimino, chlorosulfonyl, alcoxicarbimidoilo, alquilcarboniloxicarbonilo (substituted or unsubstituted), alquilcarbonilimidazolilo, succini ido-oxycarbonyl, group preferably fixed to a biradical C1-C10 hydrocarbon. Suitable examples of hydrocarbon biradicals are biradicals derived from benzene, Ci-Cβ alkanes, C-C alkenes and C 1 -C 4 alkylbenzenes. Examples of suitable chelating agents of the general formula III are described in the international patent application WO 89/07456, such as 2-iminothiolanes and substituted or unsubstituted 2-iminothiacyclohexanes, in particular 2-imino-4-mercaptomethylthiolane. The above-labeled biotin compounds have been tested in a number of suitable model experiments that are predictive for iri vivo application. These experiments are described in the examples. From the results of these experiments it will be evident that the labeled biotin compounds of the present invention have properties that make them suitable for diagnostic and therapeutic purposes. If labeled with an appropriate atom for diagnostic purposes, the labeled biotin compound remains intact long enough after its administration to allow image formation of the target tumor without presenting a disturbing fundus. If labeled with a suitable radioisotope for therapy, said labeled biotin compounds are promising therapeutic agents for the treatment of a number of malignant tumors. The novel metal-labeled biotin compounds of the invention can be prepared in a manner known per se for the related compounds. For this purpose, the biotin molecule is derived with the desired chelating agent as defined above, eg, a tetradentate chelating agent of NtPqS (4-tq or EDTA, DTPA, etc., after the introduction of the group Sp separator as defined above, after which the obtained compound having the general formula
wherein: n is 1 or 2, R is a chelator group for chelating a metal atom, and Sp is a spacer group having at least 4 atoms that separate NH from R; it is brought into reaction with a metal, as defined herein above, in the form of a salt or a chelate linked to a comparatively weak chelator to form a complex. Suitable examples of salts or chelates of the desired metal are citrate and min acetate, 99mTc tartrate, etc.
The complex forming reaction can be carried out generally in a simple manner and under moderate conditions. The invention also relates to a biotin compound of the general formula I as defined above, which can be used for the above-described method of preparing a labeled biotin compound. The present invention further relates to a pharmaceutical composition comprising a labeled biotin compound as defined above, in addition to a pharmaceutically acceptable carrier and, if desired, at least one pharmaceutically acceptable auxiliary as the active substance. The invention also relates to a method for detecting and locating tumors in the body of a warm-blooded living being, which comprises (i) administering to said being a composition comprising (strept) avidin conjugated to a polypeptide having an affinity selective to said tumor, (ii) subsequently, after the avidination of said tumor, to administer to said being a composition comprising, in an amount sufficient for external imaging, a biotin compound labeled as defined hereinbefore said biotin compound being labeled with (a) a radioactive metal isotope selected from the group consisting of 9 * "Tc, 203pD, s ^ Ga, 6? Ga, 68 Ga. 72As,? nin> g3min) 97RU > 62r, u, 64 <; u, sape, 52 Mn &siCr, or (b) with a paramagnetic metal atom selected from the group consisting of Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Yb, Gd, Tb, Dy, Ho and Er, and (iii) finally submitting said being to a training of external image to determine the identified sites in the body of said being in relation to the background activity. In place of the previous two-step protocol, the three-step re-identification method such as that described hereinabove can also be used. In this method the following protocol is used: (i-a) administering to said being a composition comprising a biotinylated polypeptide having a selective affinity to said tumor, (i-b) then administering a composition comprising (strept) avidin; both steps in substitution of step (i) above. The invention also relates to a method for detecting and localizing tumors intraoperatively in the body of a warm-blooded living being, which comprises (i) administering to said being a composition comprising (strept) avidin conjugated to a polypeptide having a selective affinity to said tumor, (ii) subsequently, after the avidination of said tumor, administer to said being a composition comprising, in an amount sufficient for detection by means of a gamma detection probe, a biotin compound labeled as that defined hereinbefore, said biotin compound being labeled with i6iT, and (iii) finally, after allowing said active substance to be bound and assimilated by said tumor and after purification of blood from radioactivity, subjecting said to be a radioimmunodetection technique in the relevant area of the body of said being, using a gamma detection probe. The above radioisotope, namely i6itb, allows the use of said labeled peptide compound in the technique of radioguided surgery, in which the relevant tissues of a patient's body can be detected and located intraoperatively by means of a probe. detection range. The surgeon can use this probe intraoperatively to find the lesions in which the assimilation of the compound labeled with said radioisotope has taken place., which is a low energy gamma photon emitter. It will be clear that instead of the previous two-step protocol, the three-step re-identification method such as the one mentioned above can be used here. The biotin compounds of the present invention, as long as they are radioactively labeled with isotopes suitable for that purpose, can be used for the therapeutic treatment of tumors. Therefore, the invention also relates to a method for the therapeutic treatment of tumors in the body of a warm-blooded living being, comprising (i) administering to said living being a composition comprising (strept) avidin conjugated to a polypeptide having a selective affinity for said tumor, (ii) after which, after treating said tumor with avidin, administering to said being a composition comprising, in an amount effective to combat or control tumors, a biotin compound labeled as defined above, said biotin compound being labeled with a metal isotope selected from the group consisting of H4"ln, ßßRe, 188Re, 77AS) 9 ??, 66Ga, 67 u, 9Er, H sn, i2isn, 27j ,
142pr > 143pr > 198AU, U, l * 9Tb, 161 T »109 d, 165Dy, * pm > 151Pm, 153Srn, 157Qd, 59Gd, 66H ?, 2Trn > 169Y, 175Yb, 177 U, 105Rh and niAg. It will be clear that instead of the previous two-step protocol, the three-step pre-marking method can be used as described above. In case a radiolabeled biotin compound is used as a diagnostic agent, it is often impossible to make the composition ready for use by the user in relation to the storage life with poor frequency of the radiolabelled compound and / or the short half-life of the radionuclide used. In these cases, the user will carry out the labeling reaction with the radionuclide in the clinical hospital or laboratory. For this purpose, the different reaction ingredients are then offered to the user in the form of a so-called "equipment". It will be obvious that the manipulations necessary to carry out the desired reaction should be as simple as possible to allow the user to prepare, using the equipment, the radioactive composition marked using the facilities that are available to him. Therefore, the invention also relates to a device for preparing a radiopharmaceutical composition. Said kit according to the present invention may comprise (a) a composition comprising (strept) avidin conjugated to a polypeptide having a selective affinity for tumors, (b) a biotin compound of the general formula I, shown above, in wherein the symbols have the above meanings, to which compound, if desired, a pharmaceutically acceptable inert carrier and / or formulation agents and / or adjuvants can be added, (c) a solution of a salt or chelate of a selected metal isotope. of the group consisting of 203 p > 6ßG, 67Qa, 68Ga, 72As, lllm, H3mIn, H * mln, 97RU > 62 U, 99 Tc, ißßRe, ißßRe, 6"cu," Fßf S2mMn, siCr, 77As, 0Y> 67CU, 169EG >
H7mSn, 21Sn, 12 Te, l «Pr > 143pr > 198Au, 199Au, l? 9Tb > 161Tb > 109pd, 165Dy, 14pm, ldlpm, 153Sm, 5d, 166HO, 1 2T, 169Yb, i75Yb, i77 | _u,? ° 5Rh and? A? Ag, and (d) instructions for use with a prescription to react the ingredients present in the equipment. Preferably, the biotin compound to be used as an ingredient of the above equipment has been modified by a spacer group Sp and a chelating agent R as defined above. The resulting biotin compound provides a means to firmly attach the radionuclide in a simple manner. Suitable chelating agents for modifying the biotin molecule were described in detail above. The tetradentate chelating agents of N? PqS (Atq) or di-or polyacetic acids containing N or their derivatives, such as the compounds mentioned above, have proven to be pre-eminently suitable for joining various metal radionuclides, such as In-111 and In-113m, to the biotin molecule. The equipment to be provided to the user may also comprise the ingredient (s) defined sub (a) and (b) above (s), together with instructions for use, while the solution of a salt or chelate of the radionuclide, defined sub (c) above, whose solution has a limited storage life, can be provided separately at the user's disposal. The above equipment is intended for use in a two-step protocol. If, instead of the same, the three-step pre-identification method is used, as described above, the following equipment is suitable: (ai) a composition comprising a biotinylated polypeptide having a selective affinity for said tumor, and (a-ii) a composition comprising (strept) avidin; both compositions replace the previous composition (a). In case the equipment serves to prepare a radiopharmaceutical composition labeled with Tc-99m, Re-186 or Re-188, said equipment according to the present invention may comprise, in addition to the ingredient (s) defined sub (a) and (b) above, (c) a reducing agent and, if desired, a chelating agent, and (d) instructions for use with a prescription to react the ingredients of the equipment with Tc-99m in the form of a pertechnetate solution, or with Re-186 or Re-188 in the form of a perrhenate solution. If desired, certain ingredients of the equipment can be combined, as long as they are compatible. The pertechnetate or perrhenate solution can be obtained simply by the user from a suitable provider. When the radionuclide is present in the equipment itself, the reaction which forms the complex with the biotin compound of the general formula I above can be produced simply by combining the components in a neutral or pH-regulated medium and causing them to react. For that purpose, the radionuclide can be presented with said biotin compound in the form of a chelate attached to a comparatively weak chelating agent, as described above. When the kit comprises a biotin compound as defined above and is intended to prepare a radiopharmaceutical composition, labeled with Tc-99m, Re-186 or Re-188, the radionuclide will preferably be added separately in the form of a pertechnetate solution or perrhenate. In that case, the equipment will comprise a suitable reducing agent and, if desired, a chelating agent, the first to reduce the pertechnetate or the perrhenate. As reducing agent, for example, a reducing agent of dithionite or a reducing agent can be used. metal. As the reducing agent for the aforementioned equipment, a metallic reducing agent is preferably used, for example Sn (II), Ce (III), Fe (II), Cu (I), Ti (III) or Sb (III); Sn (II) is excellently adequate. Examples of suitable Sn (II) compounds are SnCl2, Sn (II) tartrate, Sn (II) phosphonate or pyrophosphate and Sn (II) glucoheptonate. The modified biotin constituent of the aforementioned equipment, ie, preferably the biotin compound, can be provided as a solution, for example, in the form of a physiological saline solution, or in some pH buffer solution, or it can be present in a dry condition, for example, in a lyophilized condition. When used as a component for an injectable liquid it must be sterile, in which case, when the constituent is in the dry state, the user should preferably use a sterile physiological saline solution as a solvent. If desired, the above-mentioned constituent can be stabilized in the conventional manner with suitable stabilizers, for example, ascorbic acid, gentisic acid, or salts of these acids, or can comprise other auxiliary agents, for example, fillers, such as glucose, lactose , mannitol, and the like. The invention will now be described in greater detail in relation to the following specific examples.
EXAMPLE I
Synthesis of 6- (biotinyl N-sulfoxide) -p-aminobenzyl) - 1,4,8,11-tetraazaundecane (6) (Fig. 1)
Fig. 1. Biotin-N-sulphoxide "Biotin sulfoxide is synthesized in accordance with
Melville (D.B.Melville, J. Biol. Chem., 1954, 208, 495). Sulfoxide exists in two isomeric forms: biotin sulphoxide a - (+) and biotin sulphoxide &- (-) (Fig. 2).
Figure 2. Two isomeric forms of biotin sulfoxide. They can be separated by fractional crystallization and / or silica gel chromatography.
6- (p-nitro-benzyl) -l, 4,8, 11-tetraaza-5,7-dioxoundecane (1) 4 moles (1.07 g) of diethyl ester of p-nitrobenzylmalonic acid are suspended (G. Ruser et al. Bioconj. Chem. 1990, 2, 345) in 40 ml of methanol; 5.3 ml (80 mmoles) of ethylendia ina are added, and the mixture is heated under reflux for 12 hours. The solvent and excess ethylene diamine are evaporated, and the crude product is purified by silica gel chromatography (CHCl3 / MeOH / NH3 (25%) = 5: 5: 1, Rf = 0.3). Yield: 1.4 g. MS (FAB) m / z (relative intensity): 324 (MH +, 100); 1 H NMR (300 MHz; de-DMSO). 8.14 (d, 2H, o-Ar-H-), 8.04 (t, 2H, CH2-NH-C0),
7. 46 (d, 2H, m-Ar-H), 3.45 (t, 1H, CH-CH2-Ar), 3.15 (d, 2H, CH2-Ar), 3.05 (m, 4H, CH2-NH-), 2.50 (m, 4H, CH-NH2); 13 C-NMR (90 MHz dβ-DMSO): 168.25 (2C, C = 0), 147.71 (1C, C (Ar) -N02), 145.86 (1C, CH 2 -C (Ar)), 129.95 (2C, Ar) , 123.06 (2C, Ar), 54.00 (1C, CH-CH2-Ar), 41.93 (2C, CH2-NH (C0)), 40.86 (2C, CH2-NH2),
34. 48 (1C, CH2-Ar) The elemental analysis corresponds to CHH21N5O4.
6- (p-nitrobenzyl) -l, 4,8fll-tetraazaundecane (2) The crude extract (1) (480 mg, 1.48 mmole) is reacted at room temperature with 1M BH3 / THF solution (30 ml, 20 ml). eq), and the reaction mixture is refluxed for 60 hours. To decompose the excess BH3, MeOH is added dropwise with care to the reaction mixture, which is previously cooled to 0 ° C. The MeOH is evaporated in vacuo, and the residue is suspended in EtOH, and treated with sound for several minutes. The undissolved part is filtered, and the HCl gas is introduced for 20 minutes to the filtrate. The formed precipitate is collected and further purified by column chromatography (SiO2; CHCl3 / MeOH / 25% NH3, 5/5/2). The resulting purified amine is dissolved in EtOH, and the corresponding hydrochloric salt is obtained as a white solid by passing HCl gas to this solution (460 mg). Alternatively, the precipitate is recrystallized directly from MeOH saturated with HCl gas without prior purification by chromatography. Yield: 70%; Rf: 0.36 (SiO2; CHCl3 / MeOH / 25% NH3, / 5/5/2); MS (FAB) m / z (relative intensity): 296 (MH +, 100); H-NMR (360 MHz, de-DMSO) (hydrochloride): 8.21 (d, 2H; 0-Ar-N0), 7.68 (d, 2H, m-Ar-N02), 3.50-264 (m, 15H); 13 C-NMR (90 MHz, de -DMSO): 146.29 (2C, C (Ar) -N0, CH 2 -Ar), 130.46 (2C, Ar), 123.36 (2C, Ar), 47.56, 44.68, 35.04, 34.97. The elemental analysis is consistent with C14CI H29 5O2.
N, N, N ', N' "-tetrabutyloxycarbonyl-6- (p-nitrobenzyl) -l, 4,8.11- te raazaundecane (3) 1.5 g (3.5 mmoles) of compound (2) are suspended in 5 ml of dioxane , and add IN NaOH to pH 12. At ice temperature, add 4.5 ml (21 mmol / 6 eq) of di-tert-butyl dicarbonate in 30 ml of dioxane, and 40 ml of IN NaOH. At room temperature overnight, 100 ml of diethyl ether and 50 ml of H2O are added to this mixture.The ether layer is separated and extracted four times with 30 ml of water, dried with Na2SO4 &4 and evaporated. The resulting oil can not be crystallized, but shows a structure that confirms FAB-MS (m / z: 696) and is pure in TLC (silica gel, RF = 0.5, ethyl acetate: hexane = 9: 1) Yield: 2.2 g, 90% FAB-MS: m / z: 696. 1 NMR and IR are consistent with the structure.
N, N ', N' ', N' "-tetrabutyloxycarbonyl-6- (p-aminobenzyl) -l, 4,8, ll-raazaundecane (4) 1.3 g (1.9 mmol) of the compound (3) are dissolved in 40 ml of 80% MeOH, 150 mg of Pd / (C (10%) are added, and the hydrogenation is carried out for 3 hours at room temperature.The catalyst is removed by filtration, the mixture is evaporated and the product is evaporated. Pure is obtained by silica gel chromatography (silica gel 60, 32 cm x 2 cm, eluent: hexane: acetic acid ethyl ester = 2: 3) Yield = 0.53 g (43%) .The compound is pure in TLC and CLAR, and characterized by FAB-MS (m / z = 666) and H-NMR.
6- (N- (biotinyl sulphoxide) -pa ino-benzyl) -N, N ", N" '-tebutyloxycarbonyl-l, 4,8,1-tetraazaundecane (5) 34.4 mg of biotinyl sulphoxide are dissolved or - (+) in 700 μl of DMF; 42.5 mg of HATU (0- (7-azabenzotriazol-1-yl) -l, 3,3-tetramethyluronium hexafluorophosphate) and 23 μl of diisopropylethylamine (H? nig base) are added, and the mixture is left room temperature for 10 minutes. Then, 88 mg of compound (4) and 23 μl of H? Nig base in 1 ml of DMF are added. Stirring is continued for 20 minutes. The reaction mixture is added to 2 ml of ethyl acetate and 2 ml of 5% NaHCO 3 solution. The organic layer is washed twice with sodium bicarbonate and saturated sodium chloride solution, dried over sodium sulfate, evaporated and crystallized from diethyl ether / isopropyl ether / hexane. Yield: 96 mg (80%). The product is chromatographically pure and characterized by FAB-MS (m / z = 908).
6- (N- (biotinyl sulphoxide) -p-aminobenzyl) -1,4,8,1-tetraazaundecane (6) (Fig. 1) 96 mg of the compound (5) are dissolved in 2 ml of trifluoroacetic acid: thioanisole : water = 96: 2: 2, and left for 2 hours at room temperature. Then, the product is precipitated by the addition of 2 ml of diethyl ether and dried under high vacuum. Yield: 96 mg. To remove small impurities and remaining thioanisole, the compound is purified by C18-HPLC. FAB-MS: m / z = 508.
EXAMPLE II
Labeling compound (6) with 99"Tc 5 μg of compound (6), obtained as described in example I, is dissolved in 300 μl of an aqueous solution of sodium citrate dihydrate (5 mg). add 200-400 μl (1000-2000 MBq) of generator eluate 9 tco4 and 20 μl (20 μg) of a freshly prepared solution of SnCl2-2 H2O purged with N2 (10 mg / 10 ml of 0.1 M HCl). it is adjusted to 10 with NaOH.Incubation is carried out at room temperature for 30 minutes.The yield of the complex is greater than 97% on a Hamilton PRP-1 column (10 μm, 4.1 x 150 mm) and isocratic elution with Phosphate pH regulator at 10 mM and 100% (pH 7.0-5 min), followed by a linear gradient (5 to 10 minutes, 20% MeCN / 80% phosphate pH regulator) and isocratic elution until 15 minutes, the 9mtc complex elutes at 10'04"(flow: 1.5 ml per min.) Under the same conditions (99mtc) -6- (p-aminobenzyl) -l, 4,8, ll-tetraazaundecane elutes at 8 '45' 'The complex is stable in reg Phosphate and citrate pH meter for at least 10 hours.
EXAMPLE III
Union of (99 «Tc) - (6) to avidin (99mTc) - (6), obtained as described in the example
II, is loaded onto a column of avidin coupled to stratified agarose that was previously conditioned 3 times with 1.5 ml of phosphate buffer (pH 8.9). The lava column 5 times with 1.5 ml of phosphate pH regulator. The activity retained in the column is 97 ± 3% (n = 3). If the column is previously saturated with cold biotin, less than 2% of the activity is retained. Thus, the conclusion is that the binding to avidin is specific.
EXAMPLE IV
Stability of (99 «tc) - (6) in human serum Biotinidase is an enzyme found in different organs and in human serum that functions as a biotin-amide to idohydrolase; for example, it hydrolyzes the acid (N- (d-biotinyl) -p-aminobenzoic acid and the biocitin, the stability of the amide bond in fresh human serum is studied here.) During 4 hours of incubation, the amount of (99? »Tc) - (6) intact, obtained according to example II, decreases by approximately 15 ± 2% which is much higher than the corresponding conjugate with biotin, considering the fact that the optimal scintigraphy time with a biotin conjugate labeled with (mtc) ) is within 2 hours after injection, the stability of 99mtc (6) in human serum is suitable for human studies.
Claims (17)
1. - A labeled biotin compound, wherein said biotin compound is represented by the general formula wherein: n is 1 or 2, R is a chelator group for chelating a metal atom, and Sp is a spacer group having at least 4 atoms that separate NH from R; and wherein said biotin compound is labeled with a metal atom selected from a) the group consisting of the radioactive isotopes 9mtc, 203pb # 66Ga, 7Qa, 68Ga, 72As > niin, H3mln, ll «"> In, 97RU> 62Cu, 4CU, 52pe, 52mMn, 5lCr, 186e, 188e, 77As> 90Y> 67CU, 6 Er> 1 7mSn, 2lSn, 1 je l * 2 r> «3pr> 198Au> 199Au> 149Tb> 161T p 109pdf 165Dy>« 9pm, 151pm ( 153Sm, 15 Q, 166HO, 169Yb, 175Y > 177 | _U, lOS and 111 g or b) the group consisting of the paramagnetic metal atoms Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Yb, Gd, Tb, Dy, Ho and Er; said metal atom being fixed to the biotin compound by means of said chelator group.
2. - A labeled biotin compound according to claim 1, further characterized in that the spacer group Sp is a group of the general formula
JCEL? P where A is a radical bi of the formula -NH- (CH2) m- or -NH-C (= X) - (CH-2)? - Y- (CH2) mC (C02H) H-, where x and y are each independently 0 or 1; m is an integer from 1 to 4; p is an integer from 0 to 4; X is 0 or S; and Y is NH, CO or S. 3. A labeled biotin compound according to claim 1 or 2, further characterized in that the R group is preferably selected from the group consisting of NtPqS tetradentary chelating agents («- tq ), where t + q = 2-4, or groups derived from ethylenediamine tetraacetic acid (EDTA), diethylenediane pentaacetic acid (DTPA), cyclohexyl 1,2-diaminotetraacetic acid (CDTA), ethylene glycol-0,0'- bis (2-aminoethyl) -N, N, N ', N'-tetra-acetic acid (EGTA), acid
N, N-bis (hydroxybenzyl) -ethylenediamine-N, N'-diacetic (HBED), triethylene tetraamino hexaacetic acid (TTHA), 1,4,7,10-tetraazacyclododecane-N, N ', N "N, N acid '' '-tri and tetra-acetic (D03A and DOTA), l, 4,7,10-tetraazacyclotridecane-N, N', N ", N" '-tri and tetra-acetic acid (TRI3A and TRITA), acid hydroxyethyl diacetic acid (HEDTA), 1,4,8,11-tetra-azacyclotetradecane-N, N ', N ", N'" -tetraacetic acid (TETA), substituted DTPA, substituted EDTA or deferoxamine (desferrioxa) ina) or a compound of the general formula wherein Ri is an optionally substituted branched or unbranched hydrocarbyl radical that can be interrupted by one or more heterogeneous atoms selected from N, 0 and S and / or by one or more NH groups, and Q is a group that is capable of reacting with an amino group of the peptide and which is preferably selected from the group consisting of carbonyl, carbimidoyl, Ci-Ce alkylcarbimidoyl, N-hydroxycarbimidoyl and N-alkoxycarbimidoyl of O-C6. 4. A labeled biotin compound according to claim 3, further characterized in that the chelator group R is a group selected from
OV)) (XD aD (XiiD wherein R6-R20 are each individually hydrogen atoms or Ci-C4 alkyl groups, with the proviso that at least one of C a to C 9 is the symbol Y; R21 is a hydrogen atom to a C? 2 alkyl group (C? -C4); R22 and R23 are each individually alkylcarbonyl of Ci -CA, benzoyl or benzyl groups; v is O or 1; s is 2 or 3; R24 is CH2COOH or a functional derivative thereof; A is Ci-C alkylene? , if desired, substituted with alkyl CO, CH2C0alkyl, CONH2, C0NHCH2C02alkyl; phenylene, phenylene substituted by alkyl CO2, wherein the alkyl groups have 1 to 4 carbon atoms; G is NH or S; And it is a union of valence or a bifunctional group capable of linking with the separating group; and Z is S or 0. 5. A method of preparing a labeled biotin compound according to claim 1, further characterized in that a biotin compound of the general formula I, as shown in claim 1, wherein the symbols have the meanings given in claim 1, is reacted with a metal atom according to claim 1, in the form of a salt or a linker of chelating agent to a comparatively weak chelator, to form a complex.
6. A biotin compound for use in the method according to claim 5, having the general formula wherein: n is 1 or 2, R is a chelator group for chelating a metal atom, and Sp is a spacer group having at least 4 atoms that separate NH from R.
7. - A pharmaceutical composition further comprising a pharmaceutically acceptable carrier and, if desired, at least one pharmaceutically acceptable adjuvant as the active substance of a labeled biotin compound according to claim 1, 2, 3 or 4. 8.- The use of a biotin compound labeled as in accordance with claim 1, 2, 3 or 4, said biotin compound being labeled with (a) a radioactive metal isotope selected from the group consisting of m? C > 203 bp | 66 Ga, 67 Qa, 8 Ga, 72 As > l l l ln > H 3 ln > 97 RU > 62 CU, 6 * CU, 52pe, 52mMn and Cr or (b) with a paramagnetic metal atom selected from the group consisting of Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Yb, Gd, Tb, Dy, Ho and Er , in the preparation of a composition to be used in a method for detecting and locating tumors in the body of a warm-blooded living being, same comprising (i) administering to said living being a composition comprising streptavidin conjugated to a polypeptide having a selective affinity for said tumor, (ii) after which after the avinidation of said tumor, administering to said living being said composition comprising the labeled biotin in an amount sufficient for external image formation, and ( iii) finally subjecting said living being to an external image formation to determine the identified sites in the body of said living being in relation to the background activity. 9. The use of a labeled biotin compound according to claim 1, 2, 3 or 4, said biotin compound being labeled with (a) a radioactive metal isotope selected from the group consisting of myCt 203 bp > 66 Ga, 6 Ga, 8 a, 72 s > i i i m, H 3 «In, 97 RU > 62 CU, 64 CU, 52pe, 52m ny sicr or (b) with a paramagnetic metal atom selected from the group consisting of Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Yb, Gd, Tb , Dy, Ho and Er, in the preparation of a composition to be used in a method for detecting and locating tumors in the body of a warm-blooded human being, same comprising (i) administering to said living being a composition which comprises a biotinylated polypeptide having a selective affinity to said tumor, (ii) then administering a composition comprising streptavidin, (iii) after which after the avinidation of said tumor, administering to said living being the composition comprising the biotin labeled in an amount sufficient for the formation of external images, and (iv) finally subjecting said living being to an external image formation to determine the identified sites in the body of said living being in relation to the background activity. 10. The use of a labeled biotin compound as defined hereinbefore, said biotin compound being labeled with 1 1Tb in the preparation of a composition to be used in a method for intraoperatively detecting and localizing tumors in the body of a warm-blooded living being, comprising (i) administering to said living being a composition comprising streptavidin conjugated to polypeptide having a selective affinity to said tumor, (ii) after which, after aviding said tumor, the composition comprising the labeled biotin is administered to said living being in an amount sufficient for detection by means of a gamma-ray detection probe, and (iii) finally, after allowing said active substance to be ligated and assimilated into said tumor and after its elimination by the blood of the radioactivity, submit said living being to a radioimmunodetection technique in the relevant area of the rpo of said living being using a gamma-ray detection probe. 11. The use of a labeled biotin compound according to claim 1, 2, 3 or 4, said biotin compound being labeled with i6itb in the preparation of a composition to be used in a method for intraoperatively detecting and locating tumors in the body of a warm-blooded living being, comprising (i) administering to said living being a composition comprising a biotinylated polypeptide having a selective affinity to said tumor, (ii) then administering a composition comprising streptavidin, (iii) after which after the avinidation of said tumor, administering to said the composition comprising the tagged biotin in a sufficient amount for detection by a gamma ray detection probe, and (iv) finally, after allowing said active substance to be ligated and assimilated into said tumor and after its removal by the blood of radioactivity, subjecting said living being to a radioimmunodetection technique in the relevant area of the body of said living being using a da detection range. 12. The use of a labeled biotin compound according to claim 1, 2, 3 or 4, said biotin compound being labeled with a metal isotope selected from the group consisting of? * «Lnf 186RT >; i88Re, 77As > 90Y > 6Ga, 7CU, 16 £ r, H Sn, 2lSn, 12 Je, "2pr, 143pr> 198Au > 199Au, l9Tb, 161T, 10 pd, 165Dy, pm > 151 pm, 153Sm, 157Gd,? S9Qd, 1 6H0, i 2tm, Yb > i75Yb > I7 U, i05Rh and i iAg in the preparation of compositions to be used in a method for the therapeutic treatment of tumors in the body of a warm-blooded living being, comprising (i) administering to said living being a composition comprising (strept) avidin conjugated to a polypeptide having a selective affinity for said tumor, (ii) after which, after treating said tumor with abidin, administering to said living being the composition comprising the labeled biotin in an effective amount to fight or control tumors. 13. The use of a labeled biotin compound according to claim 1, 2, 3 or 4, said biotin compound being labeled with a metal isotope selected from the group consisting of n * mIn, i86 e,? B8 e > 77As > 90Y > 6Ga, 67CU, i69Er,? I7mSn, i isn, 1 Te, l «2pr > 143Pr > 198AUf 199 Uj l¿ Tb, 61Tb, l ° 9pd, 165 y, * pm > 15lpm, 153Sm, 5Gd, i59d, 66H0, 2jm, Yb) i75Y > i77 u > i05 hyiiig in the preparation of compositions to be used in a method for the therapeutic treatment of tumors in the body of a warm-blooded living being, comprising (i) administering to said living being a composition comprising a biotinylated polypeptide which it has a selective affinity to said tumor, (ii) then administering a composition comprising streptavidin, (iii) after which after the avinidation of said tumor, administering to said living being the composition comprising the biotin labeled in a sufficient amount to fight or control tumors. 14. A kit for preparing a pharmaceutical composition, comprising (a) a composition comprising (strept) avidin conjugated to a polypeptide having a selective affinity for tumors (b) a biotin compound of the general formula I, in accordance with claim 1, wherein the symbols have the meanings given in claim 1, to which compound, if desired, a pharmaceutically acceptable inert carrier and / or formulating agents and / or adjuvants is added, (c) a solution of a salt or chelator of a metal isotope selected from the group consisting of 203p > dßQa, 6 Qa, ßGa, 2ASp nim, H3in, n * In, 97RU, 62CU, 99 Tc, 186 ß, lßßRe, 6 «U, 52Fe, 52mMn, SlCr, 7? AS, 90Y > 67CU, 1 Er > 117SN, 121Sn, 2 Je, l «2pr, 143pr > 198Au > 199Au > l «9Tb, 161Tb, 10Pc | t 165Dy > l «9pm, ISlpm, 153Sm, 15G, 166H ?, 72Tm, 6 Y > 175Yb > 177 | _U, 105Rh and 111 Ag, and (d) instructions for use with a prescription to react the ingredients present in the equipment. 15. A kit for preparing a pharmaceutical composition, comprising (a) a composition comprising a biotinylated polypeptide having a selective affinity to tumors, (b) a composition comprising (strept) avidin conjugated to a polypeptide having a selective affinity for tumors (c) a biotin compound of the general formula I, according to claim 1, wherein the symbols have the meanings given in claim 1, to which compound, if desired, is added a pharmaceutically acceptable inert carrier and / or formulation agents and / or adjuvants, (d) a solution of a salt or chelator of a metal isotope selected from the group consisting of 03? p 66Qa, Ga, 68Ga, 72As, íim, H3in, n «In, 97RU, 62CU, 99mtc, 186Rβ, 188Re, 6« cu, S FT, 52m | * lri, sicr, 77As > 90Y > 67CU, £ r > H7Sn, 121Sn, 2 Te, l «2pr, 143pr, 198Au > 199AUj l * 9Tb > lßljb, 10 pd, 16Sny, l «9pm, lSlPrri) 153Sm, 15 Qd, 166HO, 172? m > 169Y > i 5Y > i 7Lu, i05 and niAg, and (e) instructions for use with a prescription to react the ingredients present in the equipment. 16. A kit for preparing a pharmaceutical composition, comprising (a) a composition comprising (strept) avidin conjugated to a polypeptide having a selective affinity for tumors (b) a biotin compound of the general formula I, according to claim 1, wherein the symbols have the meanings given in claim 1, to which compound, if desired, a pharmaceutically acceptable inert carrier and / or formulating agents and / or adjuvants are added, ( c) a reducing agent and, if desired, a chelator, and (d) instructions for use with a prescription to react the ingredients present in the equipment with 9mtc in the form of a pertechnetate solution or with sß e 088R in The shape of a perrenate solution. 17. A kit for preparing a pharmaceutical composition, comprising (a) a composition comprising a biotinylated polypeptide having a selective affinity to tumors, (b) a composition comprising (strept) avidin conjugated to a polypeptide having a selective affinity for tumors (c) a biotin compound of the general formula I, according to claim 1, wherein the symbols have the meanings given in claim 1, to which compound, if desired, is added a pharmaceutically acceptable inert carrier and / or formulating agents and / or adjuvants, (d) a reducing agent and, if desired, a chelating agent, and (e) instructions for use with a prescription to react the ingredients present in the equipment with 99mtc in the form of a pertechnetate solution or with i86 e © i88Re in the form of a perrenate solution. SUMMARY OF THE INVENTION The invention relates to a labeled biotin compound, wherein said biotin compound is represented by the general formula wherein: n is 1 or 2, R is a chelator group for chelating a metal atom, and Sp is a spacer group having at least 4 atoms that separate NH from R; and wherein said biotin compound is labeled with a metal atom selected from a) the group consisting of the radioactive isotopes 9m? c > 203pbf ßßGa, 6 Qa, 6β a, 72 s > ? n? n, H3mln, H * ™ ln, 97RU > 62CU, «CU, 52pe, 52mMnf 51Cr, Ißß e, 188Re, 77As > 90Y > 6 Cu, i69Er, i "» Sn, isn, je? «Pr, l * 3Pr> 198AU> 199AU> 149T> 161Tb, 109Pdf 165Dy, l? 9pm> 15lpm, 153Sm, 15Gd, 166HO, 72jm, 16 Y > 175Yb > 177 U, lOSRh 111 Ag or b) the group consisting of the paramagnetic metal atoms Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Yb, Gd, Tb, Dy, Ho and Er; said metal atom being fixed to the biotin compound by means of said chelator group; The invention also relates to a pharmaceutical composition comprising the labeled biotin compound, to the use of said composition for diagnosis and therapy, and to a device for preparing a radiopharmaceutical composition. JN / MG / JJ / amm * apm * P98 / 269F
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP95202512 | 1995-09-18 | ||
EP95202512.0 | 1995-09-18 |
Publications (2)
Publication Number | Publication Date |
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MX9802107A MX9802107A (en) | 1998-08-30 |
MXPA98002107A true MXPA98002107A (en) | 1998-11-12 |
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