EP2593218A2 - Dispositif de synthèse de composés à marquage radioactif - Google Patents

Dispositif de synthèse de composés à marquage radioactif

Info

Publication number
EP2593218A2
EP2593218A2 EP11801964.5A EP11801964A EP2593218A2 EP 2593218 A2 EP2593218 A2 EP 2593218A2 EP 11801964 A EP11801964 A EP 11801964A EP 2593218 A2 EP2593218 A2 EP 2593218A2
Authority
EP
European Patent Office
Prior art keywords
cartridge
reaction product
reaction vessel
reaction
solid support
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.)
Withdrawn
Application number
EP11801964.5A
Other languages
German (de)
English (en)
Inventor
Marco Müller
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.)
ABX Advanced Biochemical Compounds GmbH
Original Assignee
ABX Advanced Biochemical Compounds GmbH
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 ABX Advanced Biochemical Compounds GmbH filed Critical ABX Advanced Biochemical Compounds GmbH
Publication of EP2593218A2 publication Critical patent/EP2593218A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07B59/005—Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00788—Three-dimensional assemblies, i.e. the reactor comprising a form other than a stack of plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00801—Means to assemble
    • B01J2219/0081—Plurality of modules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00801—Means to assemble
    • B01J2219/0081—Plurality of modules
    • B01J2219/00813—Fluidic connections
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00801—Means to assemble
    • B01J2219/0081—Plurality of modules
    • B01J2219/00817—Support structures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00891—Feeding or evacuation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00891—Feeding or evacuation
    • B01J2219/00898—Macro-to-Micro (M2M)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00905—Separation
    • B01J2219/00916—Separation by chromatography
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00925—Irradiation
    • B01J2219/00927—Particle radiation or gamma-radiation
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a device for the synthesis of radioactively labeled compounds and to a use of this device.
  • radiotracers In medical diagnostics, short-lived, radiolabelled compounds, so-called radiotracers, are increasingly used whose physiological and biochemical properties enable a non-invasive tomographic detection of metabolic processes in the human body. Using the modern tomographic method of positron emission tomography (PET), these radiotracers can be used to quantify metabolic processes and to record the biodistribution of the radiodiagnostic from the outside. The tomographic acquisition of radiotracers, such.
  • PET positron emission tomography
  • B. 2-deoxy-2- [ 18 F] fluoro-D-glucose ([ 18 F] -FDG) allows early diagnosis of tumors that differ significantly in terms of glucose metabolism of normal tissue.
  • the development of new radiotracers based on pharmacologically interesting compounds has opened up new possibilities for the non-invasive diagnosis of different clinical pictures in recent years.
  • PET positron emission tomography
  • [ 18 F] fluoride as a radioactive probe, as it in the form of the F-18-labeled sugar derivative ([ 18 F] -FDG) makes the exact localization of tumors down to the millimeter range using PET visible and a precise localization the tumor expansion allows.
  • the [18 F] fluoride produced in the cyclotron is separated by ion exchange on an anion exchange cartridge from the target water, whereby as phases usually a mixture of Kryptofix ® (K2.2.2) and potassium carbonate sentransferreagenz in water / acetonitrile is used.
  • the phase-transfer catalysts activated [ 18 F] fluoride with the corresponding starting material (also referred to as precursor compound or precursor) in an organic solvent, eg. As acetonitrile, reacted (label). All chemical-physical processes take place in synthesis modules, which, due to a large number of reaction steps (eg ion exchange, distillation, drying, reaction) are equipped with relatively complex control systems.
  • DE 697 32 599 T2 discloses a device for the automated synthesis of radiolabeled compounds, which is said to be particularly suitable for the synthesis of 2- [ 18 F] fluoro-2-deoxy-D-glucose.
  • the device can be realized as a so-called disposable equipment set, which is integrated into a synthesis module.
  • the reaction vessel, a first cartridge and a second cartridge are connected to each other via lines.
  • the cartridges are filled with carrier material for the separation of hydrophilic or lipohilic components of the precursor compound.
  • the precursor compound is adsorbed on a C18 cartridge to allow deprotection by basic or acid hydrolysis.
  • hydrochloric acid or sodium hydroxide solution is passed through the cartridge, and held by the shut-off by means of a valve for a longer residence time on the cartridge, for complete hydrolysis.
  • the cartridge may be of the type C18, C18 ec, C8, C4, tC18, diol, phenyl, NH 2 , among others.
  • the cartridge may contain between 50 mg and 10 g of solid carrier, with 200 to 800 mg being preferred.
  • a C18 cartridge of the Sep-Pak Short Body type is used for the hydrolysis, which contains 400 mg of solid carrier.
  • the reaction of the precursor compound takes place in a reaction vessel at a temperature of 105.degree.
  • the reaction vessel is not made of plastic, but of glass.
  • a radiochemical yield of about 60% With the device shown in the example of DE 697 32 599 T2 can be achieved in the synthesis of [ 18 F] -FDG a radiochemical yield of about 60%.
  • an initial activity of 150 GBq approximately 50 patient doses of 300 MBq can thus be obtained.
  • a dose is understood to mean the amount of [ 18 F] -FDG that must be administered to a patient for a PET examination.
  • the object of the invention is to eliminate the disadvantages of the prior art.
  • a device for the synthesis of radioactively labeled compounds, in particular for the synthesis of [ 18 F] -FDG, which enables the production of a higher number of doses, based on the amount of radioactive isotope, is made possible. Furthermore, a use of this device should be specified.
  • an apparatus for the synthesis of radioactively labeled compounds comprising
  • reaction vessel for reacting a precursor compound having protecting groups with a radioactive isotope to obtain a first reaction product; a first cartridge for hydrolysis of protecting groups of the first reaction product to obtain a second reaction product; and a second cartridge for purifying the second reaction product, wherein the reaction vessel, the first cartridge and the second cartridge are connected to each other via conduits and wherein the first cartridge 801 to 1200 mg of a solid support and / or that the reaction vessel is a reaction vessel of ei - A temperature-resistant plastic, wherein the plastic has a temperature resistance of at least 120 ° C.
  • the first cartridge contains 810 to 1000 mg of the solid carrier, more preferably 815 to 900 mg of the solid carrier, most preferably 820 mg of the solid carrier.
  • the reaction vessel is preferably a reaction vessel of a fluoride-free plastic to avoid exchange reactions between the fluoride of the plastic and the radioactive isotope.
  • the temperature-resistant plastic is a cycloolefm copolymer. Particularly suitable are cycloolefm copolymers having a heat distortion temperature (measured according to ISO 75-1, -2 HDT / B 0.45 MPa) of 120 ° C and more, in particular of 150 ° C and more.
  • a particularly suitable cycloolefin copolymer for example, Topas ®, especially Topas ® 6015S-04, the TOPAS Advanced Polymers GmbH, Frankfurt / Main, DE. It has surprisingly been found that in a cycloolefm copolymer reaction vessel the penetration of [ 18 F] fluoride ions into the material of the reaction vessel is prevented and that fact is a cause of the considerable yield loss in the use of the prior art glass reaction vessels.
  • the device according to the invention which comprises a first cartridge with an increased proportion of solid support and a reaction vessel of a temperature-resistant plastic and otherwise unchanged from DE 697 32 599 T2
  • a yield of at least 70% In the prior art, a yield of only 60% could be achieved. This represents an increase in the doses to be achieved by about 17%.
  • the first and second cartridges contain the same type of solid support.
  • Suitable solid carriers are, for example, support of type C18, C18 ec, C8, C4, tC18, NH2, diol, polystyrene divinylbenzene or phenyl.
  • the solid support is preferably C18.
  • the device is preferably automated.
  • the device should include valves for controlling the flow of starting materials and reaction products as well as auxiliaries and process gases.
  • An example of a process gas is nitrogen (N 2 ).
  • auxiliaries are solvents such as water or acetonitrile. protective agents for deprotecting the precursor compound and fluid detergents.
  • the required starting materials, the auxiliaries and the process gas are known to the person skilled in the art.
  • the reaction vessel, the first cartridge, the second cartridge and the conduits interconnecting the reaction vessel, the first cartridge and the second cartridge are components of a disposable element.
  • This disposable element can be used in a stationary element and used there for the unique synthesis of the radiolabeled compound.
  • the amount of solid support in the first cartridge is twice or more the amount of solid support in the second cartridge.
  • the use of the device according to the invention for the preparation of 2-deoxy-2- [ 18 F] fluoro-D-glucose is also provided.
  • a process for the preparation of synthesizing radiolabeled compounds by the apparatus of the present invention comprising the steps of: (a) substituting the precursor compound with a radioactive isotope in the reaction vessel at a temperature of 100 ° C or higher to obtain a first reaction product;
  • step (a) is carried out at a temperature of 120.degree. C. or higher, particularly preferably at 125.degree.
  • Fig. 1 is a schematic representation of a disposable element comprising components of the device according to the invention
  • Figure 2 is a graph showing a comparison of radiochemical yields in the preparation of prior art 2-deoxy-2- [ 18 F] fluoro-D-glucose and according to the present invention.
  • Example 1 Construction of an embodiment of the device according to the invention
  • the embodiment of the device according to the invention shown in FIG. 1 comprises three tap banks G, H, I each having five control valves, wherein the tap banks G and H are connected to a hose and the tap banks H and I pass through the first cartridge, ie a long compared to the prior art C18 cartridge with increased amount of solid support material are connected.
  • the reaction vessel is connected via hoses on the control valve 6 and 15 with the tap banks.
  • the second cartridge, a tC18 cleaning cartridge attached to the control valve 12 and linked via a hose with control valve 13.
  • At the control valve 11 is the outlet for the final product, which is passed at the end of an AluminaN cartridge for the removal of excess fluoride.
  • hoses are located on the control valves 1 and 1 for the supply and discharge of gases and liquids.
  • control valves 3 5, 8 and 9 are so-called plastic spikes on which the Storage vessels for the chemicals are attached.
  • a slightly larger sized spike is connected via a hose with control valve 6 and serves to attach a water reservoir for injections.
  • the device according to the invention is inserted into the module (Tracerlab Mx from General
  • Fig. 2 shows the time uncorrected radiochemical yield in the synthesis of [ 18 F] -FDG for the individual cases in a number of nine experiments. In all experiments, the change in the amount of solid support and the additional replacement of the reaction vessel to increase the yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

Dispositif de synthèse de composés à marquage radioactif, qui comporte une cuve de réaction pour la mise en réaction d'un composé précurseur contenant des groupes protecteurs avec un isotope radioactif, ce qui permet d'obtenir un premier produit de réaction, une première cartouche pour séparer les groupes protecteurs du premier produit de réaction, ce qui permet d'obtenir un second produit de réaction, et une seconde cartouche pour purifier le second produit de réaction, la cuve de réaction la première cartouche et la seconde cartouche étant reliés les unes aux autres par des conduits. Selon l'invention, la première cartouche contient 801 à 1200 mg d'un support solide et/ou la cuve de réaction est une cuve de réaction constituée d'un plastique résistant à la chaleur, ledit plastique résistant à une température d'au moins 120 °C.
EP11801964.5A 2010-07-12 2011-07-05 Dispositif de synthèse de composés à marquage radioactif Withdrawn EP2593218A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010036356A DE102010036356A1 (de) 2010-07-12 2010-07-12 Vorrichtung zur Synthese radioaktiv markierter Verbindungen
PCT/DE2011/075157 WO2012041306A2 (fr) 2010-07-12 2011-07-05 Dispositif de synthèse de composés à marquage radioactif

Publications (1)

Publication Number Publication Date
EP2593218A2 true EP2593218A2 (fr) 2013-05-22

Family

ID=45372683

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11801964.5A Withdrawn EP2593218A2 (fr) 2010-07-12 2011-07-05 Dispositif de synthèse de composés à marquage radioactif

Country Status (5)

Country Link
US (1) US20130144052A1 (fr)
EP (1) EP2593218A2 (fr)
CA (1) CA2805121A1 (fr)
DE (1) DE102010036356A1 (fr)
WO (1) WO2012041306A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7344702B2 (en) 2004-02-13 2008-03-18 Bristol-Myers Squibb Pharma Company Contrast agents for myocardial perfusion imaging
GB201420094D0 (en) * 2014-11-12 2014-12-24 Ge Healthcare Ltd Flouride trapping arrangement
SG183134A1 (en) * 2010-02-08 2012-09-27 Lantheus Medical Imaging Inc Methods and apparatus for synthesizing imaging agents, and intermediates thereof
AU2013203000B9 (en) 2012-08-10 2017-02-02 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
CA2930479C (fr) 2013-11-13 2023-03-28 Ge Healthcare Limited Cassette a double traitement pour la synthese de composes marques par 18f
CN103706297B (zh) * 2013-12-30 2017-01-04 中国原子能科学研究院 氚标记反应装置

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE1010280A3 (fr) * 1996-05-02 1998-05-05 Coincidence S A Procede et dispositif de synthese de 2-[18f] fluoro-2-deoxy-d-glucose.
KR100789847B1 (ko) * 2004-12-15 2007-12-28 (주)퓨쳐켐 알코올 용매하에서 유기플루오로 화합물의 제조방법
WO2006133732A1 (fr) * 2005-06-17 2006-12-21 Advanced Accelerator Applications Procede pour la synthese de composes etiquetes
EP2123621A1 (fr) * 2008-05-20 2009-11-25 Bayer Schering Pharma Aktiengesellschaft Nouveaux acides de glutamine L marqués au {F-18} et dérivés de glutamine L (I), leur utilisation et leur procédé de fabrication
EP2111293A2 (fr) * 2006-12-21 2009-10-28 Hammersmith Imanet Limited Radiofluoration nucléophile utilisant des dispositifs micro-fabriqués

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012041306A2 *

Also Published As

Publication number Publication date
WO2012041306A3 (fr) 2012-11-15
US20130144052A1 (en) 2013-06-06
WO2012041306A2 (fr) 2012-04-05
CA2805121A1 (fr) 2012-04-05
DE102010036356A1 (de) 2012-01-12

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