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WO1992011039A1 - Agents de chelation a base de tricatechol derives - Google Patents

Agents de chelation a base de tricatechol derives Download PDF

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Publication number
WO1992011039A1
WO1992011039A1 PCT/US1991/009153 US9109153W WO9211039A1 WO 1992011039 A1 WO1992011039 A1 WO 1992011039A1 US 9109153 W US9109153 W US 9109153W WO 9211039 A1 WO9211039 A1 WO 9211039A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
solution
radiometal
ncs
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.)
Ceased
Application number
PCT/US1991/009153
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English (en)
Inventor
Otto A. Gansow
Tom Mcmurry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
United States Department of Commerce
US Department of Health and Human Services
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United States Department of Commerce
US Department of Health and Human Services
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 United States Department of Commerce, US Department of Health and Human Services filed Critical United States Department of Commerce
Publication of WO1992011039A1 publication Critical patent/WO1992011039A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6887—Antibody-chelate conjugates using chelates for therapeutic purposes
    • 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
    • A61K51/0478—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 complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • 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
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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 novel "bifunctionai" chelating agents. More specifically, the present invention relates to bifunctionai chelating agents which are designed to sequester certain radioactive metals and to provide a means for covalently attaching these radionuclides to a macromolecule, such as an antibody.
  • the invention further relates to methods for preparing these compounds as well as methods of using these compounds in radioimmunoimaging, positron emission tomography and in vivo treatment.
  • the present invention further relates to these compounds attached to antibodies.
  • Monoclonal antibodies are immunoglobulins of well-defined chemical structure. A characteristic feature of monoclonal antibodies is reproducibility of function and high specificity. Diagnostic methods are adversely affected unless substantially all of the compound used for labeling is securely attached to the targeting agent. Any of the labelling compound that does not attach to the targeting agent can create an undesirable background. If radiometals are used, they can disseminate in the body and have the potential of doing damage.
  • U.S. Patent 4,454,106 relates to metal chelate conjugated monoclonal antibodies for diagnostic and therapeutic techniques.
  • the chelating agent is derived from diethylenetriaminepentaacetic acid (DTPA) , and the conjugate is substantially free of adventitiously bound metal.
  • the chelate conjugated to the monoclonal antibody is a derivative of DTPA bonded to an organic functional group which serves to link the DTPA chelate to the monoclonal antibody.
  • the foregoing objects and others are accomplished in accordance with the present invention, generally speaking, by providing bifunctionai chelating agents having a tris-catechol structure and a method for preparing the same, wherein these agents are useful for sequestering radioactive metals (radionuclides) and for providing a means for covalently attaching these radionuclides to a macromolecule, such as an antibody.
  • the present invention further encompasses therapeutic and diagnostic techniques which employ the bifunctionai chelating agents in the form of radiometal chelate conjugated monoclonal antibodies.
  • the present invention provides bifunctionai chelating agents designed to sequester radioactive metals and to provide a means for covalently attaching these radionuclides to a macromolecule.
  • the macromolecule is a tumor-seeking monoclonal antibody
  • the radioactive conjugate can be used in patients for cancer diagnosis or therapy.
  • the chelating agents of the present invention bind metals through three deprotonated 2,3- dihydroxyterephthalate moieties, known to have a much greater affinity for small, highly charged ions, such as Fe(III) and Ga(III), than for divalent ions, such as Ca(II) or Cu(II) .
  • two of the binding subunits are endocyclic within a 26 me bered ring, a feature which should enhance the kinetic stability of the metal complex.
  • the bifunctionai chelating agents of the present invention are represented by the formulas 1 and la shown below. Notable features of the chelating agents of the present invention include the 2,3-dihydroxyterephthalate binding subunits and the presence of a functionalized sidearm which allows the chelate to be covalently attached to a monoclonal antibody through, for example, a thiourea linkage.
  • the disuccinimido-2,3- dibenzyloxyterephthalate 2 is reacted with two equivalents of the ligand tris(2-aminoethyl)amine (TREN) in the presence of iron (III) to give the metal complex 3.
  • TREN tris(2-aminoethyl)amine
  • This reactive intermediate may be reacted with 1- amino-2-(p-N0 2 -Benzyl)ethane to give the derivatized complexes 4a, .
  • the reactive alkylamine is then protected with acetic anhydride to give 5a, b and then the aromatic amine reduced to provide the aniline metal complex derivative 6 that is subsequently demetalated to provide the amino ligand 1 which may be reacted with thiophosgene to give the isothiocyanate ligand la.
  • Both 1, la are useful for linkage of the ligand to proteins, such as antibodies, by carbohydrate modification methods for 1 and by direct reaction with amino acid residues with la.
  • the present invention employs metal chelate conjugated monoclonal antibodies for diagnostic and therapeutic techniques, particularly in vivo.
  • the metal may be radioactive, exhibit fluorogenic properties, exhibit paramagnetic properties or the like.
  • Monoclonal antibodies are immunoglobulins of well- defined chemical structure, in contrast to polyclonal antibodies which are heterogeneous mixtures. Reproducibility of function cannot be controlled for either polyclonal or autologous antibodies, whereas unaltered function is characteristic to monoclonal antibodies. Experimental techniques for obtaining monoclonal antibodies have been extensively discussed. A useful text is Monoclonal Antibodies (R.H. Kennett, T.J. McKearn & K.B. Bechtol eds. 1980). See also Koprowski et al. U.S. Patent 4,196,265 which is incorporated herein by reference. Any monoclonal antibody which exhibits cell binding or antigen binding at the cell targeted for therapy or which is catabolized to inside the cell membrane can be employed. The selection and production of suitable monoclonal antibodies is within the skill of the art.
  • the antibodies are generally maintained in an aqueous solution that contains an ionic compound.
  • a physiologic normal saline solution is very often employed and is widely available.
  • Other ionic solutions such as those containing sodium or potassium phosphate, sodium bicarbonate and the like, are known in the art and may also be employed.
  • the invention contemplates an in vivo therapeutic procedure in which radiometal chelate conjugated monoclonal antibodies are introduced into the body and allowed to concentrate in the target region.
  • radiometal isotopes which form stable complexes with the chelating agents of the present invention and emit cytotoxic beta or positron particles, or Auger electrons.
  • Useful beta or positron particle emitting isotopes include but are not limited to Sc-46, Sc-47, Sc-48, Ga-66, and Ga-68.
  • the choice of radionuclide to be used depends on the purpose of the use, whether diagnosis of therapy, and is within the skill of the art.
  • the therapeutic effect occurs when the conjugates are near or in contact with and bind to the targeted cells. Cell death, it is believed, is a direct or indirect result of the radiation event of the radiometal which is positioned in close proximity to the cell.
  • the benefits of this aspect of the invention are several.
  • the high specificity of the conjugated monoclonal antibody minimizes the total radiation dosage. Only enough radiation for the target cells need be employed.
  • radiometal chelates generally are cleared rapidly from the body should the conjugated antibody be disrupted.
  • the isotope can be short-lived and the affinity constant by which the isotope that is retained in the chelate is very high resulting in a stably bound metal.
  • the amount of radiometal employed is minimized, the radiation hazard to persons preparing and administering the radiometal chelate conjugated antibody is also minimized.
  • tissue damage or whole body dose during therapy are markedly reduced as compared to that from presently employed methods of radiation therapy such as isotope implants, external radiation therapy such as isotope implants, external radiation therapy, and immunoradiotherapy employing iodine-131 labeled polyclonal or autologous antibodies. Additionally, both biological and physical half-lives of the targeting radiobiological may now be controlled, minimizing whole body radiation effects. Since radiation is targeted specifically to cell types (e.g. neoplastic cells), a therapeutic dose is delivered specifically to malignant cells, either localized or metastasized.
  • the present invention employs the metal chelate conjugated monoclonal antibody containing a positron emitting radiometal to treat cellular disorders. It is desirable in most applications that the radiometal have a half-life of less than about four days and decay rapidly to a stable isotope once the alpha particle is emitted.
  • the preferred isotopes employed in the present invention are Ga-66 and 68. Particularly preferred is Ga-66 with a half life of 9.4 hr.
  • the present invention contemplates in vivo diagnostic procedure which comprises introducing a metal chelate conjugated monoclonal antibody into the body, allowing sufficient time for the conjugate to localize and identifying the degree and location of localization, if any.
  • the present invention also contemplates in vitro analytical procedures employing a chelate conjugated monoclonal antibody.
  • the conjugated antibody of the present invention is substantially free of adventitiously or weakly chelated metal.
  • isotopes useful for diagnostic purposes form stable complexes with the chelate of the present invention.
  • Gamma or positron emitting isotopes are particularly useful for imaging target sites both in vivo and in vitro in radioimaging procedures. Examples of gamma or positron emitting isotopes include Tc-99m, Ga-
  • Tc-99m in In-Ill are preferred.
  • Sc-43, S ⁇ -44, Fe-52, Co-55 and Ga-66,68 may be employed.
  • lanthanides may be employed, in particular, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm and Yb.
  • Paramagnetic diagnostic techniques would typically employ the stable iron isotopes such as Fe-54, Fe-56, Fe-
  • the metal chelate conjugated antibodies of this invention can be administered in vivo in any suitable pharmaceutical carrier.
  • a physiologic normal saline solution can appropriately be employed.
  • the carrier will include a minor amount of carrier protein such as human serum albumin to stabilize the antibody.
  • concentration of metal chelate conjugated antibodies within the solution will be a matter of choice. Levels of about 0.5 mg per ml are readily attainable but the concentrations may vary considerably depending upon the specifics of any given application. Appropriate concentrations of biologically active materials in a carrier are routinely determined in the art.
  • the effective dose of radiation or metal content to be utilized for any application will also depend upon the particulars of that application.
  • the dose will depend, inter alia, upon tumor burden, accessibility and the like.
  • the use of metal chelate conjugated antibodies for diagnostic purposes will depend, inter alia, upon the sensing apparatus employed, the location of the site to be examined and the like.
  • the circulating antigens can be removed prior to the treatment.
  • Such removal of antigens can be removed prior to treatment.
  • Such removal of antigens can be accomplished, for example, by the use of unlabeled antibodies, or by plasmapheresis in which the patient's serum is treated to remove antigens.
  • the present invention also contemplates the above- described chelating agents attached to macromolecules, such as antibodies.
  • the antibody anti-Tac is known to localize in adult t-cell leukemias.
  • the antibody B72.3 localizes on the surface of colon cancer cells, and the antibody B-l localizes in B-cell lymphomas.
  • FeCl 3 (.378 g, 2.32 mmol in ca. 30 ml DMF) were added simultaneously. The resulting dark reddish brown solution was transferred to addition funnel A and DMF added to make the total volume 250 ml.
  • Triethylamine (0.27 ml, ca. 1.9 mmol) was added to neutral ferric complex 4a (0.36 g, .36 mmol) suspended in 10 ml MeOH. The resulting deep burgundy solution was stirred 15 minutes, then evaporated to dryness. The solid was redissolved in methanol (10 ml) and again evaporated to dryness. The solid was vacuum dried 48 hours to give 0.4 g (0.33 mmol).
  • Neutral complex 5a (0.15 g, .14 mmol) was suspended in 5 ml CHgOH and stirred while triethylamine (0.12 ml, 0.086 g, .85 mmol) was added. The resulting burgundy solution was evaporated to dryness, redissolved in 20 ml methanol and again evaporated to dryness. The solid was taken up in ca. 1 ml methanol, precipitated by the addition of diethyl ether, and collected on a fine glass frit. The solid was vacuum dried to give 0.19 g (.14 mmol, 95%) of the triethylammonium salt 5b. Elemental Analysis: Calc for
  • the pH of the solution was adjusted to 7.4, and was then transferred via syringe to a 50 ml 3 neck flask containing 250 g 10% Pd/C (saturated with H 2 ) . Hydrogenation at atmospheric pressure was complete in 7-8 hours, as evidenced by the analytical HPLC (conditions #2) which showed the complete conversion of starting material (RT 10.4) to a single product (RT 9.6).
  • the catalyst was removed by filtration and washed with water (10 ml) (Buchner) . To the filtrate was added Na 2 EDTA 21 ⁇ 0 (1.41 g, 3.8 mmol, 10 eq) and glacial acetic acid (12 ml) . The solution was stirred 2 hours at room temperature, then left to stand at room temperature 12 hours.
  • the precipitate was filtered and washed with 15 ml 0.1 M AcOH.
  • the filtrate was diluted to 100 ml with 0.1 M AcOH and purified by HPLC using a Gilson autoprep system and conditions #3. The fraction between 10.5 and 12 minutes was collected and evaporated to dryness.
  • the brown solid (ca. 300 mg) was taken up in 140 ml boiling absolute ethanol and cooled to room temperature. Et 2 0 (125 ml) was added and the solution cooled to 4C. The resulting solid was collected, washed with Eto and dried to give 0.19 g (0.2 mmol, 52%) of the neutral tris(catecholate) ligand.

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Abstract

L'invention se rapporte à des agents de chélation bifonctionnels qui sont conçus pour séquestrer certains métaux radioactifs, tels que les isotopes du gallium (III), et qui constituent un moyen permettant de fixer par covalence ces radionucléides à des macromolécules, tels que des anticorps monoclonaux. Ces agents de chélation peuvent être utilisés dans diverses techniques thérapeutiques et diagnostiques, telles que l'imagerie radio-immunologique et la tomographie par émission de positons.
PCT/US1991/009153 1990-12-17 1991-12-12 Agents de chelation a base de tricatechol derives Ceased WO1992011039A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62800290A 1990-12-17 1990-12-17
US628,002 1990-12-17

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WO1992011039A1 true WO1992011039A1 (fr) 1992-07-09

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PCT/US1991/009153 Ceased WO1992011039A1 (fr) 1990-12-17 1991-12-12 Agents de chelation a base de tricatechol derives

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048991A1 (fr) * 1999-02-18 2000-08-24 The Regents Of The University Of California Complexes salicylamides lanthanides utilises comme marqueurs luminescents
WO2000048990A1 (fr) * 1999-02-18 2000-08-24 The Regents Of The University Of California Complexes de phthalimide-lanthanide utilises en tant que marqueurs luminescents
US6982431B2 (en) 1998-08-31 2006-01-03 Molecular Devices Corporation Sample analysis systems
US7070921B2 (en) 2000-04-28 2006-07-04 Molecular Devices Corporation Molecular modification assays
US7632651B2 (en) 1997-09-15 2009-12-15 Mds Analytical Technologies (Us) Inc. Molecular modification assays
US8173800B2 (en) 2006-08-15 2012-05-08 The Regents Of The University Of California Luminescent macrocyclic lanthanide complexes
US8507199B2 (en) 2007-01-25 2013-08-13 Lumiphore, Inc. Multi-color time resolved fluorophores based on macrocyclic lanthanide complexes
US8551453B2 (en) 2003-12-30 2013-10-08 The Regents Of The University Of California Aromatic triamide-lanthanide complexes
WO2013187971A3 (fr) * 2012-05-31 2014-04-03 The Regents Of The University Of California Macrocycles
US9273059B2 (en) 2009-08-24 2016-03-01 Lumiphore, Inc. Macrocyclic HOPO chelators
US9556122B2 (en) 2006-07-10 2017-01-31 The Regents Of The University Of California Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides
US11453652B2 (en) 2013-03-15 2022-09-27 Lumiphore, Inc. Di-macrocycles

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4732974A (en) * 1986-03-05 1988-03-22 Mallinckrodt, Inc. Metal ion labeling of carrier molecules

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4732974A (en) * 1986-03-05 1988-03-22 Mallinckrodt, Inc. Metal ion labeling of carrier molecules

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF AMERICAN CHEMICAL SOCIETY, Volume 109, No. 11, issued November 1987, (USA), T.J. MCMURRAY et al., "Template and Stepwise Synthesis of a Macrobicyclic Catechoylamide Ferric Ion Sequestering Agent", see pages 3451-3453. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7632651B2 (en) 1997-09-15 2009-12-15 Mds Analytical Technologies (Us) Inc. Molecular modification assays
US6982431B2 (en) 1998-08-31 2006-01-03 Molecular Devices Corporation Sample analysis systems
US7442558B2 (en) 1999-02-18 2008-10-28 The Regents Of The University Of California Phthalamide-lanthanide complexes for use as luminescent markers
WO2000048990A1 (fr) * 1999-02-18 2000-08-24 The Regents Of The University Of California Complexes de phthalimide-lanthanide utilises en tant que marqueurs luminescents
JP2003523312A (ja) * 1999-02-18 2003-08-05 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 発光マーカーとして使用するためのフタルアミド−ランタニド錯体
US6864103B2 (en) 1999-02-18 2005-03-08 The Regents Of The University Of California Phthalamide-lanthanide complexes for use as luminescent markers
US6406297B1 (en) 1999-02-18 2002-06-18 The Regents Of The University Of California Salicylamide-lanthanide complexes for use as luminescent markers
US7018850B2 (en) 1999-02-18 2006-03-28 The Regents Of The University Of California Salicylamide-lanthanide complexes for use as luminescent markers
US6515113B2 (en) 1999-02-18 2003-02-04 The Regents Of The University Of California Phthalamide lanthanide complexes for use as luminescent markers
US7404912B2 (en) 1999-02-18 2008-07-29 The Regents Of The University Of California Salicylamide-lanthanide complexes for use as luminescent markers
WO2000048991A1 (fr) * 1999-02-18 2000-08-24 The Regents Of The University Of California Complexes salicylamides lanthanides utilises comme marqueurs luminescents
US7070921B2 (en) 2000-04-28 2006-07-04 Molecular Devices Corporation Molecular modification assays
US8551453B2 (en) 2003-12-30 2013-10-08 The Regents Of The University Of California Aromatic triamide-lanthanide complexes
US9556122B2 (en) 2006-07-10 2017-01-31 The Regents Of The University Of California Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides
US8173800B2 (en) 2006-08-15 2012-05-08 The Regents Of The University Of California Luminescent macrocyclic lanthanide complexes
US8729258B2 (en) 2006-08-15 2014-05-20 The Regents Of The University Of California Luminescent macrocyclic lanthanide complexes
US8507199B2 (en) 2007-01-25 2013-08-13 Lumiphore, Inc. Multi-color time resolved fluorophores based on macrocyclic lanthanide complexes
US9273059B2 (en) 2009-08-24 2016-03-01 Lumiphore, Inc. Macrocyclic HOPO chelators
US10352938B2 (en) 2009-08-24 2019-07-16 Lumiphore, Inc. Macrocyclic HOPO chelators
WO2013187971A3 (fr) * 2012-05-31 2014-04-03 The Regents Of The University Of California Macrocycles
US11453652B2 (en) 2013-03-15 2022-09-27 Lumiphore, Inc. Di-macrocycles

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