Abstract:
The invention relates to a device and a process for nucleophilic fluorination of a substance, especially for synthesis of an  18 F-labeled substance for examination using a positron emission tomograph. The device comprises an anion exchange device ( 102 ) for extraction of [ 18 F]fluoride ions by means of adsorption from a target fluid, whereby the anion exchange device ( 102 ) can be charged via a supply device ( 101 ) with the target fluid; and a measurement device ( 104 ) with a measurement chamber ( 103 ) for measuring initial radioactivity of the [ 18 F]fluoride ions, the anion exchange device ( 102 ) being arranged at least partially in the measurement chamber ( 103 ) of the measurement device ( 104 ). (FIG.  1 )

Description:
[0001]    This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/468,963 filed May 9, 2003. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The invention relates to the area of nucleophilic fluorination of a substance, especially for synthesis of an  18 F-labeled substance for examination using a positron emission tomograph. 
       BACKGROUND OF THE INVENTION 
       [0003]    Positron emission tomography (PET) is a technology of nuclear medicine in which radiopharmaceutical agents are used that are formed from biologically relevant molecules that are labeled with positron-emitting isotopes. PET is used to study metabolic processes and physiological processes. Based on the use of analysis of radiation of short-lived radioisotopes of elements that are found in the human body, PET delivers additional information to other diagnostic processes, such as, for example computer-based tomography or examinations using magnetic resonance. PET radiopharmaceutical agents participate in biochemical reactions of the body with a dose that is not critical for humans. 
         [0004]    The utility of PET depends essentially on the availability of nontoxic radiopharmaceutical agents. Fluorine-18 ( 18 F) has proven to be one of the preferred radioisotopes because its decay energy of 0.64 MeV makes possible a high inherent resolution during PET measurements.  18 F, moreover, has an advantageous half-life of 109.8 minutes. In the past, especially 2-[ 18 F]fluoro-2-desoxy-D-glucose ([ 18 F]FDG) has been successfully used. This labeling substance is used worldwide for the most varied applications. [ 18 F]FDG is a sugar compound that is labeled with  18 F and that can be easily administered to a patient. [ 18 F]FDG is easily processed by growing cancer cells, the brain or cardiac muscles. The described properties of [ 18 F]FDG have led to its being successfully used in nuclear medicine. The use of PET in clinical applications has led to development of devices for synthesizing radiopharmaceutical agents such as [ 18 F]FDG. 
         [0005]    The publication by N. Satyamurthy: Electronic Generators for the Production of Positron-Emitter-labeled Radiopharmaceutical Agents: Where Would PET Be Without Them? Clinical Positron Imaging, Vol. 2, No. 5, pages 233-253, 1999, describes in survey form various devices for automated FDG synthesis. 
         [0006]    Document U.S. Pat. No. 5,932,178 discloses an FDG synthesis module with a column that is filled with a polymer-supported catalysis resin. U.S. Pat. No. 5,808,020 describes an optical reaction cell and a light source for processes for synthesis of  18 F-labeled radiotracers using [ 18 F]fluoride. 
         [0007]    Document WO 02/36581 describes novel radiopharmaceutical agents that bind to the CCR1 receptor, which occurs in conjunction with Alzheimer&#39;s disease in the brain areas of patients. 
         [0008]    Based on the search for novel, suitable radiopharmaceutical agents that are based on new synthesis processes, there is a demand for devices that can be used for the synthesis of radiopharmaceutical agents. 
       THE INVENTION 
       [0009]    The object of the invention is therefore to devise an improved device and an improved process for nucleophilic fluorination that makes possible application-dependent synthesis of nucleophilically fluorinated substances in a manner that is suitable for flexible clinical applications. 
         [0010]    This object is achieved according to the invention by a device according to independent claim  1  and a process according to independent claim  9 . 
         [0011]    A device that is used for nucleophilic fluorination of a substance, especially for synthesis of an  18 F-labeled substance for examination using a positron emission tomograph, comprises an anion exchange device for extraction of [ 18 F]fluoride ions by means of adsorption from a target fluid, and the anion exchange device can be charged via a supply device with the target fluid, and a measurement device with a measurement chamber for measuring the initial radioactivity of the [ 18 F]fluoride ions. Here, the anion exchange device is located at least partially in the measurement chamber of the measurement device. This has the advantage that the initial radioactivity of the [ 18 F]fluoride ions can be measured while they are in the anion exchange device. Because of an additional collecting vessel for the target fluid, no losses occur. 
         [0012]    In one feasible further development of the invention, there is a vessel for holding a nucleophilically fluorinated reaction product, the vessel being located at least partially in the measurement chamber of the measurement device in order to measure the radioactivity of the nucleophilically fluorinated reaction product. In this way, the initial radioactivity and the radioactivity of the reaction product can be measured using an individual measurement device. Both measurements can be taken without the need to move or re-arrange parts of the measurement device. 
         [0013]    The accuracy of the radioactivity measurements is improved in one feasible configuration of the invention in that the measurement device is a measurement device that can be calibrated. This has the advantage, moreover, that in a subsequent measurement, background radioactivity due to residues in the measurement chamber can be eliminated by compensation of the background radioactivity as measured value adulteration. 
         [0014]    A compactly executable measurement device that is provided with the required accuracy can be formed in one advantageous further development of the invention in that the measurement device is an activity meter. An activity meter is used for fast and accurate determination of the radioactivity of radionuclides. Important advantages of radioactivity measurement with an activity meter consist in 4-π measurement geometry, the large linear measurement range and the nuclide-specific calibration. 
         [0015]    The use of the device for nucleophilic fluorination, in which purity of the reaction product that is as great as possible is necessary, is made possible in one advantageous embodiment of the invention in that there is an HPLC device (HPLC—“High Performance Liquid Chromatography”) with an HPLC column for purifying a reaction mixture. Such an HPLC device that is also called preparative HPLC is used for isolation and purification of components. In nucleophilic reactions, reaction mixtures often occur that can be separated using the HPLC device. 
         [0016]    One preferred development of the invention can provide that the HPLC device comprises a sample feed valve that is connected to a coupling line for charging the metering device; the sample feed valve is coupled via a waste line to a waste tank; a fluid sensor device is connected upstream from the sample feed valve for detecting the reaction mixture in the coupling line; and the sample feed valve is made to be controllable so that the sample feed valve is set in the initial state in order to form, via the metering device, a fluid connection between the coupling line and the waste line, when using the fluid sensor device the reaction mixture in the supply line is detected, and the sample feed valve is switched into an injection state for charging the HPLC column in order to form a fluid connection between the metering device and the HPLC column in the injection state, when the reaction mixture is no longer being detected in the supply line using the fluid sensor device. Using this configuration prevents the fact that when the HPLC device is being charged with the reaction mixture, air that is in the lines connected upstream from the HPLC device is transferred into the metering device of the HPLC device before the reaction mixture travels into these lines; this could adversely affect the yield of the isolation and the effectiveness of separation in the HPLC device. 
         [0017]    One feasible configuration of the invention can provide for formation of a direct coupling between the fluid sensor device and a reaction vessel by means of the coupling line. Direct coupling reduces the probability of losses in the transfer of the reaction mixture. 
         [0018]    One feasible embodiment of the invention can provide for the HPLC device to comprise a purification device with a UV detector device and a gamma detector device that follows the UV detector device for purifying the reaction mixture using the UV detector device and then using the gamma detector device. This arrangement makes it possible to isolate a radioactive peak such that as few chemical impurities as possible with the corresponding UV absorption are contained, and the losses of the radioactive end product can be minimized. 
         [0019]    The features from the dependent claims of the process for nucleophilic fluorination of a substance have the advantages named in conjunction with the pertinent features in the dependent device claims. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0020]    The invention is explained in more detail below using embodiments with reference to a drawing. 
           [0021]    Here: 
           [0022]      FIG. 1  shows a diagrammatic visualization of a device for nucleophilic fluorination of a substance; 
           [0023]      FIG. 2  shows a synthesis diagram for 4-[ 18 F]FBA (2) from TMABATf(1) and [ 18 F]fluoride; 
           [0024]      FIG. 3  shows a synthesis diagram for [18f]ZK8111460 (4) from a piperazine derivative (3) and [ 18 F]FBA (2); and 
           [0025]      FIG. 4  shows a diagrammatic visualization of a sample feed valve. 
       
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
       [0026]      FIG. 1  shows a diagrammatic representation of a device  1  for nucleophilic fluorination of a substance. The use of the device  1  for synthesis is explained using the example of the production of the labeled compound 1-(5-chloro-2-{2-[(2R)-4-(4-[ 18 F]fluorobenzyl)-2-methylpiperazine-1-yl]-2-oxo-ethoxy}phenyl)urea, which is formed starting from TMABATf(1) by means of radiosynthesis of 4-[ 18 F]FBA (2) and its reductive amination with a piperazine derivative (3) (cf.  FIGS. 2 and 3 ). The labeled compound that is obtained in this way is hereinafter abbreviated [ 18 F]ZK811460 (4). Other specific details, especially with respect to the chemical substances used and reaction parameters, if they do not follow from the following description, can be taken from the publication by Mäding, et al., Annual Report 2002, Institute of Bioorganic and Radiopharmaceutical Chemistry, FRZ-363, 40, and are not critical for the implementation of the invention in its different embodiments. 
         [0027]    The [ 18 F]fluoride ions contained in a target fluid are supplied via a supply  101  and a valve V 10  to an anion exchange device  102 . The anion exchange device  102  is used to extract [ 18 F]fluoride ions from the target fluid. The extraction is done using adsorption. According to  FIG. 1 , the anion exchange device  102  is located in a measurement chamber  103  of a measurement device  104  that is used for measuring the radioactivity. In this connection, the measurement device  104  is made preferably as an activity meter. Using the measurement device  104 , the initial radioactivity of [ 18 F]fluoride ions can be measured during and after their extraction from the target fluid using the anion exchange device  102 . 
         [0028]    The anion exchange device  102  is connected via a valve V 10  to the supply  101  and a valve V 1 . Via the valve V 1 , substances that are available in the storage tank SB 1  can be delivered to the valve V 10 . In this connection, the substances are transferred using a vacuum or in an alternative manner by means of a gas, for example nitrogen, through lines and valves. The anion exchange device  102  is furthermore coupled to a valve V 11  via which the extracted [ 18 F]fluoride ions after their desorption after passing through a valve V 13  travel into a reaction vessel  105 . Via the valve V 11 , [ 18 O]H 2 O that is separated by opening the valve V 23  with the vacuum pump  20  that is turned on travels from the anion exchange device  102  into a tank  106 . The valves V 24  and V 25  are used to apply a vacuum to the reaction vessel  105  or to ventilate it. 
         [0029]    According to  FIG. 1 , the reaction vessel  105  is connected to other valves V 2 , V 3 , V 4 , V 5  and V 6  that are coupled to the respective storage tank SB 2 -SB 6 . Via the valves V 2 -V 6 , the chemical substances stored in the respective storage tanks SB 2 -SB 6  can be added in a given volume to the reaction vessel  105  in order to carry out the desired chemical reaction for synthesis of [ 18 F]ZK811460 (4). In this connection, the substances are transferred using a vacuum or in an alternative manner by means of a gas, for example nitrogen, through lines and valves. A valve V 20  is used to control the feed of protective gas from a line  107  to the reaction vessel  105 . To remove the exhaust gases that form in the chemical reaction, the reaction vessel  105  is furthermore connected via a valve V 24  and V 25  to an exhaust gas opening  30 . 
         [0030]    To synthesize [ 18 F]ZK811460 in the reaction vessel  105 , first the [ 18 F]fluoride is eluted with a solution of Kryptofix 2.2.2 and potassium carbonate in aqueous acetonitrile (from SB 1 ) from the anion exchange device  102  and is dried by means of a vacuum and nitrogen stream at 95° C. Additional drying takes place by adding anhydrous acetonitrile (from SB 2 ) and its vaporization. After adding a solution of TMABATf(1) in DMF (from SB 6 ), the reaction mixture  10  is heated for 10 minutes at 120° C. Then, in succession, an acetic acid solution of the piperazine precursor (3) (ZK258394 from SB 3 ) and a solution of NaBH 3 CN in DMF (from SB 5 ) are added. After 10 minutes of heating at 120° C., the reaction mixture is neutralized with aqueous NaOH (from SB 4 ). 
         [0031]    To adjust the desired reaction parameters, in the area of the reaction vessel  105 , there are a heating device  108 , a stirring device  109  and a cooling device  110 . 
         [0032]    Via a direct coupling line  111  in which there is a valve V 14 , the reaction mixture [ 18 F]ZK811460 (4) travels to a fluid sensor  112  that detects a fluid in the direct coupling line  111 . The fluid sensor  112  is connected directly upstream from an injection valve or sample feed valve  113 , the operation of which is described below with reference to  FIGS. 1 and 4 , the latter showing a diagrammatic representation of a 6-way sample feed valve. Using the sample feed valve  113 , a metering loop  114  is charged via a direct coupling line  111  to the reaction mixture. Here, the sample feed valve  113  is controlled such that first via points  1  and  2  (cf.  FIG. 4 ), a connection is formed between the direct coupling line  111  and the fluid sensor  112  and a waste line  115  that leads from the sample feed valve  113  to a waste tank  116 . In this way, air that is located in the direct coupling line  111  in front of the reaction mixture is forced into the waste line  115 . In this position of the sample feed valve  113  (injection state), the metering loop  114  is flushed by an HPLC eluent, the HPLC eluent in the sample feed valve  113  traversing a path along points  4 ,  3 ,  6  and  5 . 
         [0033]    When the fluid sensor  112  detects the arrival of the reaction mixture from the reaction vessel  105 , the sample feed valve  113  for charging the metering loop  114  is switched into the charging state so that via the metering loop  114 , a connection between the direct coupling line  111  and the waste line  115  along the points  1 ,  6 ,  3 , and  2  is formed, which is shown in  FIG. 4  by the continuous lines, and leads to the metering loop&#39;s  114  being charged with the reaction mixture. The volume of the metering loop  114  is generally greater than the volume of the reaction mixture. The HPLC eluent passes through the sample feed valve  113  via a short circuit along a path with points  4  and  5  in  FIG. 4 . If the reaction mixture is no longer being detected by the fluid sensor  112 , the sample feed valve  113  is switched again into the injection state so that a connection is formed along the path with the points  4 ,  3 ,  6 , and  5  (broken line in  FIG. 4 ). The HPLC eluent can then force the reaction mixture out of the metering loop  114  to an HPLC column  201  with a precolumn  201   a.    
         [0034]    Using the HPLC device  200 , the reaction mixture is purified. Depending on the specific use of the device  1  for different synthesis purposes, the parameters on the HPLC device  200  can be set and optimized according to the desired purpose. 
         [0035]    The HPLC device  200  in this embodiment shown comprises an HPLC pump  117 , the sample feed valve  113  with the metering loop  114 , the HPLC column  201  with precolumn  201   a  as well as a UV detector device  118  and a gamma detector device  119 , which are arranged in series. 
         [0036]    Via a valve V 18 , a mixing tank  120  with a water receiver and a stirring device  121  and a valve V 17 , the isolated product fraction travels to an RP18 cartridge  122  for collecting the reaction product by means of solid-phase extraction. After washing the cartridge  122  with water (from SB 9 ), [ 18 F]ZK811460 (4) is eluted by means of ethanol (from SB 8 ). The ethanolic solution of [ 18 F]ZK811460 (4) is then routed for filtering out of the elution vessel  123  through a sterilizing filter  124  that afterwards is flushed with an injection solution based on salt (from SB 7 ). In this way, a clear, sterile isotonic NaCl solution of [ 18 F]ZK811460 (4) is obtained that contains ethanol and is collected in a product vessel  125 . The elution vessel  123  is arranged in the measurement chamber  103 , which makes possible direct measurement of the radioactivity of the reaction product [ 18 F]ZK811460 (4). In one preferred embodiment of the measurement device  104  that can be calibrated, when the radioactivity of the reaction product is measured, the radioactivity background can be compensated such that residual radioactivity that is still present after dissolving out the [ 18 F]fluoride ions in the anion exchange device  102  is compensated as the background radioactivity of the radioactivity measurement of the reaction product that is to be carried out. The measurement of the initial radioactivity in the anion exchange device  102  and the radioactivity of the reaction product in the elution vessel  123  can be carried out in this way with high precision using the measurement device  104 . 
         [0037]    The features of the invention that are disclosed in the description above, the claims and the drawings can be important both individually and also in any combination for the implementation of the invention in its different embodiments. 
         [0038]    Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. 
         [0039]    In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated. 
         [0040]    The entire disclosures of all applications, patents and publications, cited herein and of corresponding German application No. 103 20 552.7, filed May 7, 2003, and U.S. Provisional Application Ser. No. 60/468,963, filed May 9, 2003 are incorporated by reference herein. 
         [0041]    The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. 
         [0042]    From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.