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WO2024200180A1 - Nouveau marqueur à l'iode radioactif de l-thyroxine et son procédé de production - Google Patents

Nouveau marqueur à l'iode radioactif de l-thyroxine et son procédé de production Download PDF

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Publication number
WO2024200180A1
WO2024200180A1 PCT/EP2024/057530 EP2024057530W WO2024200180A1 WO 2024200180 A1 WO2024200180 A1 WO 2024200180A1 EP 2024057530 W EP2024057530 W EP 2024057530W WO 2024200180 A1 WO2024200180 A1 WO 2024200180A1
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WIPO (PCT)
Prior art keywords
compound
iodine
group
radioiodine
thyronine
Prior art date
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PCT/EP2024/057530
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German (de)
English (en)
Inventor
Birte DREWES
Dirk BIER
Marcus HOLSCHBACH
Swen HUMPERT
Daniela Schneider
Bernd Neumaier
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Forschungszentrum Jülich GmbH
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Publication of WO2024200180A1 publication Critical patent/WO2024200180A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to specific intermediates in the synthesis process according to the invention, the radiomarkers obtainable according to the invention and the use of the radiomarkers in imaging methods in nuclear medicine or in in vitro applications.
  • Thyroid hormones are essential for the fetal and postnatal development of the nervous system and also play an important role in maintaining brain function in adulthood. They are essential endocrine signaling molecules that regulate a variety of physiological functions. These include, for example, body temperature, heart function, metabolism and consciousness. Thyroid hormones are metabolized several times in the human organism and thus regulate hormone activity.
  • THs are synthesized by the thyroid gland primarily as a prohormone in the form of 3,5,3',5'-tetraiodo-L-thyronine in the thyroid and released into the bloodstream.
  • 3,5,3',5'-tetraiodo-L-thyronine is deiodinated enzymatically at the tissue level by deiodinases (DIOs), mainly to biologically active 3,3',5-triiodothyronine and other, non-biologically active derivatives.
  • DIOs deiodinases
  • 3,3',5-triiodothyronine is generally regarded as the biologically active form of the hormone and acts by binding to TH nuclear receptors.
  • the activation/deactivation cascade can be represented, for example, by the following scheme: In vivo, the prohormone (top compound) is reductively deiodinated by iodothyronine deiodinases, whereby an iodine atom of the outer phenol ring (3' or 5' position) is predominantly replaced by a hydrogen atom.
  • the most important deiodinase is DIO2, which is the only enzyme capable of converting the prohormone into the biologically active hormone T3 (solid arrow, left compound) by monodeiodination of the outer phenol ring.
  • THs play a crucial role not only in various thyroid diseases.
  • Allan-Herndon-Dudley syndrome (AHDS) also known as MCT8 deficiency (monocarboxylate transporter 8 deficiency) - is caused by a genetic disorder that severely affects a child's cognitive abilities, mobility and general health.
  • MCT8 deficiency monocarboxylate transporter 8 deficiency
  • MCT8 is strongly expressed in the liver and brain.
  • the syndrome is characterized by congenital hypotonia, which develops into spastic paralysis with severe psychomotor delays. Affected boys also have muscle hypoplasia, general muscle weakness and limited speech ability. Radioactively labeled thyroxines have been used as molecular probes for some time to study the in-vivo and in-vitro distribution of the biologically active hormone. However, these markers were labeled in the 3',5' position of the outer ring. These positions are unfavorable, however, because the iodine atoms in this position are metabolically very labile.
  • EP 0257352 A1 describes a method for determining the concentration of the free portion of an active substance present in a biological fluid in the presence of natural binding agents, whereby the free and bound portions of the active substance are in equilibrium with one another by a) bringing a sample of the fluid into contact with an unlabeled antibody; b) separating the sample from the unlabeled antibody; c) incubating the unlabeled antibody with a labeled substance (tracer) that cross-reacts with it; d) measuring the portion of the tracer that is bound or not bound to the antibody and using this to determine the concentration of the free portion of the active substance.
  • a labeled substance tracer
  • the method is characterized in that a sample of the blood serum, the thyroxine content of which is to be determined, is mixed with a reagent which essentially consists of a buffered solution which contains radioactive thyroxine and an inhibitor for inhibiting the binding of the thyroxine to thyroxine-binding globulin; adding to the mixture an antiserum which contains an antibody capable of having immunoreactivity with the thyroxine and which has been prepared from an immunogen which contains a conjugate of the N-acetyl derivative of thyroxine coupled to bovine serum albumin with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide; incubating the resulting mixture at a temperature and for a time sufficient to bring the thyroxine bound to the antibody and the unbound thyroxine into substantial equilibrium; separating the unbound thyroxine from the thyroxine bound to the antibody; and determining the relative amounts of the radioactive th
  • EP 0026103A1 also describes a method for determining the concentration of the free fraction of a ligand present in a biological fluid.
  • the liquid may also contain the ligand bound to one or more natural binders, with the bound and free portions of the ligand in equilibrium.
  • the method comprises (a) mixing a sample of the liquid with a labeled derivative of the ligand and with a specific binder for the ligand; (b) causing a Reaction between the free ligand, its labeled derivative and the specific binding agent; (c) if necessary, separation of that portion of the ligand and its labeled derivative which has been bound to the specific binding agent from that portion which has not been so bound; (d) measuring the amount of labeled derivative of the ligand which is bound or not bound to the specific binding agent, and (e) using this measurement to determine the concentration of free ligand in the biological fluid, wherein the labeled derivative of the ligand is selected such that it binds to the specific binding agent, but does not bind to the natural binding agents at all or binds much more weakly than the ligand itself, and the specific binding agent is used in an amount which is insufficient to significantly disturb the equilibrium of bound to free ligand.
  • a process for producing an L-thyroxine radioiodine-labelled in the 3-position on the inner ring which comprises at least the steps: a) reacting 3,5-diiodo-L-thyronine (compound I) with one or more protective group reagents Z, Z', wherein the protective group reagent(s) react with the amine group and the carboxylic acid group of the thyronine to obtain an amino acid-protected thyronine compound (compound II), wherein the individual protective groups Z, Z' can be covalently bonded to one another and used as a single compound: b) Exchange of the two iodine atoms in the 3,5-position of the inner thyronine ring of compound II by stannylation with an organotin compound to obtain a di-3,5-stannyl compound (compound III), wherein R 3 , R 3 ' are independently selected from the group of C1-C4 alkyl or
  • the radiotracer (VII) is produced in a 6-step synthesis starting from 3,5-diiodo-L-thyronine (I). First, the 4-step organic-preparative synthesis of a monostannylated radiolabel precursor (V) takes place.
  • the process according to the invention is a process for producing an L-thyroxine radioiodine-labeled in the 3-position on the inner ring.
  • L-thyroxine is a non-proteinogenic ⁇ -amino acid and has two aromatic rings that are connected to each other via an oxygen bridge.
  • the inner ring is the ring that carries the side chain with the amino acid function.
  • the outer ring is the aromatic ring that carries the OH group.
  • the labeling position in the 3-position is named according to IUPAC nomenclature in relation to the target compound. Accordingly, a radioactive iodine atom is covalently bound to at least this position of the inner ring.
  • the compound can also be in the form of a salt or generally charged.
  • the radioactive iodine isotopes in general and in particular the radioactive iodine isotopes that can be used in medicine are known to the person skilled in the art.
  • the process comprises process step a), in which 3,5-diiodo-L-thyronine (compound I) is reacted with one or more protecting group reagents Z, Z', wherein the protecting group reagent(s) react with the amine group and the carboxylic acid group of the thyronine to obtain an amino acid-protected thyronine compound (compound II) react, whereby the individual protecting groups Z, Z' can be covalently linked and used as a single compound: I II
  • the amino acid group on the side chain of the inner ring is protected.
  • the compound I is reacted with one or more protective groups simultaneously or consecutively.
  • the process comprises process step b), in which the exchange of the two iodine atoms in the 3,5-position of the inner thyronine ring of the compound II takes place by stannylation with an organotin compound.
  • a di-3,5-stannyl compound (compound III) is obtained, where R 3 , R 3 ' are selected independently of one another from the group of C1-C4 alkyl or mixtures thereof:
  • the two iodine groups of the inner ring are replaced by organotin compounds in the form of stannyl groups.
  • the stannyl groups each carry 3 alkyl chains, whereby the alkyl chains can have the same or different numbers of carbon atoms.
  • the alkyl chains can preferably have the same number of carbon atoms, whereby the alkyl chains can range from methyl, ethyl, propyl to butyl.
  • the inner ring carries a stannyl group in the 3rd and 5th positions.
  • the process comprises process step c), in which the amino acid-protected compound III is deprotected to obtain the free amino acid compound (compound IV).
  • the protective group functions on the amine group and the carboxylic acid group can be removed again.
  • the necessary reactions are a function of the protective groups selected and are known to the person skilled in the art. Depending on the function of the selected protective groups, this can be done in one or two steps, for example, whereby the intermediate product can be isolated in a two-step process, but does not have to be.
  • the process comprises process step d), in which the 5-mono-iodo compound V is obtained by selective iodination of the compound IV in the 5-position of the inner ring with elimination of a stannyl group: IV V
  • one of the stannyl groups is exchanged by reaction with an iodine compound, so that an iodine group takes up this position instead of the stannyl group.
  • the reaction of just one stannyl group can, for example, take place in an alcoholic solution by adding iodine which is also dissolved in an alcoholic solvent.
  • the reaction of just one organotin group can, for example, be controlled stoichiometrically.
  • the process comprises process step e), with exchange of the other stannyl group with radioiodine to obtain a thyroxine compound radioiodine-labeled in the 3-position on the inner ring (compound VI): V VI
  • the remaining stannyl group on the inner ring is exchanged for a radioactive iodine atom in this step.
  • This can be done, for example, by reaction with an iodine salt from the group of alkali or alkaline earth elements in aqueous solution.
  • the reaction can preferably be carried out in the presence of an acid at a pH of less than or equal to 4.0.
  • the process comprises process step f), in which the iodination of the outer ring of the compound VI takes place to obtain a compound VII iodinated in the 3' and 5' positions: .
  • VI VII As a final synthesis step, the outer ring is doubly iodinated to obtain an (S)-2-amino-3-[4-(4-hydroxy-3',5'-diiodophenoxy)-3,5-[3- * I]diiodophenyl]propanoic acid.
  • This step can be carried out, for example, in aqueous solution using an alkali or alkaline earth iodide.
  • the reaction can be started, for example, using chloramine-T.
  • a phosphate buffer can be used, for example, to control the pH of this step.
  • Suitable pH ranges for the selective diiodination of the outer ring can be between pH 5.5 and pH 9.5.
  • 9-borabicyclo[3.3.1]nonane can be used as a protecting group reagent in process step a). The use of only one protecting group reagent has proven to be particularly suitable for the simple, rapid and efficient implementation of the two amino acid functions.
  • This reagent reacts with both the amine and the carboxylic acid group to form the complex compound 4'-(4-(4-hydroxyphenoxy)-3,5-diiodobenzyl)-9 ⁇ 4 -boraspiro[bicyclo[3.3.1]-nonan-9,2'-[1,3,2]oxazaborolidin]-5'-one according to the following structural formula:
  • the reaction can be carried out with high yields in an organic, preferably alcoholic solvent under protective gas.
  • the stannylation in process step b) can be carried out with organotin compounds in a pressure range of greater than or equal to 100 MPa and less than or equal to 800 MPa.
  • the pressure range in the reaction can preferably be greater than or equal to 110 MPa and less than or equal to 700 MPa, further preferably greater than or equal to 110 MPa and less than or equal to 600 MPa.
  • the reaction can preferably be carried out under protective gas in an organic solvent, for example dioxane.
  • the radioactive iodination of the inner thyronine ring in process step e) can take place at a pH of greater than or equal to 1 and less than or equal to 2.
  • the radioactive iodination can, for example, be carried out in aqueous solution under acidic conditions. This step can preferably take place in hydrochloric acid solution in the pH range specified above. Alkali or alkaline earth iodides, for example, can be used as a radioactive iodine source. Under these conditions, very rapid and complete reactions with a high specific activity of the products result.
  • the chemical purity can thus be greater than or equal to 85%, preferably greater than or equal to 90% and further preferably greater than or equal to 95%.
  • the non-radioactive iodination of the outer thyronine ring in process step f) can take place at a pH of greater than or equal to pH 8.0 and less than or equal to pH 12.0.
  • the last step of the non-radioactive iodination of the outer ring can preferably be carried out in the pH range specified above. This pH range in particular can lead to rapid and selective iodination in the 3' and 5' positions of the outer ring.
  • the reaction can be carried out, for example, in a buffered ammonium hydroxide solution using an alkali or alkaline earth iodide.
  • the reaction can be started, for example, by adding chloramine-T.
  • the pH can preferably be, for example, greater than or equal to pH 8.5 and less than or equal to pH 11.0, further preferably greater than or equal to pH 9.5 and less than or equal to pH 10.5. Radioactive markers with very high specific activity and very high chemical purity can be obtained within these ranges. Furthermore, the invention relates to an intermediate in the preparation of radioactive iodine compounds of thyronine, wherein the intermediate is selected from the group consisting of the compounds VIII or their amino acid-protected derivatives, wherein the X is selected from the group consisting of I, * I or SnR 3 or combinations thereof, wherein X and X' are not simultaneously I: .
  • the invention provides a radioiodine label, wherein the radioiodine label comprises radioactive (S)-2-amino-3-[4-(4-hydroxy-3',5'-diiodophenoxy)-3,5-[3- * I]diiodophenyl]propanoic acid (compound VII) or a salt thereof: .
  • This radioiodine marker is characterized by a high specific activity and by an improved stability of the compound in various media.
  • the radioactive iodine compound VII can comprise the iodine isotopes iodine-120, iodine-122, iodine-123, iodine-124, iodine-125, iodine-131 or mixtures of these isotopes.
  • the radioiodine markers according to the invention can be labeled with a large number of different radioactive iodine isotopes. Very stable radioiodine markers are obtained which can be used flexibly in a large number of different environmental conditions.
  • the radioiodine marker can have a molar activity of greater than or equal to 3.5 GBq/ ⁇ mol.
  • the radioiodine markers according to the invention can have a particularly high specific initial activity. These high activities can in particular contribute to the markers according to the invention being able to deliver statistically very significant signals even in very small concentrations, for example under in vivo conditions and concentrations.
  • the invention allows the use of a radiomarker according to the invention as a marker in imaging procedures in nuclear medicine or as a radiomarker in in-vitro applications. Due to the improved chemical and radiochemical stability and the high specific activity of the radiomarkers according to the invention, these are significantly better suited for examination in comparison to known radiomarkers marked on the outer ring. physiological and non-physiological media.
  • the imaging methods of nuclear medicine can be selected from the group of positron emission tomography (PET) or single photon emission computed tomography (SPECT). Due to the improved chemical and radiochemical stability and the high specific activity of the radiomarkers according to the invention, these are significantly better suited in the field of imaging diagnostics compared to known radiomarkers marked on the outer ring.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • Synthesis Figure 1 shows the general 6-step synthesis scheme starting from 3,5-diiodo-L-thyronine to obtain the radioiodine marker according to the invention (S)-2-amino-3-[4-(4-hydroxy-3',5'-diiodophenoxy)-3,5-[3- * I]diiodophenyl]propanoic acid.
  • the intermediates according to the invention are prepared and the last two steps (box) show the radioiodine labeling on the inner ring and the iodination of the outer ring.
  • the protection of the amino acid group takes place in one step using a reagent which simultaneously comprises the amine and the carboxylic acid function.
  • a trimethylstannyl group is chosen for the stannylation.
  • 3,5-Diiodo-L-thyronine-9-BBN complex (II) (1.50 g, 2.33 mmol) and Pd(PPh 3 ) 4 (270 mg, 0.23 mmol) are placed in a pressure vessel and purged with argon before the addition of 1,4-dioxane (20 mL) and hexamethyldistannane (1.207 mL, 1.91 g, 5.80 mmol).
  • 3rd stage (S)-2-amino-3-(4-(4- (3,5-Bis(trimethylstannyl)-L-thyronine (IV)) Bis(trimethylstannyl)-L-thyronine 9-BBN complex (III) (490 mg, 0.68 mmol) is dissolved in 2.35 mL methanol, diluted with 117.6 mL chloroform and stirred for 48 h at room temperature. The solvents are evaporated under reduced pressure and the residue is purified by column chromatography (dichloromethane/methanol, 80/20, v/v) to obtain IV as light yellow crystals.
  • the reaction is started by adding aqueous chloramine-T solution (20 ⁇ L, 8 nmol). After a reaction time of 1 min, the resulting [ 131 I]VI is further converted in situ.
  • the chemical purity of [ 131 I]VI is > 95%, the radiochemical purity is > 99% (HPLC) and the molar activity is 13 GBq/ ⁇ mol. 6th step (S)-2-amino-3-[4-(4-hydroxy-3',5'-diiodophenoxy)-3,5-[3- 131 I]diiodophenyl]propanoic acid (L-[ 131 I]thyroxine, VII) .
  • reaction solution is adjusted to a pH of 10 by adding 10 mM ammonium hydroxide solution.
  • Non-radioactive aqueous sodium iodide solution is then added (20 ⁇ L, 16.5 nmol sodium iodide).
  • the reaction is started by pipetting in a chloramine-T solution in phosphate buffer (0.1 M, pH 7.5). Care must be taken to adjust the volume of buffer used so that the final pH of the reaction solution is approximately 7.5. After a reaction time of 1 min, the reaction solution is separated by HPLC.
  • reaction solution is analyzed or purified in an acidic eluent
  • the reaction is first quenched with 1 ⁇ l concentrated formic acid.
  • An HPLC system consisting of a Kromasil column 5RP18250X4.6 mm, the eluent of methanol, water, acetic acid in a ratio of 60:40:0.1 at a flow rate of 1 ml / min and UV detection at 254 nm is suitable for separating and detecting the relevant compounds.
  • Typical capacity factors (k' values) are 1.1 for VI and 7 for VII.
  • the peak cut of the radioiodinated L-[ 131 I]thyroxine ([ 131 I]VII) is collected and measured in an activity meter.
  • the radiochemical yield is given as the ratio of the product activity to the activity used. This value is multiplied by 100 to obtain the radiochemical yield in percent. If short-lived radioiodine isotopes are used, the product activities must be calculated back to the time of measurement of the starting activity (decay correction).
  • the labeling product [ 131 I]VII in the eluent listed above proves to be stable over a period of one week.
  • Radioiodinated product can then be administered as a radiopharmaceutical.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un procédé de synthèse en plusieurs étapes, à partir de 3,5-diiodo-L-thyronine, pour la synthèse d'une L-thyroxine marquée à l'iode radioactif sur le cycle intérieur en position 3. L'invention concerne en outre des intermédiaires spécifiques dans le procédé de synthèse selon l'invention, les marqueurs radioactifs pouvant être obtenus ainsi que l'utilisation des marqueurs radioactifs dans des procédés d'imagerie de la médecine nucléaire ou dans des applications in vitro et ex vivo.
PCT/EP2024/057530 2023-03-29 2024-03-21 Nouveau marqueur à l'iode radioactif de l-thyroxine et son procédé de production WO2024200180A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102023108022.9A DE102023108022A1 (de) 2023-03-29 2023-03-29 Neuer L-Thyroxin-Radioiodmarker und Verfahren zu seiner Herstellung
DE102023108022.9 2023-03-29

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WO2024200180A1 true WO2024200180A1 (fr) 2024-10-03

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2627455A1 (de) 1975-06-26 1977-01-13 Byk Mallinckrodt Chem Prod Verfahren zur radioimmunologischen in-vitro-bestimmung von thyroxin und abgepacktes testbesteck zur durchfuehrung dieses verfahrens
EP0026103A1 (fr) 1979-09-24 1981-04-01 AMERSHAM INTERNATIONAL plc Procédé de détermination de la proportion libre des substances dans les fluides biologiques
EP0257352A1 (fr) 1986-08-05 1988-03-02 Hoechst Aktiengesellschaft Procédé et trousse pour déterminer les agents libres dans les liquides biologiques
EP2662079A1 (fr) * 2012-05-10 2013-11-13 Ordway Research Institute, Inc. Utilisations de formulations d'antagonistes d'hormone thyroïdienne et leurs formes nanoparticulaires associées pour augmenter la chimio-sensibilité et radio-sensibilité dans les cellules cancéreuses ou tumorales

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2627455A1 (de) 1975-06-26 1977-01-13 Byk Mallinckrodt Chem Prod Verfahren zur radioimmunologischen in-vitro-bestimmung von thyroxin und abgepacktes testbesteck zur durchfuehrung dieses verfahrens
EP0026103A1 (fr) 1979-09-24 1981-04-01 AMERSHAM INTERNATIONAL plc Procédé de détermination de la proportion libre des substances dans les fluides biologiques
EP0257352A1 (fr) 1986-08-05 1988-03-02 Hoechst Aktiengesellschaft Procédé et trousse pour déterminer les agents libres dans les liquides biologiques
EP2662079A1 (fr) * 2012-05-10 2013-11-13 Ordway Research Institute, Inc. Utilisations de formulations d'antagonistes d'hormone thyroïdienne et leurs formes nanoparticulaires associées pour augmenter la chimio-sensibilité et radio-sensibilité dans les cellules cancéreuses ou tumorales

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRAVERMAN LEWIS E. ET AL: "Conversion of Thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects", JOURNAL OF CLINICAL INVESTIGATION, vol. 49, no. 5, May 1970 (1970-05-01), pages 855 - 864, XP093180368, ISSN: 0021-9738, DOI: 10.1172/JCI106304 *
DATABASE CAPLUS [online] Chemical Abstract Service, Columbus, Ohio, US; 3 February 1967 (1967-02-03), KIMURA KAZUFUMI: "Preparation and metabolism of doubly labeled radiothyroxine", XP093180688, retrieved from https://stn.org/stn/# Database accession no. 1968:66051 *
KIMURA KAZUFUMI: "Preparation and metabolism of doubly labeled radiothyroxine", NIPPON NAIBUNPI GAKKAI ZASSHI, 3 February 1967 (1967-02-03), pages 746 - 757,671, XP093180697, DOI: 10.1507/endocrine1927.43.8_746 *

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