Device and method for the production of radiochemical compounds

Abstract

The invention relates to a method for the preparation of radiochemical compounds using a device having at least a reaction module, a dosing module, and a storage module, wherein the reaction module has at least one reaction vessel having a closable opening through which substances needed for the preparation of a predetermined radiochemical compound can be introduced into the reaction vessel of the reaction module and through which the prepared radiochemical compound can be removed from the reaction vessel of the reaction module; the dosing module has at least one pipetting head which can be moved relative to the storage module and the reaction module and in x, y, and z directions and also has at least one dosing unit; and at least one reservoir for one of the substances needed for the preparation of the respective radiochemical compound is formed in the storage module. Substances needed for the preparation of the respective radiochemical compound are introduced into the reaction vessel of the reaction module by means of dosing units, wherein the dosing units can be moved via a pipetting head in x, y directions or in x, y, and z directions.

Claims

1. A method for the preparation of radiochemical compounds comprising: introducing substances needed for the preparation of a respective radiochemical compound by means of dosing units into a reaction vessel of a reaction module of a device comprising at least one reaction module, a dosing module, and a storage module, wherein the reaction module has at least one reaction vessel having a closable opening through which substances needed for the preparation of a predetermined radiochemical compound can be introduced into the reaction vessel of the reaction module and through which the prepared radiochemical compound can be removed from the reaction vessel of the reaction module, the dosing module having at least one pipetting head which can be moved relative to the storage module and the reaction module and in x, y, and z directions and also having one or more dosing units, wherein at least one dosing unit is a triple lumen dosing unit having a first channel for taking up, transporting, and releasing a substance needed for the synthesis of the radio-chemical compound, a second channel for supplying a gas into a reaction vessel and a third channel for draining off gaseous reaction products from the reaction vessel, and at least one reservoir for one of the substances needed for the preparation of the respective radiochemical compound is formed in the storage module, wherein purification means required for the separation of the prepared radiochemical compound from the reaction mixture are integrated into the storage module, and wherein the reaction module, the dosing module, and the storage module are arranged in a hot cell; wherein the dosing units are movable via a pipetting head in x, y directions or in x, y, and z directions; and reacting at least one of the substances to form the radiochemical compound.

2. The method according to claim 1, wherein the substances needed for the preparation of the respective radiochemical compound are sequentially introduced into the reaction vessel of the reaction module.

3. The method according to claim 1, wherein a prepared radiochemical compound is taken up from the reaction vessel by means of a dosing unit.

4. The method according to claim 3, wherein the prepared radiochemical compound is transferred to a purification module by means of the dosing unit.

5. The method according to claim 1, wherein the dosing units are rinsed in a washing unit after taking up and releasing a substance.

Description

(1) In the following, the invention is explained in more detail with the help of examples not intended to limit the invention with respect to the drawings. Here,

(2) FIG. 1 shows a schematic representation of an embodiment of the device according to the invention;

(3) FIG. 2a shows a schematic sectional view of the reaction module and a dosing unit having three channels the pipetting tip of which is introduced into the reaction vessel;

(4) FIG. 2b shows a schematic sectional view of the reaction module and a dosing unit the pipetting tip of which is introduced into the reaction vessel;

(5) FIG. 2c shows a schematic sectional view of the reaction module with the reactor being closed during a reaction; and

(6) FIG. 3 shows a schematic representation of the embodiment of the device according to the invention shown in FIG. 1 inserted into a hot cell.

(7) Example 1:

(8) The synthesis device 1 according to the invention schematically shown in FIG. 1 has a reaction module 2 with two reaction vessels 3. Each reaction vessel 3 is arranged within a housing 4 which is open at the top. In the housing 4 a cooling and/or heating facility 5 is arranged (see, FIG. 2a). The synthesis device 1 can be arranged in a hot cell 24, as shown in FIG. 3.

(9) As can be seen in FIG. 2a, the reaction vessel 3 is a substantially cylindrical container having an opening 6 at its top through which substances can be introduced into and removed from the reaction vessel 3. Opening 6 of the reaction vessel 3 is closed with closure 7 if no substances are introduced into or removed from the reaction vessel 3.

(10) According to FIG. 1, the device 1 further has a dosing module 8. The dosing module 8 comprises a pipetting head 9 which can be moved relatively and channel-selectively in the z-axis to the reaction vessel by means of a robotics which is part of the dosing module 8. In the embodiment shown in FIG. 1 the pipetting head 9 can be moved as a whole in the x, y-axis with the x and y-axis lying in the plane of the page whereas the z-axis runs vertically to the plane of the page. The motion of the pipetting head 9 is controlled by a software. The robotics is controlled by a control module (not shown).

(11) In FIG. 1 the pipetting head 9 carries four dosing units 10a, 10b, 10c, and 12. Of course, the number of dosing units can be smaller or greater than four as long as at least one dosing unit is provided. A dosing unit 10 is a facility which can take-up, transport and release a substance. In FIG. 1 the pipetting head 3 carried the following dosing units: three dosing syringes 11 and one powder pipette 12. Each of the dosing syringes 11 is connected to a syringe pump arranged in the dosing module 8. The powder pipette 12 is connected to a vacuum-compressed air unit arranged in the dosing module 8. By means of the syringe pump and the vacuum-compressed air unit of the dosing module 8 take-up and release of a substance by the dosing units 10 is controlled.

(12) At least one of the dosing syringes 11 (for example dosing syringe 11b of the dosing unit 10b) has two channels for taking-up, transporting and releasing a substance required for the synthesis of the radiochemical compound as well as for supplying a gas into the reaction module and a third channel for draining off gaseous reaction products. For that, a vacuum can be applied to the third channel. Via the first channel, for example acetonitrile (ACN) or a solution of acetonitrile can be supplied, transported and drained off. Via the second channel, for example nitrogen can be supplied.

(13) Furthermore, device 1 comprises a storage module 13 containing a storage vessel 14 for the substances needed for the synthesis of the desired radiochemical compound. In the embodiment shown in FIG. 1 two types of storage vessels 14 are provided, a storage vessel 15 for receiving a powdered substance (for example Mannose Triflate, as shown in example 2) and a storage module 16 for receiving liquids. The storage module 16 can comprise several reservoirs 17 for receiving various liquids. The number of reservoirs 17 should correspond to the number of liquid substances needed for the synthesis of the radiochemical compound or should be greater than that. FIG. 1 shows a storage module 16 with six reservoirs 17.

(14) FIG. 1 shows a washing station 18 which can be formed separately from the storage module 13. The washing station 18 has reservoirs containing purification substances for the dosing units 10.

(15) The mode of operation of the device shown in FIG. 1 is described in example 2 below with respect to the preparation of [.sup.18F]-FDG.

(16) Example 2: Synthesis of [.sup.18F]-FDG

(17) In the following the synthesis of [.sup.18F]-FDG using the device illustrated in FIG. 1 is described.

(18) Basic Principles of the Preparation of [.sup.18F]-FDG

(19) As precursor for the preparation of [.sup.18F]-FDG there is used anhydrous 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-beta-D-mannopyranose (also known as Mannose Triflate or TATM). Fluorination of the precursor is done by introducing .sup.18F by means of nucleophilic substitution to give 2-[.sup.18F]fluoro-1,3,4,6-tetra-O-acetyl-D-glucose in acetonitrile under nitrogen atmosphere. Subsequently, the protective groups are removed by basic hydrolysis. The basic hydrolysis is typically performed with sodium hydroxide solution at temperatures of 80 C. Subsequently, the reaction solution is neutralized with hydrochloric acid and then diluted with water.

(20) The thus obtained crude product is purified by means of liquid chromatography, for example using a purification cartridge to give FDG. More details on the preparation of [.sup.18F]-FDG are described in Coenen H. H. et al., Recommendation for a practical production of 2-[.sup.18F]Fluoro-2-Desoxy-D-Glucose. Appl. Radiat. Isot. (38) 1997, 605-610.

(21) Starting Materials

(22) For the Preparation of [.sup.18F]-FDG by means of the device shown in FIG. 1 the following substances are needed as starting materials. There are also given the place of provision in device 1 prior to the start of synthesis and the amount provided. Both the place and also the amount are only exemplary. (1) Mannose Triflate: powdered; reservoir 15 of storage vessel 13; 20 mg (2) [.sup.18F] fluoride: half-life 110 min; in aqueous solution 1.2 ml, in reservoir 19 (3) Eluent Solution consisting of: 22 mg Kryptofix 2.2.2, 7 mg potassium carbonate in 750 l water/acetonitrile (volume ratio 1/1); reservoir 14a of storage module 13; (4) Ethanol, 200 l second reservoir 14b of storage module 13 (5) sodium hydroxide: 0.2M aqueous solution; reservoir 14c of storage module 13; 200 l (6) hydrochloric acid: 0.2M aqueous solution; reservoir 14d of storage module 13; 200 l (5) water, reservoir 17a of storage module 16; 15 ml (6) acetonitrile, reservoir 14e of storage module 13, 1 ml (7) Citrate buffer solution, consisting of: 25.2 mg Di-sodium-hydrogen-citrate-1,5-hydrate, 144.4 mg Tri-sodium-citrate-2-hydrate, 86.9 mg sodium chloride, 2.9 ml water for injection purposes; 0.1 ml hydrochloric acid (2 M), reservoir 14f von storage module 13, (8) 0.9% NaCl solution, reservoir 17c of storage module 16

(23) Storage module 13 and storage module 16 each are pre-conditioned kits. Both kits comprise a kit plate. Storage module 13 further comprises a QMA cartridge for separating the enriched water from the [.sup.18F] fluoride. Storage module 16 comprises substances needed in most of the methods for the preparation of radiochemical compounds, whereas storage module 13 comprises substances specifically needed for the preparation of the predetermined radiochemical compound. The aqueous [.sup.18F] fluoride solution is placed in a separate storage module.

(24) Step 1

(25) Dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a toward storage vessel 19. By means of the syringe pump 1.2 ml of [.sup.18F] fluoride are taken up by the dosing syringe 11a. Then, the pipetting head 9 moves the dosing syringe 11a containing the [.sup.18F] fluoride to the storage module 13 present as kit and having the QMA cartridge and applies the [.sup.18F] fluoride to the QMA cartridge. The passing aqueous solution is taken up with a dosing syringe 11c of the dosing unit 10b and released in the storage vessel 21. The eluent solution of the storage module 13 (kit) is taken up with the dosing syringe 11a and applied to the QMA cartridge. The passing eluent solution with the [.sup.18F] fluoride is taken up by the second dosing syringe 11b of the second dosing unit 10b and filled into the reaction vessel 3.

(26) Step 2

(27) Following step 1 the dosing module 8 moves the pipetting head 9 with the second dosing syringe 11b to the reaction vessel 3. Dosing syringe 11b is a triple lumen dosing syringe with a first internal channel 21 for supplying nitrogen, a second internal channel for adding acetonitrile for azeotropic drying and a third internal channel for vacuum suction. The channel for vacuum suction 23 serves to drain off the supplied nitrogen and optional waste products. During introduction of the pipetting tip of the dosing syringe 11b into the reaction vessel 3 the closure 7 of opening 6 of the reaction vessel 3 is opened, at this moment the penetrating dosing syringe 11 hermetically seals opening 6 of the reaction vessel 3. After penetration of the dosing syringe 11b alternately nitrogen and acetonitrile is introduced via channel 21 and channel 22 into the reaction vessel 3 and in this way, an azeotropic drying is realized. By means of the cooling and heating facility 5 the temperature of the eluent mixture contained in the reaction vessel 3 is increased to 95 C. The supplied nitrogen, the water, and the acetonitrile are removed from the reaction vessel 3 by means of the second channel 23 under vacuum of the dosing syringe 11b. Upon completion of drying the dosing syringe 11b is removed from the reaction vessel 3 with the opening 6 of the reaction vessel 3 being closed by the closure 7.

(28) Step 3

(29) The dosing module 8 moves the pipetting head 9 with the powder pipette 12 from its initial position to storage vessel 15 for powdered substances. Powder pipette 12 takes up 20 mg of Mannose Triflate from storage vessel 15 by means of a vacuum-compressed air unit. Then, pipetting head 9 moves the powder pipette 12 containing the Mannose Triflate to an empty vial 22 placed on the storage module 13 (kit). After penetration of the dosing syringe of the powder pipette 12 the release of the Mannose Triflate into the empty vial 22 is effected by the vacuum-compressed air unit. The dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the second reservoir 14 in the storage module 13. By means of the syringe pump 1000 l of acetonitrile are taken up by the dosing syringe 11a and are moved to vial 22 to dissolve the 20 mg of Mannose Triflate and take up the solution with the same dosing syringe 11a again. Subsequently, the pipetting head 9 moves the dosing syringe 11a containing the precursor solution to the reaction vessel 3. During introduction of the dosing syringe into the reaction vessel 3 closure 7 is removed from the opening 6 of the reaction vessel 3 with opening 6 being hermetically sealed by the penetrating dosing syringe. After penetration of the dosing syringe 11a release of the precursor solution into the reaction vessel 3 is effected by the syringe pump. During introduction of the dosing syringe 11a into the reaction vessel 3 closure 7 is removed from the opening 6 of the reaction vessel 3 with opening 6 being hermetically sealed by the penetrating dosing syringe. After penetration of the dosing syringe 11a release of the precursor solution into the reaction vessel 3 is effected by the syringe pump. By means of the cooling and heating facility 5 the temperature of the reaction mixture contained in the reaction vessel 3 in increased to 100 C. Then, dosing syringe 11a is removed from the reaction vessel 3 with opening 6 of the reaction vessel being closed by the closure 7. Then, the dosing module 8 moves the pipetting head 9 with the dosing syringe 11a to washing station 18 where the dosing syringe 11a is washed with acetone.

(30) Step 4

(31) After a reaction time of 5 min for evaporation of the acetonitrile nitrogen is introduced via channel 21 into the reaction vessel by the penetration of the triple lumen dosing syringe 11b into the closure of the reaction vial. After complete evaporation of the acetonitrile and cooling the reaction vessel down to 50 C. the dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the second storage vessel 14 in the storage module 13. By means of the syringe pump 200 l of ethanol are taken up by the dosing syringe 11a. Then, the pipetting head 9 moves the dosing syringe with the ethanol to the reaction vessel 3. During introduction of the pipetting tip of the dosing syringe 11a into the reaction vessel 3 closure 7 is removed from the opening 6 of the reaction vessel 3 with opening 6 being hermetically sealed by the penetrating dosing syringe. After penetration of the pipetting tip of the dosing syringe 11a release of the ethanol into the reaction vessel 3 is effected by the syringe pump. Then, the dosing module 8 moves the pipetting head 9 with the dosing syringe 11a to the washing station 18 where the dosing syringe 11a is washed with acetone.

(32) Step 5

(33) Then, the dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the second storage vessel 14 in the storage module 13 (kit). By means of the syringe pump 500 l of 2N sodium hydroxide solution are taken up by the dosing syringe 11a. Then, pipetting head 9 moves the dosing syringe 11a containing the sodium hydroxide solution to the reaction vessel 3. During introduction of the pipetting tip of the dosing syringe 11a into the reaction vessel 3 closure 7 is removed from the opening 6 of the reaction vessel 3 with opening 6 being hermetically sealed by the penetrating dosing syringe. After penetration of the pipetting tip of the dosing syringe 11a release of the sodium hydroxide solution into the reaction vessel 3 is effected by the syringe pump. By means of the cooling and heating facility 5 the temperature of the reaction mixture contained in the reaction vessel 3 in increased to 80 C. Then, dosing syringe 11a is removed from the reaction vessel 3 with opening 6 of the reaction vessel being closed by the closure 7. Then, the dosing module 8 moves the pipetting head 9 with the dosing syringe 11a to washing station 18 where the dosing syringe 11a is washed with acetone.

(34) Step 6

(35) After hydrolysis with a reaction time of 5 min dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the third storage vessel in the storage module 13. By means of the syringe pump 500 l of 2N hydrochloric acid are taken up by the dosing syringe 11a. Then, pipetting head 9 moves the dosing syringe 11a containing the hydrochloric acid to reaction vessel 3. The dosing syringe is introduced into the reaction vessel 3 as far as the temperature has reached room temperature by means of the cooling and heating facility 5 of the present reaction mixture there. During introduction of the dosing syringe 11a into the reaction vessel 3 closure 7 is removed from the opening 6 of the reaction vessel 3 with opening 6 being hermetically sealed by the penetrating pipetting tip. After penetration of the pipetting tip of the dosing syringe 11a release of the hydrochloric acid into the reaction vessel 3 is effected by the syringe pump. Then, dosing syringe 11a is removed from the reaction vessel 3 with opening 6 of the reaction vessel being closed by the closure 7. Then, the dosing module 8 moves the pipetting head 9 with the dosing syringe 11a to washing station 18 where the dosing syringe 11a is washed with acetone.

(36) Step 7

(37) Following step 6 the dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the storage reservoir 17a in the storage module 16. By means of the syringe pump 15 ml of water are taken up by the dosing syringe 11. Then, pipetting head 9 moves the dosing syringe 11a containing the water to the reaction vessel 3. The dosing syringe is introduced into the reaction vessel 3. During introduction of the dosing syringe 11a into the reaction vessel 3 the closure 7 is removed from the opening 6 of the reaction vessel 3 with opening 6 being hermetically sealed by the penetrating dosing syringe. After penetration of the dosing syringe 11a 1 to 2 ml of water are filled into the reaction vessel by means of the syringe pump and immediately drawn back into the syringe pump such that the entire 15 ml of water and the reaction mixture are mixed in a reservoir of the syringe pump. Then, dosing syringe 11a is removed from the reaction vessel 3 with opening 6 of the reaction vessel being sealed by the closure 7. Then, the dosing module 8 moves the pipetting head 9 with the dosing syringe 11a to the kit 13 for purification (cartridge) and presses the whole aqueous solution with the radiotracer .sup.18F-FDG over the cartridge. The passing aqueous solution is taken up by a second dosing syringe 11c of the dosing unit 10b and transported to the final vial 20 with a bacterial filter placed thereon. The aqueous solution is filled into the final vial 20 through the bacterial filter. The final vial 20 already contains a citrate buffer solution which has been filled in during hydrolysis of the radiotracer by the free dosing syringe 11a via the bacterial filter.

(38) Example 3

(39) Example 3 corresponds to example 2 except that an additional step, step 8, is provided for fractionation of patient's doses.

(40) Step 8

(41) After purification of the dosing syringe 11a in the washing station the normal saline solution (0.9%) is removed from the storage vessel 17c and distributed among several vials with a bacterial filter placed thereon in position 23 on device 1. Then, the individual patient's doses can be removed from the final vial 20 with the dosing module 8 and distributed among the individual normal saline solutions by means of the dosing syringe 11a.

LIST OF REFERENCE MARKS

(42) 1 Device 2 Reaction Module 3 Reaction Vessel 4 Housing 5 Cooling and/or Heating Facility 6 Opening of the Reaction Vessel 7 Closure of the Reaction Vessel 8 Dosing Module 9 Pipetting Head 10 Dosing Units 11 Dosing Syringes 12 Powder Pipette 13 Kit/Storage Module 14 Storage Vessel for Chemicals to be used 15 Storage Vessel for powdered Substances 16 Storage Module for liquid Substances 17 Reservoirs in the Storage Module 16 18 Washing Station 19 Fluoride Reservoir 20 Final Vial 21 .sup.18O Water 22 Empty Vial 23 Vials for Patient's Doses 24 Hot Cell