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WO1997010854A1 - Composes de biotine (radio) marques - Google Patents

Composes de biotine (radio) marques Download PDF

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Publication number
WO1997010854A1
WO1997010854A1 PCT/US1996/014883 US9614883W WO9710854A1 WO 1997010854 A1 WO1997010854 A1 WO 1997010854A1 US 9614883 W US9614883 W US 9614883W WO 9710854 A1 WO9710854 A1 WO 9710854A1
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WO
WIPO (PCT)
Prior art keywords
composition
group
labelled
compound
tumour
Prior art date
Application number
PCT/US1996/014883
Other languages
English (en)
Inventor
Helmut Mäcke
Original Assignee
Mallinckrodt Medical, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Priority to JP9512833A priority Critical patent/JPH11513374A/ja
Priority to EP96933801A priority patent/EP0857071A1/fr
Priority to HU9902664A priority patent/HUP9902664A3/hu
Publication of WO1997010854A1 publication Critical patent/WO1997010854A1/fr
Priority to NO981202A priority patent/NO981202L/no

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to labelled biotin compounds, to a method of preparing these compounds, to a pharmaceutical composition comprising these compounds, to the use of this composition for diagnosis and therapy, and to a kit for preparing a radiopharmaceutical composition.
  • MAb's monoclonal antibodies
  • MAb*'s radiolabelled monoclonal antibodies
  • (2nd step) and radiolabelled biotin (3rd step) are injected successively (in about 24 h time intervals) to the patient.
  • the first two steps, as well as the first step in the two-step approach, result in the avidination of the tumour.
  • the biotinylated MAb's which have not localized on the tumour but are still circulating in the blood, are macroaggregated by the excess of avidin.
  • These avidin/MAb adducts of high molecular weight are rapidly taken up and catabolized by the liver.
  • the 3rd step involves the in vivo administration of radiolabelled biotin. Due to the fast blood clearance of the non-tumour-bound biotin derivative, good tumour/background ratios are expected to be reached rapidly.
  • biotin. labelled with a radionuclide preferably a metal-radionuclide, or with a paramagnetic metal ion are required. Since biotin is lacking Q is a group which is capable of reacting with an amino group
  • the peptide and which is preferably selected from the group consisting of carbonyl, carbimidoyl, N-(C 1 -C 6 )alkylcarbimidoyl, N-hydroxycarbimidoyl and N-(C 1 -C 6 )alkoxycarbimldoyl.
  • N 1 P q S (4-t-q) tetradentate chelating agents are selected from
  • the above-defined spacing group Sp is preferably a group of the general formula
  • A is a biradical of the formula
  • n is an integer from 1 to 4.
  • p is an integer from 0 to 4.
  • X is O or S
  • Y is NH, CO or S.
  • R 1 is a branched or non-branched, optionally substituted
  • biotin compounds of the invention can be prepared in a manner known per se for related compounds.
  • the biotin molecule is derivatized with the desired chelating agent as defined hereinbefore, e.g. a N t P q S (4- ⁇ -q) tetradentate chelating agent, or EDTA
  • n i or 2
  • R is a chelating group for chelating a metal atom
  • Sp is a spacing group having at least 4 atoms spacing NH from R;
  • a metal as defined hereinbefore, in the form of a salt or of a chelate bound to a comparatively weak chelator, in order to form a complex.
  • Suitable examples of salts or chelates of the desired metal are: 111 Irvcitrate and acetate, 99m Tc-tartrate, etc.
  • the complex-forming reaction can generally be carried out 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 compound can be used for the above-described method of preparing the labelled biotin compound.
  • the present invention further relates to a pharmaceutical composition, comprising in addition to a pharmaceutically acceptable carrier material and, if desired, at least one pharmaceutically acceptable adjuvant, as the active substance a labelled biotin compound as defined hereinbefore.
  • the invention also relates to a method for detecting and localizing tumours in the body of a warm-blooded living being, which comprises (i) administering to said being a composition comprising (strept)avidin conjugated with a polypeptide having a selective affinity to said tumour, (ii) thereupon, after avidination of said tumour, administering to wherein:
  • R 6 -R 20 are each individually hydrogen atoms or (C 1 -C 4 )alkyl groups, with the proviso that at least one of C 6 to C 9 is the symbol Y;
  • R 21 is a hydrogen atom or a CO 2 (C 1 -C 4 )alkyl group
  • R 22 and R 23 are each individually (C 1 -C 4 )alkylcarbonyl, benzoyl or benzyl groups;
  • v 0 or 1
  • s 2 or 3;
  • R 24 is CH 2 COOH or a functional derivative thereof
  • A is (C 1 -C 4 )alkylene, if desired substituted with CO 2 alkyl, CH 2 COalkyl, CONH 2 ,
  • G is NH or S
  • Y is a valence bond or a functional group capable of binding with the spacing group
  • Y preferably comprises isocyanato, isothiocyanato, formyl, o-halonitrophenyl, diazonium, epoxy, trichloro-s-triazinyl, ethyleneimino, chlorosulfonyl, alkoxycarbimidoyl, (substituted or unsubstituted) alkylcarbonyloxycarbonyl, alkylcarbonylimidazolyl, succinimido-oxycarbonyl, which group is prferably attached to a
  • hydrocarbon biradicals are biradicals derived from benzene, (C 1 -C 6 )alkanes, (C 2 -C 6 )alkenes and (C 1 -C 4 )alkyibenzenes.
  • suitable chelators of the general formula III are described in the international patent application WO 89/07456, such as unsubstituted or substituted 2-iminothiolanes and 2-iminothiacyclohexanes, in particular 2-imino-4-mercaptomethytthiolane.
  • biotin compounds have been tested in a number of suitable model experiments that are predictive for in vivo application. These experiments are described in the Examples. From the results of these experiments it will be evident, that the labelled biotin compounds of the present invention have properties which make them suitable for diagnostic and therapeutic purposes. If labelled with a suitable atom for diagnostic purposes, the labelled biotin compound remains sufficientiy long intact after administration to permit imaging of the target tumour without presenting a disturbing background. If labelled with a suitable radioisotope for therapy, such-labelled biotin compounds are promising therapeutic agents for the treatment of a number of malignant tumours.
  • the body of ⁇ warm-blooded living being which comprises (i) administering to said being a composition comprising (strept)avidin conjugated with a polypeptide having a selective affinity to said tumour, (ii) thereupon, after avidination of said tumour, administering to said being a composition comprising,, in a quantity effective for combating or controling tumours, a labelled biotin compound as defined hereinbefore, said biotin compound being labelled with a metal isotope selected from the group consisting of 114m In.
  • kit may comprise (a) a composition comprising (strept)avidin conjugated with a polypeptide having a selective affinity to tumours, (b) a biotine compound of the general formula I, shown above, wherein the symbols have the above meanings, to which compound, if desired, an inert pharmaceutically acceptable carrier and/or formulating agents and/or adjuvants is/are added, (c) a solution of a salt or chelate of a metal isotope selected from the group consisting of 203 Pd, 66 Ga. 67 Ga, 68 Ga 72 As, 111 In, 113m In.
  • the biotin compound to be used as an ingredient of the above kit has been modified by a spacing group Sp and a chelating agent R as defined hereinbefore.
  • the resulting biotin compound provides a facility for firmly attaching the radionuclide in a simple manner.
  • Suitable chelating agents for modifying the biotin molecule are said being a composition comprising, in a quantity sufficient for external imaging, a labelled biotin compound as defined hereinbefore, said biotin compound being labelled with (a) a radioactive metal isotope selected from the group consisting of 99m Tn, 203 Pd, 67 Ga, 68 Ga, 72 As, 111 In, 113m ln, 97 Ru, 62 Ga, 64 Ga, 52 Fe, 52m Mn and 51 Cr, or (b) with a paramagnetic metal atom selected from the group consisting of Cr, Mn, Fe, Co, Ni, Cu,
  • the three-step pretargeting method can be used as discussed hereinbefore.
  • the following protocol is used: (i- ⁇ ) administering to said being a composition comprising a biotinylated polypeptide having a selective affinity to said tumour, (i-b) then administering a composition comprising (strept)avidin; both steps in substitution for the above step (i).
  • the invention also relates to a method of intraoperatively detecting and localizing tumours in the body of a warm-blooded living being, which comprises (i) administering to said being a composition comprising (strept)avidin conjugated with a polypeptide having a selective affinity to said tumour, (ii) thereupon, after avidination of said tumour, administering to said being a composition comprising, in a quantity sufficient for detection by a gamma detecting probe, a labelled biotin compound as defined hereinbefore, said biotin compound being labelled with 161 Tb, and (iii) finally, after allowing the active substance to be bound by and taken up in said tumour and after blood clearance of radioactivity, subjecting said being to a radioimmunodetection technique in the relevant area of the body of said being, by using a gamma detecting probe.
  • the above radioisotope allows the use of a such-labelled peptide compound in the technique of radioguided surgery, wherein relevant tissues in the body of a patient can be detected and located intraoperatively by means of a gamma detecting probe.
  • the surgeon can, intraoperatively, use this probe to find the lesions in which uptake of the compound labelled with said radioisotope, which is a low-energy gamma photon emittor, has taken place.
  • the three-step pretargeting method can be used as discussed hereinbefore.
  • the biotin compounds of the present invention provided they are radiolabelled with isotopes suitable for such purpose, can be used for the therapeutic treatment of tumours. So the invention further relates to a method for the therapeutic treatment of tumours in excellently suitable.
  • suitable Sn(II)-cornpounds are SnCl 2 , Sn(II)-tartrate, Sn(II)-phosphonate or -pyrophosphate, and Sn(II)-glucoheptonate.
  • the modified biotin constituent of the above-mentioned kits i.e.
  • the biotin compound may be supplied as a solution, for example, in the form of a physiological saline solution, or in some buffer solution, or may be present in a dry condition, for example, in a lyophilized condition.
  • a component for an injection liquid it should be sterile, in which, when the constituent is in the dry state, the user should preferably use a sterile physiological saline solution as a solvent.
  • the abovementioned constituent may be stabilized in the conventional manner with suitable stabilizers, for example, ascorbic acid, gentisic acid or salts of these acids, or it may comprise other auxiliary agents, for example, fillers, such as glucose, lactose, mannitol, and the like.
  • N t P q S (4-t-q) tetradentate chelating agents or N-containing di- or polyacetic acids or their derivatives, such as the compounds mentioned before, have proved to be pre-eminently suitable for attaching various metal radionuclides, such as ln-111 and ln-113m, to the biotin molecule.
  • the Wt to be supplied to the user may also comprise the ingredient(s) defined sub (a) and (b) above, together with instructions for use, whereas the solution of a salt or chelate of the radionuclide, defined sub (c) above, which solution has a limited shelf life, may be put to the disposal of the user separately.
  • Wt is destined for use in a two-step protocol. If, instead thereof, the three-step pretargeting method is to be used, as discussed hereinbefore, the following Wt is suitable:
  • kits serve to prepare a radiopharmaceutical composition labelled with Tc- 99m, Re-186 or Re-188
  • a Wt may comprise, in addition to the ingredient(s) defined sub (a) and (b) above, (c) a reducing agent and, if desired, a chelator, and (d) instructions for use with a prescription for reacting the ingredients of the Wt with Tc-99m in the form of a pertechnetate solution, or with Re-186 or Re-188 in the form of a perrhenate solution.
  • certain ingredients of the kit may be combined, provided they are compatible.
  • the pertechnetate or perrhenate solution can simply be obtained by the user from a suitable generator.
  • the complex forming reaction with the biotin compound of the general formula I above can simply be produced by combining the components in a neutral or buffered medium and causing them to react.
  • the radionuclide may be presented to said biotin compound in the form of a chelate bound to a comparatively weak chelator, as described hereinbefore.
  • the Wt comprises a biotin compound as defined hereinbefore and is intended for the preparation of a radiopharmaceutical composition, labelled with Tc-99m, Re-186 or Re-188
  • the radionuclide will preferably be added separately in the form of a pertechnetate or perrhenate solution.
  • the kit will comprise a suitable reducing agent and, if desired, a chelator, the former to reduce the pertechnetate or the perrhenate.
  • a suitable reducing agent may be used, for example, a dithionite or a metallic reducing agent.
  • a metallic reducing agent for example, Sn(II), Ce(III), Fe(II), Cu(I), Ti(III) or Sb(III);
  • 6-(p-Nitrobenzyl)-1,4,8,11-tetraazaundecane (2) The crude (1) (480 mg, 1 ,48 mmol) is reacted at RT with 1 M BH 3 /THF solution (30 ml, 20 eq) and the reaction mixture is refluxed for 60 h.
  • MeOH is added dropwise with caution to the reaction mixture, which is precooied at 0° C.
  • the MeOH is evaporated in vacuum and the residue is suspended in EtOH and sonicated for several minutes.
  • the undissolved part is filtered off and HCl gas is introduced for 20 min to the filtrate.
  • the formed precipitate is collected and further purified by column chromatography (SiO 2 ;CHCl 3 /MeOH/25% NH 3 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).
  • the precipitate is directly recrystallized from HCl gas saturated MeOH, without previous purification by chromatography.
  • Biotinsulfoxide is synthesized according to Melville (D.B. Melville, J. Biol. Chem., 1954, 208, 495).
  • the sulfoxide exists in two isomeric forms: ⁇ -(+)-biotinsulfoxide and ß-(-)-biotinsulfoxide (Fig.2)
  • Biotinidase is an enzyme found in different organs and in human serum which functions as a biotin-amide amidohydrolase; e.g. it hydrolyzes (N-(d-biotinyl)-p-aminobenzoic acid and biocytin.
  • the stability of the amide bond in fresh human serum is studied. Within 4 h of incubation the amount of intact ( 99m Tc)-(6), obtained according to Example II, decreases by about 15 ⁇ 2% which is by far superior to the corresponding conjugate with biotin.
  • the optimal time of scintigraphy with a 99m Tc-labelled biotin conjugate is within 2 h post injection, the stability of 99m Tc(6) in human serum is adequate for human studies.
  • EDTA ethylene diamine tetra-acetic acid
  • DTPA diethylene triamine penta
  • TTA and TRITA hydroxyethyldiamine triacetic acid
  • HEDTA hydroxyethyldiamine triacetic acid
  • TETA 1,4,8,11-tetra-azacyclotetradecane-N,N',N",N'"-tetra-acetic acid
  • substituted DTPA substituted EDTA or from deferoxamine or from a compound of the general formula
  • R 1 is a branched or non-branched, optionally substituted
  • hydrocarbyl radical which may be interrupted by one or more hetero-atoms selected from N, O and S and/or by one or more NH groups, and
  • Q is a group which is capable of reacting with an amino group
  • peptide which is preferably selected from the group consisting of carbonyl, carbimidoyl, N-(C 1 -C 6 )alkylcarbimidoyl, N-hydroxycarbimidoyl and

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Radiology & Medical Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composé de biotine marqué dans lequel ledit composé de biotine est représenté par la formule générale (I). Dans la formule, n vaut 1 ou 2, R représente un groupe de chélateur servant à chélater un atome métallique, et Sp représente un groupe d'espacement comprenant au moins 4 atomes qui écartent NH de R; ledit composé de biotine étant marqué avec un atome métallique sélectionné dans (a) le groupe formé par les isotopes radioactifs ?99mTc, 203Pb, 66Ga, 67Ga, 68Ga, 72As, 111In, 113mIn, 114mIn, 97Ru, 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, 175Yb, 177Lu, 105Rh and 111¿Ag ou dans (b) le groupe formé par les atomes métalliques paramagnétiques Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Yb, Gd, Tb, Dy, Ho et Er; ledit atome métallique étant attaché au composé de biotine par ledit groupe chélateur. Cette invention concerne également une composition pharmaceutique comprenant ledit composé de biotine marqué, l'utilisation de cette même composition pour le diagnostic et la thérapie, et un nécessaire servant à préparer une composition pharmaceutique radiomarquée.
PCT/US1996/014883 1995-09-18 1996-09-17 Composes de biotine (radio) marques WO1997010854A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP9512833A JPH11513374A (ja) 1995-09-18 1996-09-17 （放射性）標識化ビオチン誘導体類
EP96933801A EP0857071A1 (fr) 1995-09-18 1996-09-17 Composes de biotine (radio) marques
HU9902664A HUP9902664A3 (en) 1996-09-17 1996-09-17 (radio) labelled biotin derivatives, procedure for producing this compounds and pharmaceutical compositions which contain this compounds and kit for producing such composition, as well as procedure for detection and localization of tumors
NO981202A NO981202L (no) 1995-09-18 1998-03-17 (Radio) merkede biotinderivater

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP95202512 1995-09-18
EP95202512.0 1995-09-18

Publications (1)

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WO1997010854A1 true WO1997010854A1 (fr) 1997-03-27

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Application Number Title Priority Date Filing Date
PCT/US1996/014883 WO1997010854A1 (fr) 1995-09-18 1996-09-17 Composes de biotine (radio) marques

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EP (1) EP0857071A1 (fr)
JP (1) JPH11513374A (fr)
CA (1) CA2232411A1 (fr)
CZ (1) CZ75498A3 (fr)
IL (1) IL123725A0 (fr)
NO (1) NO981202L (fr)
WO (1) WO1997010854A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
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EP0837696A1 (fr) * 1995-06-07 1998-04-29 Immunomedics, Inc. Apport ameliore d'agents diagnostiques ou therapeutiques a un site cible
WO2002066075A3 (fr) * 2001-02-16 2003-01-30 Sigma Tau Ind Farmaceuti Aminoderives de biotine et leurs conjugues avec des agents de chelation macrocycliques
JP2003521475A (ja) * 1999-05-25 2003-07-15 バーンズ−ジューウィッシュ・ホスピタル 部位特異的結合系、核画像化組成物及び方法
US7371579B1 (en) * 1999-07-01 2008-05-13 The University Of Maryland Nickel-based reagents for detecting DNA and DNA-protein contacts
CN102336908A (zh) * 2010-07-20 2012-02-01 中国科学院上海应用物理研究所 一种99mTc配合物、其制备方法、中间体及其应用

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GB0416062D0 (en) * 2004-07-19 2004-08-18 Amersham Plc Improved N4 chelator conjugates
ES2547307T3 (es) * 2007-12-05 2015-10-05 King's College London Procedimiento de ayuda al diagnóstico de un trastorno

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0837696A1 (fr) * 1995-06-07 1998-04-29 Immunomedics, Inc. Apport ameliore d'agents diagnostiques ou therapeutiques a un site cible
EP0837696A4 (fr) * 1995-06-07 2005-09-28 Immunomedics Inc Apport ameliore d'agents diagnostiques ou therapeutiques a un site cible
JP2003521475A (ja) * 1999-05-25 2003-07-15 バーンズ−ジューウィッシュ・ホスピタル 部位特異的結合系、核画像化組成物及び方法
US7371579B1 (en) * 1999-07-01 2008-05-13 The University Of Maryland Nickel-based reagents for detecting DNA and DNA-protein contacts
WO2002066075A3 (fr) * 2001-02-16 2003-01-30 Sigma Tau Ind Farmaceuti Aminoderives de biotine et leurs conjugues avec des agents de chelation macrocycliques
AU2002237517B2 (en) * 2001-02-16 2006-11-30 Alfasigma S.p.A Biotin-derivatives and their conjugates with chelating agents
US7390828B2 (en) * 2001-02-16 2008-06-24 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Aminoderivatives of biotin and their conjugates with macrocyclic chelating agents
CN100457192C (zh) * 2001-02-16 2009-02-04 希格马托制药工业公司 生物素的氨基衍生物及其与大环螯合剂的结合物
US8044081B2 (en) 2001-02-16 2011-10-25 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Aminoderivative of biotin and their conjugates with macrocyclic chelating agents
CZ305442B6 (cs) * 2001-02-16 2015-09-23 Sigma-Tau Industrie Farmaceutiche Riunite S. P. A. Aminoderiváty biotinu a jejich konjugáty s makrocyklickými chelatačními činidly
CN102336908A (zh) * 2010-07-20 2012-02-01 中国科学院上海应用物理研究所 一种99mTc配合物、其制备方法、中间体及其应用
CN102336908B (zh) * 2010-07-20 2013-07-03 中国科学院上海应用物理研究所 一种99mTc配合物、其制备方法、中间体及其应用

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EP0857071A1 (fr) 1998-08-12
IL123725A0 (en) 1998-12-06
CZ75498A3 (cs) 1999-09-15
JPH11513374A (ja) 1999-11-16
NO981202D0 (no) 1998-03-17
NO981202L (no) 1998-05-18
MX9802107A (es) 1998-08-30
CA2232411A1 (fr) 1997-03-27

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