WO2009141137A2 - New molecule [124i][2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy-benzothialzole] for pet investigations and radiotherapy - Google Patents

New molecule [124i][2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy-benzothialzole] for pet investigations and radiotherapy Download PDF

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WO2009141137A2
WO2009141137A2 PCT/EP2009/003605 EP2009003605W WO2009141137A2 WO 2009141137 A2 WO2009141137 A2 WO 2009141137A2 EP 2009003605 W EP2009003605 W EP 2009003605W WO 2009141137 A2 WO2009141137 A2 WO 2009141137A2
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benzothialzole
pet
solution
iodo
hydroxy
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WO2009141137A3 (en
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Domenico Martini
Paola Panichelli
Gianluca Valentini
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Sparkle S.R.L.
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29D—PRODUCING PARTICULAR ARTICLES FROM PLASTICS OR FROM SUBSTANCES IN A PLASTIC STATE
    • B29D35/00—Producing footwear
    • B29D35/12—Producing parts thereof, e.g. soles, heels, uppers, by a moulding technique
    • B29D35/14—Multilayered parts
    • B29D35/142—Soles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • the present invention concerns a new molecule, [ 124 I] [2-(3'-iodo-4'- methylaminophenyl)-6-hydroxy-benzothialzole] ideal for use in PET diagnostic imaging.
  • PET Pulsitron Emission Tomography
  • PET diagnostics introduces two clinical parameters, early diagnosis and optimization of treatment, which change the life expectations of patients and improve the management of their illness.
  • Other fields of application are acquiring an increasingly important role, such as neurology, cardiology and rheumatology.
  • PET is destined to play a role of major importance in the study of age-related diseases such as Parkinson's and Alzheimer's disease, as it has had in the study of molecules by means of which it is possible to make early diagnoses of acute cardiac events which are, nowadays, one of the main causes of death.
  • PET is carried out by injecting a radiopharmaceutical into the patient and following the distribution of the radiopharmaceutical inside the human body with special machines called PET (Positron Emission Tomography) scanners.
  • the radiopharmaceuticals are composed of two essential parts: a radioisotope (which emits beta rays) and a molecule which binds with the radioisotope, l constructing the metabolic substrate of the PET investigation.
  • the radioisotopes are produced by an instrument called a Cyclotron and they are bound to the molecule to be studied by specific methods of chemical synthesis.
  • the most commonly used radioisotope today is 18-Fluoro which has a half- life of approx. two hours and has suitable chemical characteristics for being easily bound, in liquid form, to various molecules.
  • FDG 18-Fluoro-deoxyglucose
  • Another new tracer is [18F]Fluorothymidine.
  • Proliferation Imaging Tracer in Humans Correlation of [ F]FLT Uptake by Positron Emission Tomography with Ki-67 Immunohistochemistry and Flow Cytometry in Human Lung Tumors Clinical Cancer Research Vol. 8, pagg. 3315-3323, November 2002. 4%.3-Deoxy-3-[ ]8 FJFluorothymidine-Positron Emission Tomography for Noninvasive Assessment of Proliferation in Pulmonary Nodules Cancer Research Vol. 62, pagg. 3331-3334, June 15, 2002.
  • TargetedRadiopharmaceuticals Labelede with alfa-, beta-, and Auger
  • the Hypoxic cell a targhet for selective cancer therapy.
  • Iodine- 124[ 124 I] which makes it possible to quantify thyroid lesions. It is currently used in conventional nuclear medicine, but with rather unsatisfactory and sketchy results. Iodine- 124 [ 124 I] is an unstable isotope that does not exist in nature. It has a half-life of 4/18 days and is produced through a nuclear reaction: 124 Te (p,n) enriched by 99.8 % with 124 TeO 2 using proton energy in a range of 14-10 MeV.
  • Iodinel24 [ 124 I] is therefore an ideal isotope used as a radiotracer in nuclear medicine for positron emission tomography (PET).
  • PET positron emission tomography
  • S6.PET quantitation and imaging of the non-pure positron-emitting iodine isotope 1241 Applied Radiation and Isotopes 56 (2002) 673-679.
  • Applied Radiation and Isotopes 52 (2000) 181-184.
  • AD Alzheimer's Disease
  • the anatomopathological detail that distinguishes it is the presence of cerebral deposits of amyloid-beta peptide plaques with intracellular filaments which contain the hyperphosphorylated protein tau.
  • the depositing of these plaques in the cerebral substance can take place prior to the emergence of the symptoms typical of the disease and is a diagnostic target on which studies have been focusing for many years now.
  • the radiopharmaceuticals that show up deposits of amyloid plaques in the cerebral tissue represent the more advanced diagnostic phase for defining the early stages of the disease.
  • Iodine- 124[ 124 I] in the form Of Na 124 I is used for PET analysis and its long half-life (4/18 days) enables both the development of multiple radiochemical syntheses and the detection of slow biochemical processes that could not be detected using tracers with a short half-life such as 11 C and 18 F.
  • Iodine- 124[ 124 I] in the form Of Na 124 I is used in radio immunodiagnosis and radio immunotherapy as a dosimetry indicator to verify the status of the therapy with 131 I, used in the treatment of thyrotoxicosis and tumours of the thyroid.
  • 131 I used in the treatment of thyrotoxicosis and tumours of the thyroid.
  • Iodine- 131( 131 I) however, a PET investigation is not possible because its energy is too high and it cannot be detected by the instrument. For this reason it is used during radio immunotherapy with Iodine- 124 [ 124 I] as this enables the progress of the therapy to be followed through PET imaging.
  • Iodine- 124[ 124 I] was not considered to be suitable for PET imaging studies because it is a low emitter of positrons.
  • Iodine- 124[ 124 I] in nuclear medicine compared to the diagnostic application currently in use, i.e. Iodine- 123 [ 123 I] with the SPECT technique:
  • the new molecule [ 124 I] [2-(3'-iodo-4' -methylaminophenyl)-6-hydroxy- benzothialzole] is obtainable through a chemical synthesis process, starting from the radioisotope Iodine- 124 [ I] .
  • a 18 MeV IBA cyclotron is used, with a solid target (COSTIS) dedicated to the formation of Cu-64 and Iodine- 124[ 124 I].
  • COSTIS solid target
  • the method consists of bombardment with protons for approx. eight hours at a current of 18 ⁇ A, on enriched Tellurium oxide 124 TeO 2 , mass of tellurium oxide 250 mg, on a platinum disc (target substrate).
  • the yield of the bombardment is approx. 3.7 GBq of Iodine- 124 [ 124 I], while the energy of the beam has a maximum cross section of 14 Mev. Additionally, during irradiation of the solid targets, it is important for the proton beam to be perfectly centred; to do this, it is essential to know its shape. This is detected by a special autoradiography scanner (Cyclone) by means of which the image of a previously irradiated aluminium disc is recorded, on a phosphorus film.
  • Cyclone autoradiography scanner
  • the substrate used for the Target is a Platinum disc with a diameter of 24 mm and a circular cavity of 12 mm, which guarantees good conductivity and resistance to corrosion, and a mixture of isotopically enriched tellurium oxide 124 TeO (95%) and aluminium oxide Al 2 O 3 (5%) weighing approx. 250 mg is used, so that the alumina acts as a binding agent for the crystal matrix.
  • the mixture is smelted at 753 0 C and re-solidified in a quartz furnace for approx. 2 hours .
  • the Iodine-124[ 124 I] recovery time is approx. an hour and the mix is smelted at 753 0 C releasing 124 I 2 in the form of gas; the 124 I 2 is bubbled through a hyperpure solution of NaOH 0.02 N; the 124 I 2 is entrapped in the NaOH solution in the form of [ 124 I]NaI (sodium iodide at 95%), sodium iodate NaIO 3 and periodate NaIO_j (5%).
  • the entire chemical process takes place inside the synthesis module placed in a glove box in order to ensure the product's sterility in accordance with GMP guidelines which guarantee a product, the main features of which are quality and efficacy.
  • the radionuclidic purity of Iodio-124[ 124 I] is obtained using a Germanium Gamma ray Spectrometer in order to detect the presence of Iodine- 125 [ 125 I], Iodine- 126[ 126 I], Iodine- 130[ 130 I], Iodine-131 [ 131 I]; these impurities must be lower than 0.1%. Observing the peaks of energy, the purity of the radionuclide (excluding the presence of Iodine- 123 [ 123 I] which is, in any case, at a bare minimum) must be greater than 99.5%.
  • the chemical synthesis process consists of adding a solution containing 185 MBq OfNa 124 I in 500 ⁇ l of NaOH 0.02 N followed by 40 ⁇ l of a chloramine-T solution in glacial acetic acid (28 mg di chloramine-T dissolved in 500 ⁇ l of glacial acetic acid) to a solution containing 1.1 mg of precursor [2-(4'- methylaminophenyl)-6-methanesulfonoxy-benzothialzole] in 250 ⁇ l of glacial acetic acid.
  • the product labelled with Iodine- 124 [ 124 I] is eluted with 2 ml di ethanol.
  • the above-described new molecule is prepared by dissolving the active substance in salt solution; filtration of the solution with a 0.22 ⁇ m filter with sterilizing effect, followed by the immediate transfer of the filtrate into bottle- shaped containers.
  • the operations relative to the process of freeze-drying are prepared by dissolving the active substance in salt solution; filtration of the solution with a 0.22 ⁇ m filter (with sterilizing effect, followed by the immediate transfer of the filtrate in a sterile block), distribution into the bottle-shaped containers.
  • the product to be treated is frozen at a temperature of -40 0 C inside stainless steel containers (that meet health and hygiene standards) which are, in turn, placed inside the lyostat in which the pressure is reduced to a value such that the water present in the previously frozen product may sublimate under vacuum by heating to a temperature of 30° C, leaving the product almost completely dried. In this way a solid, porous, crumbly, hygroscopic mass is obtained that is very soluble in solvent, and that occupies the same volume of the initial frozen, or freeze-dried, mass.
  • the new molecule [ 124 I] [2-(3'-iodo-4'-methylami ⁇ ophenyl)-6-hydroxy- benzothialzole] may be administered by general oral route in the form of tablets, soft or hard gelatin oil or operculated capsules, sugar-coated pills, dispersing powders, suspensions or emulsions or by topical or transdermal route in the appropriate forms and in vehicles or devices suited for the administration of the active principle at the site of interest; it can also be administered through general parenteral route in the form of aqueous or oily solutions, or suspended in appropriate dispersing agents, even in the form of lyophilized products, to be dispersed at the time of administration.

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Abstract

New molecule [124I] [2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy-benzothialzole] obtainable through a chemical synthesis process, starting from the radioisotope Iodine-124[124I] and possessing mainly PET diagnostic imaging properties.

Description

Title
New molecule [124I] [2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy- benzothialzole] for PET investigations and radiotherapy.
Field of invention
The present invention concerns a new molecule, [124I] [2-(3'-iodo-4'- methylaminophenyl)-6-hydroxy-benzothialzole] ideal for use in PET diagnostic imaging.
Background PET (Positron Emission Tomography) is a diagnostic method through which the metabolism of the various organs under examination may be studied, in order to obtain early diagnostic parameters for various diseases. Over recent years, the use of this method has expanded considerably in the USA and PET diagnostic centres are currently increasing all over Europe, mainly in the oncology sector. In this sector, PET diagnostics introduces two clinical parameters, early diagnosis and optimization of treatment, which change the life expectations of patients and improve the management of their illness. Other fields of application are acquiring an increasingly important role, such as neurology, cardiology and rheumatology. In an era in which the average life span is continuously increasing, PET is destined to play a role of major importance in the study of age-related diseases such as Parkinson's and Alzheimer's disease, as it has had in the study of molecules by means of which it is possible to make early diagnoses of acute cardiac events which are, nowadays, one of the main causes of death. PET is carried out by injecting a radiopharmaceutical into the patient and following the distribution of the radiopharmaceutical inside the human body with special machines called PET (Positron Emission Tomography) scanners. The radiopharmaceuticals are composed of two essential parts: a radioisotope (which emits beta rays) and a molecule which binds with the radioisotope, l constructing the metabolic substrate of the PET investigation. The radioisotopes are produced by an instrument called a Cyclotron and they are bound to the molecule to be studied by specific methods of chemical synthesis. The most commonly used radioisotope today is 18-Fluoro which has a half- life of approx. two hours and has suitable chemical characteristics for being easily bound, in liquid form, to various molecules.
The molecule most commonly used today is 18-Fluoro-deoxyglucose (FDG) which permits the identification, inside the body, of sites showing a greater consumption of glucose compared to normal metabolic standards and which may, therefore, be of a cancerous nature.
1. Fluorine- 18 labeling of protein JNuvl Med 1987; 28: 462- 70.
2. PET tracer and radiochemistry. Ann Acad Med Singapore; 33: 146-154.
3. Oxygen present during azeotropic drying drastically reduces the radiochemical yeld of 2-FDG. J.Label. Compds. Radiopharm. 28, 83,
1990.
4. Factors affecting quality control of [ FJFDG injection: bacterial endotoxins test, aluminum ions test and HPLC analysis for FDG and CIDG. Applied Radiation and Isotopes 62: 889-895. 5. The United States Pharmacopeia, 25th ed., and The National Formulary, 20th ed. Rockeville, MD: United States Pharmacopeia Convention, Inc., 2002: 752-753.
6. USP monograph and tests of radipharmaceutical puritά [letter]. Am J Health Syst Pharm. 1995; 52: 1817-1818. 7. Capintec, Inc. [Pittsburg, PA], written communication, January 2002.
1 δ
8. Fludeoxiglucose ( F) injection. In: European Pharmacopeia. 4th ed Strasbourg, France: European Directorate for the Qualita of the Medicines; 2002: 2316-2319.
9. J. Cereb. Blood. Flow Metab. 11,485, 1991. 10.4,7, 13, 16,21 ,24-Hexaoxa- 1 , 10-diazobicyclo-(8,8,8)hexacosane (Kriptofix
222) [material safety data sheet]. St. Louis, MO: Sigma- Aldrich; August 3,
2000.
11.PET radiopharmaceuticals in Europe: current use and data relevant for the formulation of summaries of product characteristics (SPCs). Eur J
Nucl Med 22,1420,1995. 12.Bacterial endotoxins test (general charter 85). In: The United States
Pharmacopeia, 25th ed., and The National Formulary, 20th ed. Rockville,
MD: United States Pharmacopeial Convention, Inc.; 2002: 1889-1893. 13. Finished drug product controls and acceptance criteria. In: Guidance: PET
Drug Products — Current Good Manufacturing Practice (CGMP).
Rockville, MD: Food and Drug Administration; 2002:27-28. 14. PET tracers and radiochemistry Ann Acad Med Singapore 2004; 33: 146-
54. 15. Molecular imaging of cancer with positron emission tomography Nat Rev
Cancer, 2002; Sept (2): 683-693).
16. Quantitative imaging of the T cell antitumor response by positron- emission tomography PNAS Feb 4, 2004; 100(3): 1232-1237. 17. Clinical applications of FDG-PET in oncology Acta Med Aust 2002; 29: 162-70.
IS. Evolving role of Positron Emission Tomography in breast cancer imaging
Semin Nucl Med 2005; 35: 84-99. 19.^4 review of small animal imaging planar and pinhole SPECT F camera imaging Vet Rad Ultrasound 2005; 46(2): 162-170. 2O.Small animal imaging with high resolution single photon emission tomograohy Nucl Med Biol 2003; 30: 889-895. 21.Measurement of input functions in rodents: challenges and solutions. Nucl
Med Biol 2005; 32: 679-685. 22. Calculation of positron range and its effect on the fundamentl limit of positron emission tomography system spatial resolution. Phys Med Biol
1999 mar; 44(3): 781-799).
23.-4 review of small animal imaging planar and pinhole SPECT F camera imaging. Vet Rad Ultrasound 2005 ; 46 (2) : 162- 170.
24. Evaluation of anestesia effects on 18F-FDG uptake in mouse brain and heart using small animal PET. Nucl Med Biol 2004; 31 : 251-256. 25. J4 general approach to the non-invasive imaging of trans gene using cis- linked herpes simplex virus thymidine kinase Neoplasia Oct 1999; 1(4): 315-320.
The limitation emerging from FDG application is that of insufficient specificity in differentiating tumour sites from other possible sites of infection. In this regard, other molecules that increase diagnostic specificity have been studied, especially in connection with certain forms of tumour such as, for example, prostate, lung and brain tumours. One of these new tracers is [18F]Fluorocholine. 26. F-Fluorocholine: A New Oncologic PET Tracer The Journal of Nuclear
Medicine Vol. 42 N0. 12, December 2001.
21.Synthesis and Evaluation of F-Labeled Choline Analogs as Oncologic PET Tracers. The Journal of Nuclear Medicine VoI 42 N0 12, December
2001 28. Localization of Primary Prostate Cancer with Dual-Phase F-
Fluorocholine PET. The Journal of Nuclear Medicine Vol. 47 N0. 2,
February 2006. 29. Uptake of 18F-Fluorocholine, 18F-Fluoroethyl-L-Tyrosine, and 18F-FDG in Acute Cerebral Radiation Injury in the Rat: Implications for Separation of Radiation Necrosis from Tumor Recurrence The Journal of Nuclear
Medicine Vol. 45 N0. 11, November 2004. 30. PET for Prosatate Cancer Imaging: Still a Quandary or the Ultimate
Solution? The Journal of Nuclear Medicine Vol. 43 N0. 2, February 2002. 31.Development of 18F -Fluor oethylcholine for Cancer Imaging with PET:
Synthesis, Biochemistry, and Prostate Cancer Imaging The Journal of Nuclear Medicine Vol. 43 N0. 2, February 2002.
32.Synthesis and Evaluation of 18F-labeled Choline as an Oncologic Tracer for Positron Emission Tomography: Initial Findings in Prostate Cancer.
Cancer Research Vol. 61, pagg. 110-117, January 1, 2000
33.Pharmacokinetics and Radiation Dosimetry of F-Fluorocholine The Journal of Nuclear Medicine Vol. 43 N0. 1, January 2002.
34.Positron Emission Tomography/Computed Tomography with F-18- fluorocholine for Restaging of Prostate of Prostate Cancer Patient: Meaningful at PSA < 5 ng/ml? Molecular Imaging And Biology Vol. 8, pagg 43-48, 2006
IS 35. F-Labeled Bombesin Analogs for Targeting GRP Receptor-Expressing Prostate Cancer The Journal of Nuclear Medicine Vol. 47 N0. 3, March 2006
Another new tracer is [18F]Fluorothymidine.
36. 3 '- F-Fluoro-3 '-Deoxy-L-Thymidine: A New Tracer for Staging Metastatic Melanoma? The Journal of Nuclear Medicine Vol. 44 N0 12, December 2003.
37. [ F]FLT PET for diagnosis and staging of thoracic tumors. European Journal of Nuclear Medicine and Molecular Imaging Vol. 30 N0 10, October 2003 38. [ F] 3-deoxy-3 '-βuorothymidine positron emission tomography: Alternative or diagnostic adjunct to 2-[ F]-fluoro-2-deoxy-D-glucose positron emission tomography in the workup of suspicious central focal lesions? The Journal of Thoracic and Cardiovascular Surgery Vol. 127 N0 4 April 2004 39. Potential impact of [18F] 3 '-deoxy-3 '-βuorothymidine versus [18F]fluoro-2- deoxy-D-glucose in positron emission tomography for colorectal cancer.
European Journal of Nuclear Medicine and Molecular Imaging Vol. 30 N0
7, July 2003 40. Fully automated system of 3 '-deoxy-3 '-18 [F] βuorothymidine. Nuclear of
Medicine and Biology, August 2004 Vol. 31, 803-809. 41. Imaging Proliferation in Lung Tumors with PET: 18F-FLT Versus 18F-
FDG The Journal of Nuclear Medicine Vol. 44 N0. 9, September 2003.
42. PET Imaging with F-FLT and Thymidine Analogs: Promise and Pitfalls The Journal of Nuclear Medicine Vol. 44 N0. 9, September 2003.
43. Rat Studies Comparing 11C-FMAU, 18F-FLT, and 76Br-BFU as Proliferation Markers. The Journal of Nuclear Medicine Vol. 43 N0 12, December 2002.
44.Evaluation of 3 '-Deoxy-3 '- F-Fluorothymidine for Monitoring Tumor Response to Radiotherapy and Photodynamic Therapy in Mice. The Journal of Nuclear Medicine Vol. 45 N0 10, October 2004.
45. F-Fluoro-L-Thymidine and C-Methylmethionine as Markers of
Increased Transport and Proliferation in Brain Tumors The Journal of
Nuclear Medicine Vol. 46 N0. 12, December 2005. 46. Monitoring Tumor Cell Proliferation by Targeting DNA Synthetic
Processes with Thymidine and Thymidine Analogs The Journal of Nuclear
Medicine Vol. 44 N0. 12, December 2003. 47.7« Vivo Validation of 3 'deoxy-3 '-[18F]fluorothymidine ([18F]FLT) as a
Proliferation Imaging Tracer in Humans: Correlation of [ F]FLT Uptake by Positron Emission Tomography with Ki-67 Immunohistochemistry and Flow Cytometry in Human Lung Tumors Clinical Cancer Research Vol. 8, pagg. 3315-3323, November 2002. 4%.3-Deoxy-3-[]8FJFluorothymidine-Positron Emission Tomography for Noninvasive Assessment of Proliferation in Pulmonary Nodules Cancer Research Vol. 62, pagg. 3331-3334, June 15, 2002.
49.Usefulness of 3 '-[F-18]Fluoro-3 '-deoxythymidine with Positron Emission Tomography in Predicting Breast Cancer Response to Therapy. Molecular Imaging and Biology Vol. 8, pagg. 36-42, 2002.
5Q.A simplified analysis off FJ 3 '-deoxy-3 'fluorothymidine metabolism and retention. European Journal of Nuclear Medicine and Molecular Imaging
Vol. 32 N0 11, November 2005. 51./" F] 3 '-Fluorothymidine, a Much Promising New Oncological PET
Tracer: From Precursor Synthesis to Pet Images. Regional workshop on
F- 18 radiopharmaceuticals, Smolenice, Slovakia, November 25-27, 2001. 52.[18FJFLT-PET in oncology: current status and opportunities European
Journal of Nuclear Medicine and Molecular Imaging 23 November 2004. Another rapidly expanding sector in PET diagnostics is that of the development of radiotherapy treatment plans through which the therapeutic effect can be optimized. In this regard, there are various phases of development in the research carried out in this sector which spans from the demonstrated usefulness of FDG to the recent experiences with the isotope copper-64, in particular the molecule 64Cu-ATSM through which it is possible to obtain a map of the distribution of oxygen inside the tumour mass. 53. Molecular mechanism of copper uptake and distribution; Current Opinion in Chemical Biology 2002, 6: 171-180.
5 A. Biochemical Characterization of the Human Copper Transporter Ctrl; The Journal of Biological Chemistry, vol 277 No. 6, Issue of February 8, pp. 4380-4387, 2002. 55.A comparison of PET imaging characteristics of various copper radioisotopes; Eur J. Nucl Med MoI Imaging (2005) 32: 1473-1480. 56.Copper Radionuclides and Radiopharmaceuticals in Nuclear Medicine;
Nuclear Medicine and Biology, VoI 23, pp. 957-980, 1996. 57. Basic characterization of 64Cu-ATSM as a radiotherapy agent; Nuclear
Medicine and Biology 32 (2005) 21-28. 58. Double-tracer autoradiography with Cu-ATSM/FDG and immunohistochemical interpretation in four different mouse implanted tumor models; Nuclear Medicine and Biology 33 (2006) 743-750. 59.A novel approach to overcome hypoxic tumor resistance: Cu-ATSM- guided intensitάmodulated radiation therapy; Int. J. Radiation Oncology Biol. Phys. VoI 49, no 4, pp. 1171-1182, 2001. βO.Mouse Extrahepatic Hepatoma Detected on MicroPET Using Copper (II)-
64 Chloride Uptake Mediated by Endogenous Mouse Copper Transporter
1; MoI Immaging Biol (2005) 7:325-329. β\.Copper-64-diacetyl-bis(N4-methylthiosemicarbazone): An agent for radiotheraphy; PNAS 2001; 98; 1206-1211.
62. Enhancing Targeted Radiotherapy by Copper (II)diacetyl-bis(N4- methylthiosemicarbazone) Using 2-Deoxy-d-Glucose; Cancer Research
63, 5496-5504, September 1, 2003.
63. Molecular imaging with copper-64; Journal of Inorganic Biochemistry 98 (2004) 1874-1901.
64. Theragnostic imaging for radiation oncology: dose-painting by numbers;
Lancet Oncol. 2005; 6:112-17. 65. Hipoxia imaging-directed radiation treatment plannning; Eur J Nucl Med
MoI Imaging (2006) 33: 44-53. 66. Subcellular Localizzation of Radiolabeled Somatostatin Analogues:
Implications for Targeted Radiotheraphy of Cancer; Cancer Research 63,
6864-6869, October 15, 2003. 67 '.Three-dimensional maximum a posteriori (MAP) imaging with radiopharmaceutical lebeled with three Cu radionuclides; Nuclear
Medicine and Biology, VoI 33 (2006) 217-226.
68. Dosimetry of Internal Emitters; Journal of Nuclear Medicine VoI 46 No. 1 (Suppl) 18-27.
69. Dosimetry in Peptide Radionuclide Receptor Therapy; A Review; J Nucl.
Med 2006; 47: 1467-1475. 1 '0. Electron-and Positron-Emitting Radiolanthanides for Therapy: Aspects of
Dosimetry and Production; J Nucl. Med 2006; 47: 807-814. 1 \ .Radiation-Induced Biologic Bystander Effect Elicited In Vitro by
TargetedRadiopharmaceuticals Labelede with alfa-, beta-, and Auger
Electron-Emitting Radionuclides; J Nucl. Med 2006; 47:1007-1015. ll.Auger Electron Spectra; Acta Oncologica Vol. 39, No 6, pp. 673-679,
2000. This molecule, synthesized in the USA, changes the treatment plans thanks to its capacity to reduce the intervention area, excluding all those areas that do not present oxygen and are not, therefore, likely to respond to radiotherapy. Studies of this type exist also with molecules labelled with 18-Fluoro, such as F-MISO. 73. Hypoxia and Glucose Metabolism in Malignant Tumors: Evaluation by
[18F]Fluoromisonidazole and [18F]Fluorodeoxyglucose Positron
Emission Tomography Imaging. Clinical Cancer Research Vol.10, 2245-
2252, April 1, 2004
74. Hypoxia-induced increase in FDG uptake in MCF7 cells. J Nucl Med 2001; 42:170-5
15. Effect of intratumoral heterogeneity in oxygenation status of FMISO PET, autoradiography and electrode P02 measurament in murine tumors. Int. J.
Radiation Oncology Biol. Phys., Vol. 62, No. 3, pp. 854-861, 2005 iβ.Effects of hypoxia on the uptake of tritiated thymidine, L-leucine, L- methionine and FDG in cultured cancer cells. J Nucl Med 1996; 37:502-6. 11.Biologic correlates of (18)fluorodeoxy glucose uptake in human breast cancer measured by Positron Emission Tomography. J Clin Oncol 2002; 20:379-87.
IS. The Hypoxic cell: a targhet for selective cancer therapy. Cancer Res
1999;59:5863-70. 19. Characterization of [18F]βuoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia. J Nucl Med 1999; 40:1072-9. SO.Prognostic impact of Hypoxia Imaging withlδF-Misonidazole PET in
Non-Small Cell Lung Cancer and Head and Neck Cancer Before
Radiotherapy. J Nucl Med 2005; 46:253-260 81. Imaging oxygenation of human tumours Eur Radiol (2007) 17: 861-872
82. Assessment of Hypoxia and Perfusion in Human Brain Tumors Using PET withl8F-Fluoromisonidazole and 150-H2O. J Nucl Med 2004; 45:1851-
1859
83. On Measuring Hypoxia in Individual Tumors with Radiolabeled Agents J Nucl Med Vol. 42 No. 11 November 2001
84. Introducing fluorine- 18 βuoromisonidazole positron emission tomography for the localisation and quantification of pig liver hypoxia. Eur J Nucl
Med 1999 26:95-109
85. Fully automated one-pot sinthesis of [18F]Fluoromisonidazole. Nucl Med and Biology 32 (2005) 553-558.
But the characteristics of Copper-64, particularly its 12-hour half-life, make it a radioisotope of great future interest for this sector.
PET provides the possibility, with the use of specific tracers, to carry out more precise treatment plans in quantitative measures, both for metabolic therapy and for radiotherapy. The most interesting tracer for metabolic therapy is Iodine- 124[124I] which makes it possible to quantify thyroid lesions. It is currently used in conventional nuclear medicine, but with rather unsatisfactory and sketchy results. Iodine- 124 [124I] is an unstable isotope that does not exist in nature. It has a half-life of 4/18 days and is produced through a nuclear reaction: 124 Te (p,n) enriched by 99.8 % with 124TeO2 using proton energy in a range of 14-10 MeV. This nuclear reaction brings the 124I to a very high degree of purity compared to 125I and 126I, the purity levels of which are lower. Iodinel24 [124I] is therefore an ideal isotope used as a radiotracer in nuclear medicine for positron emission tomography (PET). S6.PET quantitation and imaging of the non-pure positron-emitting iodine isotope 1241 Applied Radiation and Isotopes 56 (2002) 673-679. 87.Preparation of 124I solutions after thermodistillation of irradiated 124TeO2 targets. Applied Radiation and Isotopes 52 (2000) 181-184.
^.Highly sensitive spectrophotometry determination of trace amounts of tellurium(IV) with the tungstate-basic dyes-poly (vinyl alcolhol) system.
Analyst, April 1998, Vol. 123 (695-697).
89.Quantitation of small — animal I activity distributions using a clinical PET/CT scanner. J Nucl Med 2004; 45:1237-1244.
90. Performance of a block detector PET scanner in imaging non-pure positron emitters modelling and experimental validation with 124I. Phys.
Mod. Biol. 49 (2004) 5505-5528.
91. Synthesis and preliminary evaluation of L-O-[123I]IODODOPA as a potential sped brainimaging agent. Journal of labelled compound and radiopharmaceuticals- Vol. XXVIII, No. 2. 92.1odine-124 labelled Annexin — V as a potential radiotracer to study apoptosis using positron emission tomography. Applied Radiation and
Isotopes 58 (2003) 55-62. 93. Imaging apoptosis in vivo using 1241-annexin V and PET. Nuclear
Medicine and Biology 32 (2005) 395^02. 94.[18FJβ-CIT - FP is superior to [l ' C] β-CIT-FP for quantitation of the dopamine transporter. Nuclear Medicine & Biology, Vol. 24, pp. 621-627, 1997.
95. Evaluation of dosimetry of radioiodine therapty in benign and malignantthyroid by means of iodine-124 and PET. Eur. J. Nucl. Med.
(2002) 29:760-767.
96.124I in PET imaging: impact on quantification, radiopharmaceutical development and distribution. Eur. J. Nucl. Med. (2006) 33:1247-1248. 91. Value of 124I-PETZCT in staging of patients with differentiated thyroid cancer. Eur. Radiol. (2004) 14:2092-2098.
An important application, already object of the Italian national patent application no. MC2007A000196 of 10/10/2007 (inventors: Martini Domenico, Panichelli Paola, Valentini Gianluca), is iodine 124βCIT Iodine- 124 [2 β-carbomethoxy-3β-(4-iodophenyl)-tropane] which enables the effecting of presynaptic diagnostics of the activities of the corpus striatum in a quantitative manner, with the possibility of pharmacological tests at a lower cost compared to iodine- 123 βCIT iodine 123 βCIT Iodine- 124 [2 β- carbomethoxy-3β-(4-iodophenyl)-tropane] and with a marked increase in quality.
Alzheimer's Disease (AD) is a degenerative disease associated with progressive cognitive and mental degeneration. The anatomopathological detail that distinguishes it is the presence of cerebral deposits of amyloid-beta peptide plaques with intracellular filaments which contain the hyperphosphorylated protein tau. The depositing of these plaques in the cerebral substance can take place prior to the emergence of the symptoms typical of the disease and is a diagnostic target on which studies have been focusing for many years now. The radiopharmaceuticals that show up deposits of amyloid plaques in the cerebral tissue represent the more advanced diagnostic phase for defining the early stages of the disease. In this regard various radioligands have been identified, the first used in studies on humans, in 2002, was FFDDNP by means of which amyloid plaques could be viewed in vivo. Subsequently, in 2004, PIB, known as the Pittsburgh compound, was used experimentally. Another tracer used is 11CSb-13, a derivative of stilbene which has been proved to possess a moderate lipophilicity and a rapid brain washout. Experiments were carried out in 2007 using tracers bound to Iodine- 125 [ I], such as [125I]IMPY and [125I]TZDM, with a benzothiazole structure.
98.Mei-Ping Kunga, Catherine Houa, Zhi-Ping Zhuanga, Bin Zhangb, Daniel Skovronskyb, John Q. Trojanowski, Virginia M.-Y. Lee, Hank F. Kung. An improved thioflavin-T derivative for in vivo labeling of β-amyloid plaques. Brain Research, 2002, 956:202-210. 99. Mei-Ping Kung, Daniel M. Skovronsky, Catherine Hou, Zhi-Ping Zhuang, Tamar L. Gur, Bin Zhang, John Q. Trojanowski, Virginia M.-Y. Lee, and Hank F. Kung. Detection of Amyloid Plaques by Radioligands for Aβ40 andAβ42 . Journal of Molecular Neuroscience, 2002, 20: 15-23.
100. Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE. Synthesis and evaluation of llC-labeled 6-substituted 2- arylbenzothiazoles as amyloid imaging. Agents J Med Chem, 2003; 46: 2740-54.
101. Brian J. Bacskai, Gregory A. Hickey, Jesse Skoch, Stephen T. Kajdasz, Yanming Wang, Guo-feng Huang, Chester A. Mathis, William E. Klunk, Bradley T. Hyman Source: Four-Dimensional Multiphoton Imaging of Brain Entry, Amyloid Binding, and Clearance of an Amyloid-β Ligand in Transgenic Mice. National Academy of Sciences, 2003; 21 : 12462-12467.
102. Yanming Wang,, Chester A. Mathis, Guo-Feng Huang, Manik L. Debnath, Daniel P. HoIt1Li Shao, and William E. Klunk. Effects of Lipophilicity on the Affinity and Nonspecific. Binding of lodinated Benzothiazole Derivatives. Journal of Molecular Neuroscience, 2003; 20:255-260.
103. Edward Zamrini, Susan De Santi, Martin Tolar. Imaging is superior to cognitive testing for early diagnosisof Alzheimer's disease. Neurobiology of Aging, 2004; 25: 685-691.
104. Randy L. Buckner. Memory and Executive Function in Aging and AD: Multiple Factors that CauseDecline and Reserve Factors that Compensate. Neuron, 2004; 44: 195-208. 105. B William E. Klunk, MD, Henry Engler, Agneta Nordberg, Yanming Wang, Gunnar Blomqvist, Daniel P. Holt, Mats Bergstrom, Irina Savitcheva, Guo-feng Huang, Sergio Estrada, Birgitta Ause'n, Manik L. Debnath, Julien Barletta, Julie C. Price, Johan Sandell, Brian J.Lopresti, Anders Wall, Prnilla Koivisto, Gunnar Antoni, Chester A. Mathis, and Bengt Langstrom. Imaging Brain Amyloid in Alzheimer's Disease with
Pittsburgh Compound-B. Orignal Articles, 2004; 55:306-319. 106. Hiroshi Toyamal, Daniel Ye, Masanori Ichise, Jeih-San Liow, Lisheng Cai, David Jacobowitz, John L. Musachio, Jinsoo Hong, Mathew Crescenzo, Dnyanesh Tipre, Jian-Qiang Lu, Sami Zoghbi, Douglass C. Vines, Jurgen Seide, Kazuhiro Katada, Michael V, Green, Victor . Pike, Robert M. Cohen, Robert B. Innis. PET imaging of brain with the β- amyloid probe, [HC]6-OH-BTA-l,in a transgenic mouse model of Alzheimer's disease. European Journal of Nuclear Medicine and Molecular Imaging , 2005; 32. 107. Julie C Price, William E Klunk, Brian J Lopresti, Xueling Lu, Jessica A Hoge, Scott K Ziolko, Daniel P Holt, Carolyn C Meltzer, Steven T DeKosky andChester A Mathis. Kinetic modeling of amyloid binding in humansusing PET imaging and Pittsburgh Compound-B. Journal of Cerebral Blood Flow & Metabolism, 2005; 25:1528-1547. 108. Hoge,a Brian J. Lopresti, Steven T. DeKosky and Julie C. Pricea. Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer 's disease. Neurolmage, 2006; 33 :94-102. 109. Steven Ng, Victor L. Villemagne, Sam Berlangieri, Sze-Ting Lee, Martin Cherk, Sylvia J. Gong, Uwe Ackermann, Tim Saunder, Henri Tochon-Danguy, Gareth Jones, Clare Smith, Graeme O'Keefe, Colin L. Masters and Christopher C. Rowe. Visual Assessment Versus Quantitative Assessment of 11 C-PIB PET and 18F-FDG PET for Detection of Alzheimer 's Disease. J Nucl Med, 2007; 48:547-552.
110. Jun Maeda, Bin Ji, Toshiaki Irie, Takami Tomiyama, Masahiro Maruyama, Takashi Okauchi, Matthias Staufenbiel, Nobuhisa Iwata, Maiko Ono, Takaomi C. Saido, Kazutoshi Suzuki, Hiroshi Mori, Makoto Higuchi and Tetsuya Suhara. Longitudinal, Quantitative Assessment of Amyloid, Neuroinβammation, and Anti-Amyloid Treatment in a Living Mouse Model of Alzheimer's Disease Enabled by Positron Emission Tomography. The Journal of Neuroscience, 2007; 27:10957-10968.
111. B. Neumaier, S. Deisenhofer, D. Fϋrst, C. A. F. von Arnim, S. Thees, A. K. Buck, G. Glatting, G. B. Landwehrmeyer, B. J. Krause, H. D. Mϋller, C. Sommer, S. N. Reske, F. M. Mottaghy. Radiosynthesis and evaluation of [HCJBTA-land [11 CJ 3 '-Me-BTA-I as potential radiotracersfor in vivo imaging of β-amyloid plaques. Nuklearmedizin, 2007; 46: 271-280.
112. Zheng MQ, Yin DZ, Shen YM, Li GC. Syntheses of 2-(paminophenyl)- 6-substituent-benzothiazoles. Chin J Organ Chem 2007; 27: 1369-73.
113. .Zheng MQ, Yin DZ, Zhang L, Cheng DF, Wang YX, Cai HC. Synthesis and evaluation of 18F-labelled PIB as amyloid imaging agents. J Label Compd Radiopharm, 2007; 50:401. 114. Henry Engler. PET and the Multitracer Concept: An Approach to Neuroimaging Pathology Uppsala, 2008; ISBN 978-91-554-7186-86.
115. Ming-qiang Zheng, Duan-zhi YIN, Lan Zhang, Bei Lei, Deng-feng Cheng, Han-cheng Cai, Yan-jiang Han, Ming-xing Wu, Hong Zhang, Jing Wang. Biological characters of [18F]O-FET-PIB in a rat model of Alzheimer 's disease using micro-PET imaging. Acta Pharmacol Sin, 2008; 29: 548-554.
116. Gjermund Henriksen, Behrooz H. Yousefi, Alexander Drzezga, Hans- Jϋrgen Wester. Development and evaluation of compounds for imagingof β-amyloid plaque by means of positronemission tomography. Eur J Nucl
Med MoI Imaging, 2008; 35 (Suppl 1): S75-S81.
Iodine- 124[124I] in the form Of Na124I is used for PET analysis and its long half-life (4/18 days) enables both the development of multiple radiochemical syntheses and the detection of slow biochemical processes that could not be detected using tracers with a short half-life such as 11C and 18F.
Iodine- 124[124I] in the form Of Na124I is used in radio immunodiagnosis and radio immunotherapy as a dosimetry indicator to verify the status of the therapy with 131I, used in the treatment of thyrotoxicosis and tumours of the thyroid. With Iodine- 131(131I), however, a PET investigation is not possible because its energy is too high and it cannot be detected by the instrument. For this reason it is used during radio immunotherapy with Iodine- 124 [124I] as this enables the progress of the therapy to be followed through PET imaging. Iodine- 124[124I] was not considered to be suitable for PET imaging studies because it is a low emitter of positrons.
In 1996, Pentlow demonstrated that despite the fact that Iodine- 124[124I] was a low emitter of positrons, it was nonetheless suitable for detecting tumours surrounded by relatively low background activity, such as thyroid diseases. In fact, PET analysis with Iodine- 124[124I] is the ideal technique for studying the kinetics of iodine in thyroid cancer therapy.
There are essentially two advantages to be gained from the use of Iodine- 124[124I] in nuclear medicine compared to the diagnostic application currently in use, i.e. Iodine- 123 [123I] with the SPECT technique:
• possibility to define in a quantitative manner the distribution of the tracer at the basal nuclei. This is only possible in a semi-quantitative manner with Iodine-123[123I] in SPECT;
• possibility to follow over time, up to 4 days, the variations of the tracer inside the basal nuclei. This also permits the conducting of pharmacological tests and the assessment of their results.
Disclosure of invention
New molecule [ 124I] [2-(3'-iodo-4' -methylaminophenyl)-6-hydroxy- benzothialzole] having the formula.
Figure imgf000018_0001
possessing a better washout compared to analogues labelled with Carbon-
H [11C] or with Fluoro-18[18F]; it is an excellent tracer and can be used for
PET diagnostic imaging.
Detailed description The new molecule [ 124I] [2-(3'-iodo-4' -methylaminophenyl)-6-hydroxy- benzothialzole] is obtainable through a chemical synthesis process, starting from the radioisotope Iodine- 124 [ I] .
For the production of the radioisotope Iodine- 124[124I], a 18 MeV IBA cyclotron is used, with a solid target (COSTIS) dedicated to the formation of Cu-64 and Iodine- 124[124I]. The method consists of bombardment with protons for approx. eight hours at a current of 18 μA, on enriched Tellurium oxide 124TeO2, mass of tellurium oxide 250 mg, on a platinum disc (target substrate).
The yield of the bombardment is approx. 3.7 GBq of Iodine- 124 [124I], while the energy of the beam has a maximum cross section of 14 Mev. Additionally, during irradiation of the solid targets, it is important for the proton beam to be perfectly centred; to do this, it is essential to know its shape. This is detected by a special autoradiography scanner (Cyclone) by means of which the image of a previously irradiated aluminium disc is recorded, on a phosphorus film. The substrate used for the Target is a Platinum disc with a diameter of 24 mm and a circular cavity of 12 mm, which guarantees good conductivity and resistance to corrosion, and a mixture of isotopically enriched tellurium oxide 124TeO (95%) and aluminium oxide Al2O3 (5%) weighing approx. 250 mg is used, so that the alumina acts as a binding agent for the crystal matrix. The mixture is smelted at 753 0C and re-solidified in a quartz furnace for approx. 2 hours .
Once the target is ready - and it must be as stable as possible against the high bombarding current in order to minimize any losses of TeO2 when the vapour pressure reaches high values - bombardment commences. The separation of Iodine- 124 [124I] from the matrix of the target disc (124TeO2/alumina) takes place by means of a thermodistillation process carried out using the TERIMO - "Automatic 1247123I iodine isotope synthesis module for PET scanning System control of 1241 radioactive iodine isotope synthesis". The control system is based on a PLC, a temperature controller and an air flow regulator, and a Scada System used for the control and acquisition of data.
The Iodine-124[124I] recovery time is approx. an hour and the mix is smelted at 7530C releasing 124I2 in the form of gas; the 124I2 is bubbled through a hyperpure solution of NaOH 0.02 N; the 124 I2 is entrapped in the NaOH solution in the form of [124I]NaI (sodium iodide at 95%), sodium iodate NaIO3 and periodate NaIO_j (5%).
The entire chemical process takes place inside the synthesis module placed in a glove box in order to ensure the product's sterility in accordance with GMP guidelines which guarantee a product, the main features of which are quality and efficacy.
At the end of the process, we obtain [124I]NaI which may be administered as a radiotracer on its own or used as a radiolabel for the synthesis of new radiopharmaceuticals.
The radionuclidic purity of Iodio-124[124I] is obtained using a Germanium Gamma ray Spectrometer in order to detect the presence of Iodine- 125 [125I], Iodine- 126[126I], Iodine- 130[130I], Iodine-131 [131I]; these impurities must be lower than 0.1%. Observing the peaks of energy, the purity of the radionuclide (excluding the presence of Iodine- 123 [123I] which is, in any case, at a bare minimum) must be greater than 99.5%.
Once the Iodine- 124 [124I] radioisotope has been obtained, the chemical synthesis process consists of adding a solution containing 185 MBq OfNa124I in 500 μl of NaOH 0.02 N followed by 40 μl of a chloramine-T solution in glacial acetic acid (28 mg di chloramine-T dissolved in 500 μl of glacial acetic acid) to a solution containing 1.1 mg of precursor [2-(4'- methylaminophenyl)-6-methanesulfonoxy-benzothialzole] in 250 μl of glacial acetic acid. After sitting for 30 minutes at ambient temperature in an inert atmosphere, 80 μl of a IM solution of NaHSO3 are added. The reaction mixture is diluted with 20 ml of H2O and the solution is transferred onto a C8 Sep-Pak Light cartridge. From the C8 Sep-Pak Light cartridge, the intermediate product labelled with Iodine- 124[124I] is eluted with 2 ml di methanol. 0.5 ml of a 1 M solution of NaOH are added. After 2 h at 50 0C, 3 ml of a IM solution Of CH3COOH are added. The solution is diluted with 20 ml of H2O and transferred onto a C8 Sep-Pak Light cartridge. From the C8 Sep-Pak Light cartridge, the product labelled with Iodine- 124 [124I] is eluted with 2 ml di ethanol. The above-described new molecule is prepared by dissolving the active substance in salt solution; filtration of the solution with a 0.22 μm filter with sterilizing effect, followed by the immediate transfer of the filtrate into bottle- shaped containers. The operations relative to the process of freeze-drying are prepared by dissolving the active substance in salt solution; filtration of the solution with a 0.22 μm filter (with sterilizing effect, followed by the immediate transfer of the filtrate in a sterile block), distribution into the bottle-shaped containers. Since the active substance for each container is in quantities that are too small and the corresponding volume of solution would be difficult to dose accurately, in addition to the fact that at the end of the process the vial or bottle would appear almost empty, it is necessary to add an atoxic excipient, free from any kind of pharmacological activity that gives the freeze-dried product an attractive appearance: 20 mg of mannitol. The product to be treated is frozen at a temperature of -40 0C inside stainless steel containers (that meet health and hygiene standards) which are, in turn, placed inside the lyostat in which the pressure is reduced to a value such that the water present in the previously frozen product may sublimate under vacuum by heating to a temperature of 30° C, leaving the product almost completely dried. In this way a solid, porous, crumbly, hygroscopic mass is obtained that is very soluble in solvent, and that occupies the same volume of the initial frozen, or freeze-dried, mass.
The new molecule [124I] [2-(3'-iodo-4'-methylamiηophenyl)-6-hydroxy- benzothialzole] may be administered by general oral route in the form of tablets, soft or hard gelatin oil or operculated capsules, sugar-coated pills, dispersing powders, suspensions or emulsions or by topical or transdermal route in the appropriate forms and in vehicles or devices suited for the administration of the active principle at the site of interest; it can also be administered through general parenteral route in the form of aqueous or oily solutions, or suspended in appropriate dispersing agents, even in the form of lyophilized products, to be dispersed at the time of administration.

Claims

1. New molecule [ ! 24I] [2-(3 ' -iodo-4 ' -methy laminopheny l)-6-hydroxy- benzothialzole] having the following structural formula:
Figure imgf000023_0001
possessing a better washout compared to analogues labelled with Carbon- H[11C] or with Fluoro-18[18F].
2. Use of the molecule [ 124I] [2-(3' -iodo-4 '-methylaminophenyl)-6-hydroxy- benzothialzole] as claimed in claim 1 for PET diagnostic imaging.
3. New molecule [124I] [2-(3' -iodo-4 '-methy laminophenyl)-6-hydroxy- benzothialzole] as claimed in claim 1, obtainable by means of a chemical synthesis process that consists of adding a solution containing 185 MBq of Na124I in 500 μl of NaOH 0.02 N followed by 40 μl of a chloramine-T solution in glacial acetic acid (28 mg di chloramine-T dissolved in 500 μl of glacial acetic acid) to a solution containing 1.1 mg of precursor [2-(4'- methylaminophenyl)-6-methanesulfonoxy-benzothialzole] in 250 μl of glacial acetic acid. After sitting for 30 minutes at ambient temperature in an inert atmosphere, 80 μl of a IM solution of NaHSO3 are added. The reaction mixture is diluted with 20 ml of H2O and the solution is transferred onto a C8 Sep-Pak Light cartridge. From the C8 Sep-Pak Light cartridge, the intermediate product labelled with Iodine- 124 [124I] is eluted with 2 ml di methanol. 0.5 ml of a 1 M solution of NaOH are added. After 2 h at 50 0C, 3 ml of a IM solution Of CH3COOH are added. The solution is diluted with 20 ml of H2O and transferred onto a C8 Sep-Pak Light cartridge. From the C8 Sep-Pak Light cartridge, the product labelled with Iodine- 124[124I] is eluted with 2 ml di ethanol.
4. New molecule [124I] [2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy- benzothialzole] as claimed in claims 1, 2, and 3, characterized by the fact that it can be administered by general oral route in the form of tablets, soft or hard gelatin oil or operculated capsules, sugar-coated pills, dispersing powders, suspensions or emulsions or by topical or transdermal route in the appropriate forms and in vehicles or devices suited for the administration of the active principle at the site of interest.
5. New molecule [ 124I] [2-(3'-iodo-4' -methylaminophenyl)-6-hydroxy- benzothialzole] as claimed in claims 1, 2 and 3, characterized by the fact that it can be administered by general parenteral route in the form of aqueous or oily solutions, or suspended in appropriate dispersing agents, even in the form of lyophilized products, to be dispersed at the time of the administration.
PCT/EP2009/003605 2008-05-23 2009-05-20 New molecule [124i][2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy-benzothialzole] for pet investigations and radiotherapy WO2009141137A2 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113480467A (en) * 2021-07-13 2021-10-08 河北维达康生物科技有限公司 Synthesis process of radioactive tracer 2-iodine melatonin

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004083195A1 (en) * 2003-03-14 2004-09-30 University Of Pittsburgh Benzothiazole derivative compounds, compositions and uses

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004083195A1 (en) * 2003-03-14 2004-09-30 University Of Pittsburgh Benzothiazole derivative compounds, compositions and uses

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
R. Finn: "CHEMISTRY APPLIED TO IODINE RADIONUCLIDES" In: M. J. Welch: "Handbook of Radiopharmaceuticals: Radiochemistry and Applications" 2003, John Wiley and S, Ltd. ons , XP007910861 ISBN: 0471495603 , pages 423-440 Page 425 *
WANG Y ET AL: "Development of a pet / spect agent for amyloid imaging in alzheimer's disease" JOURNAL OF MOLECULAR NEUROSCIENCE, BIRKHAEUSER, CAMBRIDGE, MA, US, vol. 24, 1 January 2004 (2004-01-01), pages 55-62, XP008108084 ISSN: 0895-8696 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113480467A (en) * 2021-07-13 2021-10-08 河北维达康生物科技有限公司 Synthesis process of radioactive tracer 2-iodine melatonin
CN113480467B (en) * 2021-07-13 2022-12-30 河北维达康生物科技有限公司 Synthesis process of radioactive tracer 2-iodine melatonin

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