EP2585211A2

EP2585211A2 - Device and method for the production of radiochemical compounds

Info

Publication number: EP2585211A2
Application number: EP11828159.1A
Authority: EP
Inventors: Marco Müller; Steffen Howitz
Original assignee: GeSiM Gesellschaft fur Silizium-Mikrosysteme mbH; ABX Advanced Biochemical Compounds GmbH
Current assignee: GeSiM Gesellschaft fur Silizium-Mikrosysteme mbH; ABX Advanced Biochemical Compounds GmbH
Priority date: 2010-06-22
Filing date: 2011-06-20
Publication date: 2013-05-01
Also published as: US20130144051A1; US8980184B2; CA2803023A1; US9556081B2; WO2012041305A3; DE102010017511A1; US20160115092A1; CA2803023C; US9260354B2; WO2012041305A2; US20150133650A1

Abstract

The invention relates to a device for producing radiochemical compounds. Said device comprises at least a reaction module, a dosing module, and a supply module. The reaction module has at least one reaction vessel that includes a closeable opening through which substances needed for the production of a predefined radiochemical compound can be introduced into the reaction vessel of the reaction module and through which the produced 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 supply module and the reaction module in the x, y, and z directions and also has at least one dosing unit. At least one storage tank for one of the substances needed for the production of the respective radiochemical substance is formed in the supply module.

Description

description

The invention relates to a device for producing radiochemical compounds, in particular radiochemical medicaments, to a method for producing the radiochemical compounds, to a use of the device and to a kit which can be used in the device. In medical diagnostics increasingly short-lived, radiolabeled compounds, so-called radiotracers, are used whose physiological and biochemical properties allow a non-invasive tomographic detection of metabolic processes in the human body. Applying the modern tomographic method of positron emission tomography (PET), these radiotracers can be used to quantify metabolic processes and to record the bio-distribution of the radiodiagnostic from the outside. The tomographic acquisition of radiotracers, such. 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 various clinical pictures in recent years.

The worldwide share of positron emission tomography (PET) in the overall market of diagnosis by means of imaging techniques has exploded in recent years. The largest part of this is the [ 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. But not only that ^[18 F] FDG, which is often referred to as the "workhorse" of nuclear medicine called, but also other fluorinated tracers, for. Example for the diagnosis of neurological and cardiological diseases, have become increasingly important. Unfortunately, these tracers are just WE accessible to highly specialized clinics with their own radiochemistry department. This is partly due to the short half-lives of the 18F-labeled tracers, on the other hand, the relatively large space requirement for the classical production of radiotracer. So far, one needs for the production of a single PET tracer shielded with lead plates workstation (so-called hot cell or hot cell), the space required including filling is about 2 x 3 m. This will result in a total cost of more than 100,000 euros. Due to the size of the conventional modules, multi-stage syntheses in the so-called "hotcells" are difficult to realize, which means that many well-known and promising radio tracers do not even come into clinical use. Other limiting factors are the often long reaction times and complex purification procedures in the conventional synthesis apparatuses.

For the labeling of radiotracers, which can be used for positron emission tomography, due to the pharmacokinetics only a few radionuclides into consideration. For reasons of isotopic labeling, carbon 11 with a half-life of 20 min and fluorine-18 with a half-life of 110 min has hitherto been preferred. These radioactive nuclides are produced by means of a particle accelerator (cyclotron), which generates the desired radioactive nuclides by bombarding protons or deuterons on specially developed targets. The target for the production of [ ¹⁸ F] fluoride is ¹⁸ 0-enriched water (H ₂ ¹⁸ 0, Ο-18-water), which has a relatively high price due to its rather complicated distillative production from natural water. In general, the [ ¹⁸ F] fluoride produced in the cyclotron is separated from the target water by ion exchange, whereby on the one hand losses of Ο-18-water occur and on the other hand the water can be contaminated by contact with the ion exchanger with organic substances. After an azeotropic distillation in the subsequent synthesis step activated by means of phase transfer catalysts [ ¹⁸ F] fluoride with the corresponding starting material (precursor) in an organic solvent, for. 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. Recent developments are mainly focused on the miniaturization and thus on the use of microchips. An alternative to the separation of carrier-free [ ¹⁸ F] fluoride from the target water and its radiochemical conversion are electrochemical flow cells. The separation of the anionic radionuclide is achieved by electrofixing in a flow cell with permanent electrode arrangement while maintaining an electric field. Subsequently, by reversal and optionally an intermediate rinse desorption of the radionuclide done. As a result, consuming Destillationsbzw. Drying steps avoided so that [ ¹⁸ F] fluoride can be converted by anodic fixation by simple washing with an aprotic solvent in a chemically reactive form. From there, the carrier poor ¹⁸ F mark to the desired radiotracer.

WO 03/078358 A2 discloses a miniaturized device for producing radiolabelled compounds. The device has a reaction chip with an area of 1 cm ² and has inlet openings for the supply of reactants and outlet openings for discharging the reaction mixture or its components. A further connection can be provided for introducing, for example, a deprotection means. The inlet ports, outlet ports, and other ports are interconnected via a system of microchannels formed in the device. An analysis chip can be connected to the reaction chip, which has two additional connections for the supply or removal of electrolyte buffer solutions in addition to an inlet opening, which is in connection with the outlet opening of the reaction chip, and an outlet opening. From the analysis chip, the reaction mixture finally passes into a separating device in which the desired radiotracer is then obtained. The individual chips can also be realized in a single device, wherein a plurality of microchannels is provided in the individual device.

US 2005/0232387 A1 discloses a system for synthesizing a radiochemical compound in a microfluidic environment. The system comprises a microreactor having a plurality of inlet ports, an outlet port, and a microchannel connecting the inlet ports and the outlet port. Via the inlet openings, the precursor and a solution containing the radioactive isotope are supplied. The two substances come into contact with one another in the microchannel, so that during the passage of the two substances through the microchannel, both substances react with one another to obtain the radiochemical compound. At the outlet then the radiochemical compound leaves the microreactor. The reaction in micro-channels, however, is associated with a variety of difficulties. On the one hand, the microfluidics in the channels requires a careful coordination of the fluidics of the components, which usually can only be accomplished with a high outlay on the periphery (eg pumps, valves, heating and cooling units). It becomes even more complicated when different microreactors have to be used for different radiotracers. On the other hand, the cleaning of the microchannels is associated with a high cost. This prevents various radiotracers from being made within a short time with the same microchip. Finally, the number of reaction stages that can be performed in the known microreactors is limited. Each stage requires at least one inlet that requires a microchannel that communicates with the channel in which the precursor flows. In general, other outlets are required to remove the waste products.

The object of the invention is to eliminate the disadvantages of the prior art. In particular, a device for producing radiochemical compounds, in particular radiochemical medicaments such as radiotracers, is proposed. ben, which avoids the long reaction times and elaborate purification procedures required in conventional synthesis equipment, and offers high radiochemical yields and high flexibility in the production of different radiotracers. Furthermore, a method for producing radiochemical compounds by means of the device and uses of the device are to be specified.

This object is solved by the features of claims 1, 10, 15 and 16. Advantageous embodiments of the invention will become apparent from the features of claims 2 to 9 and 11 to 14.

According to the invention, an apparatus for producing radiochemical compounds is provided which comprises at least one reaction module, a dosing module, and a storage module, wherein

- The reaction module has at least one reaction vessel with a closable opening, through which the substances required for the preparation of a given radiochemical compound, are introduced into the reaction vessel, and over which the prepared radiochemical compound is removed from the reaction vessel;

the dosing module has at least one pipetting head, which is movable relative to the supply module and the reaction module and in the x, y and z directions and has at least one dosing unit, and

- In the storage module at least one reservoir for one of the substances that are required for the preparation of the respective radiochemical compound is formed. Preferably, a washing station for the dosage units is also provided. The device is preferably controlled by means of a control unit, which is expediently formed in the dosing module and can be controlled by software. Furthermore, the device may comprise a purification module for separating the prepared radiochemical compound from the reaction mixture. The cleaning module can include cartridges customary in radiochemistry, in particular chromatographic columns, and / or other cleaning agents, for example high performance liquid chromatography (HPLC). Alternatively or additionally, the cartridges and / or other cleaning agents required to separate the prepared radiochemical compound from the reaction mixture can also be integrated into the storage module. The latter is particularly advantageous if the storage module is provided as a kit. Likewise, the device may comprise a dispensing module in which the radiochemical compound purified in the cleaning module is mixed with an aqueous solution for injection, e.g. B. isotonic sodium chloride solution is added to obtain ready-to-use preparations. The dispensing module may comprise a plurality of vials into which the purified radiochemical compound may be filled at a predetermined dose. The device according to the invention thus allows the production and dosage of a radiochemical compound, whereby the hitherto required use of a separate synthesis device and a separate dosing device is avoided. In view of the cost of known metering devices, this represents a further significant advantage of the invention.

A substance which is necessary for the preparation of the respective radiochemical compound is also referred to below as "required substance." The term "required substance" includes the starting materials which are required for the preparation of a given radiochemical compound, for example a precursor compound. It may also comprise the necessary catalysts and cleaning substances, such as solvents. Preferably, each of the reaction vessels of the reaction module has an internal volume of from 1 μΐ to 20,000 μΐ, more preferably from 1 μΐ to 5,000 μΐ, even more preferably from 1 μΐ to 2,500 μΐ, and most preferably from 1,000 μΐ to 2,000 μΐ. The reaction vessel may be a vial. Each reaction module has at least one reaction vessel, preferably 1 to 50 reaction vessels, more preferably 1 to 10 reaction vessels.

Each reaction vessel has an opening through which the substances necessary for the preparation of the respective radiochemical compound can be introduced into the reaction vessel and from which the prepared radiochemical compound can be removed from the reaction vessel. Moreover, gases can also be introduced and / or discharged via the opening. Finally, the opening can also be used to produce overpressure or vacuum (vacuum) in the reaction vessel.

If several reaction modules are provided, several radiochemical compounds can be prepared in parallel with only one device according to the invention. Even if only one reaction module is provided, it is possible to switch quickly from the production of a radiochemical compound to the production of another radiochemical compound. This requires only replacement or purification of the reaction vessel (or reaction vessels) and the dosage units. Furthermore, in contrast to the prior art, difficult-to-access radiochemical compounds can also be synthesized rapidly since only the selection of another flowchart in the control unit has to be called up and executed. This is due to the fact that it is only necessary to install additional reaction vessels and / or cleaning modules. This is particularly advantageous in radiochemical compounds that can only be obtained via multi-step reactions. The prior art synthesizers are virtually limited to two stages and require elaborate designs when more than three stages are required. The device according to the invention is for this for example, particularly suitable for the nucleophilic preparation of ¹⁸ F-DOPA (6- [ ¹⁸ F] fluoro-L-3,4-dihydroxyphenylalanine), which is known to require a three-step reaction. A reaction module preferably comprises a plurality of reaction vessels when the preparation of a given radiochemical compound requires a multi-step process. Several reaction modules are preferably provided when different radiochemical compounds are to be prepared in succession or in parallel by means of the device according to the invention.

The device according to the invention avoids the difficulties associated with the microfluidics of known miniaturized synthesis devices for radiochemical compounds. This is due in particular to the flexible control of the pipetting heads in the uptake and release of educts and solvents, while the uptake and release of starting materials and solvents in micro fluidic systems always depends strictly linearly on a flow chart. The device according to the invention is dimensioned such that it can be used in a "standard hot cell." A "standard hot cell" is understood to mean a space which is delimited against its surroundings by means of shielding walls. The shielding walls are typically made of a material that is impermeable to gamma radiation, for example lead plates. For example, the device can be used in a hot cell whose interior has dimensions of 1 mx lm x Im or less. A further advantage of the device according to the invention is that the preparation of one or more radiochemical compounds can be carried out without the intervention of an operator. For this purpose, substances required for the production of a given radiochemical compound are combined in kits. Each kit can be a supply module of the device according to the invention. The necessary for the preparation of a given radiochemical compound Substances containing a radioisotope are preferably not provided in the kits but in a separate storage module.

These kits can be prefabricated so that the device according to the invention only has to be equipped with the kits in order to produce the prescribed radiochemical compound. The assembly of the device according to the invention with the components of a kit can be made on the basis of assembly plans, different assembly plans are provided for different radiochemical compounds, for example assembly plan 1 for a first tracer, tracer A, assembly plan 2 for a second tracer, tracer B, assembly plan for a third tracer, tracer C, etc. The assembly plan is communicated to the user of the device according to the invention together with the kit.

The kit may also comprise a carrier plate, for example a microtiter plate. The support plate has reservoirs in which the substances are located. It is then only necessary to position the carrier plate at a predetermined location of the storage module. In the following, the support plate is also referred to as a kit plate. The kits can be disposable kits. The kit may contain, in addition to substances required for the preparation of a given radiochemical compound, also the cartridges and / or other required cleaning elements required for the separation of the prepared radiochemical compound from the reaction mixture. The user can insert these cartridges and / or cleaning elements into the cleaning module. The assembly of the cleaning module with the cartridges and / or cleaning elements can then be carried out according to the specifications of the assembly plan, ie the assembly plan includes not only the places where the required substances are positioned in the storage module, but also the places where the cartridges and / or cleaning elements are positioned in the cleaning module. The supply module and the cleaning module of the device according to the invention are thus integrated into the kit. If the user of the device according to the invention wants to produce a specific radiochemical compound, for example Tracer A, one or more kits are made available to him containing the required substances and the cartridges and / or cleaning agents required for this purpose. The user then populates the device according to the invention with the kit on the required substances, cartridges and, if provided, further cleaning agents are provided. Then, via the software of a control module (described below), he instructs the device to make Tracer A and starts the manufacturing process by inputting the corresponding instruction. The production of Tracer A is then fully automatic, intervention by the user is not required. If a plurality of radiochemical substances are to be produced simultaneously and / or in parallel, the user also undertakes the assembly with the kit required for the respective radiochemical substance and enters the required instructions via the software of the control module. All radiochemical substances are then produced fully automatically. This is associated with a considerable amount of time.

The preparation of several radiochemical compounds can be carried out in parallel and / or in succession. If the production of several radiochemical compounds take place in parallel, several reaction modules are required.

The reaction module preferably has a heating and / or cooling device. The heating and / or cooling device is expediently arranged below the bottom of the reaction vessel or forms a jacket around the reaction vessel. It is also possible to use a microwave to heat up the reaction vessel.

The reaction vessel preferably has a closure, wherein the opening of the reaction vessel is opened when a substance which is required for the preparation of the respective radiochemical compound is introduced into the reaction vessel or the reaction mixture or a part thereof is removed from the reaction vessel. leads, and the opening is closed by means of the closure after completion of the supply or discharge of the substance. During labeling or hydrolysis of the radiochemical compound, the reaction vessel is usually closed and the dosing module is available for further tasks during this time.

The closure of an opening of a reaction vessel is preferably gas-tight. By means of the prefix, the opening can conveniently be opened and closed automatically. This too can be done via the control unit. Preferably, the reaction vessel is mounted in the reaction module so that it can be vibrated by means of a dosage unit which is introduced into the reaction vessel. In this way, thorough mixing of the reaction mixture in the reaction vessel can be achieved. Alternatively, for this purpose, the reaction vessel may be mounted on a movable support member, so that the reaction vessel can be set in a shaking motion. The carrier element is formed in the reaction module and may contain the heating and / or cooling device. Likewise, an ultrasonic mixer or a magnetic stirrer can be arranged in the reaction module. Each pipetting head is movable relative to the supply module and the reaction module, wherein storage and reaction modules are suitably fixed.

Each pipetting head of the dosing module is movable in the x, y and z directions. The movement of the pipetting head is controlled by a control module, which is expediently arranged in the dosing module and can be controlled by software. The software can be used to specify when the pipetting head performs which movement. Furthermore, the software determines which volumes of the substances required for the production of the radiochemical compound are taken up and delivered by the dosage units of the respective pipette head. If the dosing module has two pipetting heads, then these pipetting heads are preferably movable independently of one another. The advantage of two pipetting heads is that a substance which has been passed through the cleaning module, with a dosage unit, which carries the second pipetting head, can be directly absorbed and processed, whereby an additional reservoir is spared.

A dosage unit is understood here to mean a device which has an internal volume into which a predetermined amount of a required substance or of the reaction mixture can be taken up, in which the absorbed amount of the required substance or of the reaction mixture can be transported, and from which the excluded quantity of required substance or the reaction mixture can be delivered. The uptake and release of the substance or of the reaction mixture from the dosage unit is controlled by the control unit. For this purpose, valves or actuators may be provided on the dosage unit, which can be controlled by means of motors, pumps, vacuum or a compressed gas such as compressed air. The necessary means for controlling the valves and actuators may be part of the dosage unit. For dispensing and receiving substances, a dosage unit preferably has a dosing tip. As dosing tip active tips, z. For example, piezoelectrically operated microspheres for dosing pico to nanoliter quanta or passive steel or polymer tips for dosing micro-milliliter quanta can be used. Dosing units for liquids with active and passive dosing tip allow the reproducible and repetitive addressing of single quanta with a volume of 20 picoliters ± 10%, with no upper limits.

In one embodiment, a metering unit may comprise a fluidically closed circuit of at least one reservoir for system fluids such as deionized water, at least one pump, at least one valve and at least one metering tip. The pump and the valve may be commonly connected to a system as with syringe pumps. Alternatively, however, other pump-valve Arrangements may be provided. The fluidically closed circuit can be realized by means of lines, for example by means of a hose.

A dosing module may have different dosage units, in particular dosing units with different structure, which are adapted to the given transport task.

Dosing units with dosing tips can be used for receiving, transporting and dispensing liquids. The inclusion of the predetermined amount of the required substance or the reaction mixture in the internal volume, the closure of the amount in the internal volume for transport, and the delivery of the amount of the internal volume are controlled by syringe pumps.

For receiving, transporting and delivering solids, the pipetting head can carry a dosing unit, which can remove a powdery substance from the supply module, transport it to the reaction module and introduce it via the opening into a reaction vessel of the reaction module.

In one embodiment of the invention, the pipetting head carries a dosage unit, which removes a pulverulent substance from the storage module, transports it to the reaction module and introduces it via the opening into a reaction vessel of the reaction module, and at least one further dosage unit which consists of the Supply module remove a liquid substance, transport to the reaction module and can introduce tion module via the opening in a reaction vessel of the reaction. The dosing unit, which can remove a liquid substance from the storage module, transport it to the reaction module and introduce it via the opening into a reaction vessel of the reaction module can also be used to receive from the reaction vessel the reaction mixture or a part thereof, to transport and to a given place. The term "liquid" or "liquid substance" is also intended here to include solutions and dispersions of substances in a solvent. He should also include the reaction mixture. Furthermore, a metering unit should have a first channel for supplying a gas such as nitrogen into the reaction vessel and a second channel for removing gaseous reaction products from the reaction vessel. In this case, the first channel can simultaneously serve for receiving, transporting and delivering a required substance or the reaction mixture or a part thereof. The first channel is designed so that it penetrates deeper into the reaction vessel than the second channel. Dosage units are referred to the number of channels as single-lumen, zweilumige, dreilumige, etc. dosage units. For example, a three-lumen dosage unit may include a first channel for receiving, transporting, and delivering a substance needed for the synthesis of the radiochemical compound, a second channel for delivering a gas to a reaction vessel, and a third channel for removing gaseous reaction products from the reaction vessel exhibit. For this purpose, a vacuum may be applied to the third channel.

By means of the dosage units, liquids and solids can be precisely metered. The dosage units preferably have an internal volume of 10 to 5000 μΐ, more preferably 50 to 1000 μΐ.

The device according to the invention allows the use of solids for the preparation of predetermined radiochemical compounds, in other words, the required substances can be present as solids. This relates in particular to precursor compounds and catalysts. Solids are preferably used when prolonged storage for malfunction, eg. B. leads to decomposition of the substance. The solids dosage according to the invention allows the dosage of a few μg mass quanta. For metering of solids, metering units adapted to this purpose are provided, which are also referred to hereinafter as solids pipettes. be referred to. The advantage of a solid pipette is the combination of relatively exact dosage and above all easier storage of the substance in a stable dry state. The supply module of a kit with a stock of solids is fundamentally different from a supply of liquids. The solids may be added to a solvent in the dosage unit immediately prior to their use if the substances need to be in solution for the preparation of the radiochemical compound. The use of solids in the dosage units and kits avoids problems due to the inadequate stability of solutions of these solids. This increases the durability of the kits. It is particularly advantageous that the device according to the invention enables the use of pulverulent catalysts. This significantly increases the number of radiochemical compounds which can be prepared by means of the device according to the invention. Finally, a dosage unit may be provided which can apply liquids to one end of a cleaning cartridge, push through the cleaning cartridge, and resume at the other end of the cleaning cartridge. For this purpose, such a dosing unit has a first channel with an opening which can be brought into contact with the inlet of the cleaning cartridge, so that a liquid can be introduced from the first channel into the cleaning cartridge. The dosage unit further includes a second channel having an opening in contact with the exit of the cleaning cartridge when the opening of the first channel is in contact with the entrance of the cleaning cartridge. By means of pressure exerted on the liquid via the first channel, the liquid is pressed into the cleaning cartridge and through it via the outlet of the cleaning cartridge into the second channel. When passing through the cleaning cartridge, the liquid is cleaned. The purified liquid is then in the second channel. The storage module expediently comprises reservoirs for all required substances. Each reservoir preferably has a volume of 10 to 20,000 μΐ, more preferably from 50 to 5,000 μΐ. Preferably, the storage module has a separate reservoir for a powdery substance.

In one embodiment of the invention, one or more storage modules are stored in a microplate stacker. This is particularly advantageous if the storage modules are each in the form of kits comprising kit plates.

Optionally, the microplate stacker may have means for controlling temperature and / or humidity and / or C0 ₂ concentration. A stacker is a rack in which several kits are stacked with all substances and cleaning cartridges. The microplate stacker and / or a storage module have a transport device, eg. As a gripper or a conveyor belt, which removes the necessary for the preparation of a given radiochemical connection kit from the frame and turns off at a predetermined location within the device according to the invention. Thereafter, the dosing units have access to the substances of the kit. Each kit, suitably the kit plate, can have an individual address, which is realized, for example, in the form of a transponder chip or a bar code, whereby a confusion of kits can be ruled out. In this way it is possible to equip the device with one or more kits for the synthesis of different or the same radiochemical substances, which can represent a considerable time saving. Any movement of the kit plate from the stacker to the synthesis station and back is via the control unit of the same. The dosage units transport the predetermined amounts of the required substances at a given time from the reservoirs of the storage module into the reaction vessel. If a plurality of metering units are provided, it is also predetermined which of the metering units receives what required substance at which time and transfers it to the reaction vessel. The specifications are stored by means of software in the control unit, which then controls the pipetting head via the robotics. Likewise, a dosage unit can be used to increase the reactivity or to remove a part of it from the reaction vessel and to transport to a predetermined location, for example, the inlet of the cleaning module, for example an HPLC. The reaction mixture is usually removed from the reaction vessel after reaction of the required substances and contains the desired radiochemical compound, which is then purified in the cleaning module. After completion of the cleaning, the purified radiochemical compound can be transferred to a filling cell. The filling cell is preferably a component of the device according to the invention. The term "radiochemical compound" is intended to include all organic or inorganic compounds which have a radioisotope, In particular, the term "radiochemical compound" includes radiochemicals and diagnostics, more preferably radiotracers, radiopharmaceuticals and radioligands. Preferred radioisotopes are ⁶⁸ Ga, ⁹⁰ Y, ⁹⁹ Tc, ^{11 64} Cu, Lu ¹⁷⁷ , ⁿ C, ¹⁸ F, ¹²⁴ I, ¹³ N and

15 1 1 18 124 18

O, more preferably C, F and I, and more preferably F.

Preferred ¹⁸ F-labeled radiotracer are 2-deoxy-2- [ ¹⁸ F] fluoro-D-glucose ([ ¹⁸ F] - FDG), 6- [ ¹⁸ F] fluoro-L-3,4-dihydroxyphenylalanine ([ ¹⁸ F ] -FDOPA), 6- [ ¹⁸ F] fluoro-L-meta-tyrosine ([ ¹⁸ F] -FMT), [ ¹⁸ F] fluorocholine, [ ¹⁸ F] fluoroethylcholine, 9- [4- [ ¹⁸ F] fluoro 3- (hydroxymethyl) butyl] guanine ([ ¹⁸ F] FHBG), 9 - [(3- [ ¹⁸ F] fluoro-1-hydroxy-2-propoxy) methyl] guanine ([ ¹⁸ F] -FHPG), 3- (2 '- [ ¹⁸ F] fluoroethyl) spiperone ([ ¹⁸ F] -FESP), 3 * -deoxy-3 * - [ ¹⁸ F] fluorothymidine ([ ¹⁸ F] -FLT), 4- [ ¹⁸ F] fluoro N- [2- [1- (2-methoxyphenyl) -1-piperazinyl] ethyl] -N-2-pyridinylbenzamide ([ ¹⁸ F] -p-MPPF), 2- (1- {6 - [(2 - [ ¹⁸ F] fluoroethyl) (methyl) amino] -2-naphthyl} ethylidine) malononitrile ([ ¹⁸ F] -FDDNP), 2- [ ¹⁸ F] fluoro-α-methyltyrosine, [ ¹⁸ F] fluoromisonidazole ([ ¹⁸ F] -FMISO) and 5- [ ¹⁸ F] fluoro-2'-deoxyuridine ([ ¹⁸ F] -FdUrd).

According to the invention, a method for producing radiochemical compounds is further provided by means of the device according to the invention, wherein by means of dosage units, the substances required for the preparation of the respective radiochemical compound are introduced into a reaction vessel of the reaction module and wherein the dosage units via a pipetting head in the x-, y-direction or in the x-, y- and z-direction are movable.

Preferably, substances required for the preparation of the respective radiochemical compound are introduced successively into the reaction vessel of the reaction module. For this purpose, a plurality of dosage units can be used, wherein the same dosage unit can be used for the introduction of multiple substances. In this case, the dosage unit should be rinsed after the introduction of a first substance and the inclusion of a second substance in a washing station.

The produced radiochemical compound can advantageously also be removed from the reaction vessel by means of a dosage unit. This dosage unit may be one of the dosage units already used for the introduction of a substance into the reaction vessel. Preferably, this dosage unit was previously rinsed in the wash station. After removal from the reaction vessel, the radiochemical compound produced can be transferred by means of the dosing unit to a purification module.

In one embodiment, the method according to the invention comprises the following steps:

(a) introducing a solution of a radioactive isotope into the reaction vessel;

(b) drying a radioactive isotope; (c) introducing a precursor compound of the radiochemical compound to be prepared into the reaction vessel; Reacting the precursor compound with the radioactive isotope;

Taking the prepared radiochemical compound from the reaction vessel;

(f) purifying the prepared radiochemical compound by means of one or more cartridges and / or by HPLC; and (g) dispersion of the prepared radiochemical compound with a buffer or NaCl-containing solution, as well as filling into ready-to-use vials.

In step (a), the solution of the radioactive isotope is expediently an aqueous solution.

In step (c), the precursor compound is preferably introduced into the reaction vessel as a solid or dissolved in an organic solvent. If the precursor compound is to be introduced as a solution, the precursor compound can be mixed with an organic solvent immediately before it is introduced into the reaction vessel or can already be provided in dissolved form. If a kit with a kit plate is used, the solution may already be present in the kit, or a solvent may be transferred by means of a dosing unit into the solid material vial on the kit plate in which the undissolved precursor compound is present.

Following step (d) and before step (e), it may be provided that one or more protecting groups having the precursor group are split off from the reaction mixture obtained in step (d). This can be done for example by hydrolysis. The device according to the invention is particularly suitable for the production of radiotracers, radiopharmaceuticals and radioligands.

Precursor compounds are also referred to as precursors. The term "precursor compound" or "precursor" includes organic or inorganic compounds that react with a radioisotope to yield a radiochemical compound. Examples of precursor compounds are amino acids, nucleosides, nucleotides, proteins, sugars and derivatives of these compounds. Specific examples are 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-beta-D-mannopyranose for the production of [ ¹⁸ F] -FDG; N ² - (p-anisyldiphenylmethyl) -9 - [(4-p-toluenesulfonyloxy) -3- (p-anisyldiphenylmethoxymethyl) butyl] guanine for the preparation of [ ¹⁸ F] -FHBG; N ² - (p-anisyldiphenylmethyl) -9 - [[1- (p-anisyldiphenylmethoxy) -3- (p-toluenesulfonyloxy) -2-propoxy] methyl] guanine for the preparation of [ ¹⁸ F] -FHPG; 8- [4- (4-fluorophenyl) -4,4- (ethylenedioxy) butyl] -3- [2 '- (2,4,6-trimethylphenylsulfonyloxyethyl)] - 1-phenyl-, 3,8-triazaspiro 4.5] decan-4-one for the production of [ ¹⁸ F] -FESP; 5 ^* -O-Boc-2,3 ^* - anhydrothymidine or N-Boc-5'-O-dimethoxytrityl-3'-O- (4-nitrophenylsulfonyl) -thymidine for the preparation of [ ¹⁸ F] -FLT; N- [2- [4- (2-methoxyphenyl) -l-piperazinyl] ethyl] -4-nitro-N-2-pyridinyl-1-benzamide for the preparation of [ ¹⁸ F] p-MPPF; 2- (1 - {6 - [(2- (p-Toluensulfonyloxy) ethyl) (methyl) amino] -2-naphthyl} ethylidine) malononitrile for the preparation of [ ¹⁸ F] -FDDNP; 1,2-bis (tosyloxy) ethane and Ν, Ν-dimethylethanolamine for the preparation of [ ¹⁸ F] fluoroethylcholine; and ditosylmethane or dibromomethane on the one hand and N, N-dimethylethanolamine on the other hand for the production of [ ¹⁸ F] fluorocholine. The precursor compound often contains protecting groups to protect functional groups that are not intended to react with the radioactive isotope. Following step (c) and before carrying out step (d), the protecting groups are preferably separated from the reaction product obtained in step (c). The term "radiotracer" in the present invention, an artificial, radioactively labeled endogenous or exogenous substance understood after Contribution to the living body participates in the metabolism and allows a variety of studies or facilitated.

The term "radioligand" in the present invention is understood to mean a radionuclide-labeled substance which can bind as a ligand to a target protein, for example to a receptor.

According to the invention, a kit is also provided, the

(i) a backing plate having reservoirs for receiving substances necessary for the production of a radiochemical compound,

(Ii) one or more cartridges for the purification of the substances and / or the radiochemical compound and

(iii) Substances required for the preparation of a radiochemical compound.

The kit may comprise other ingredients, in particular the ingredients described above in connection with the kit.

The invention will be explained in more detail below with reference to embodiments, which are not intended to limit the invention, with reference to the drawings. Show

Fig. 1 is a schematic representation of an embodiment of the device according to the invention; Figure 2a is a schematic sectional view of the reaction module and a metering unit with three channels, the pipette tip is inserted into the reaction vessel.

Figure 2b is a schematic sectional view of the reaction module and a dosage unit whose pipetting tip is inserted into the reaction vessel.

Fig. 2c is a schematic sectional view of the reaction module with closed reactor during a reaction; and

Fig. 3 is a schematic representation of the embodiment of the device according to the invention shown in Fig. 1, which is a hot cell used.

Example 1 :

The synthesis device 1 according to the invention shown schematically 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 device 5 is arranged (see Fig. 2a). As shown in FIG. 3, the synthesizer 1 may be arranged in a hot cell 24.

As can be seen in FIGS. 2 a, the reaction vessel 3 is a substantially cylindrical container which has an opening 6 at its top through which substances can be introduced into the reaction vessel 3 and removed from the reaction vessel 3. The opening 6 of the reaction vessel 3 is closed with a closure 7, when no substances are supplied to the reaction vessel 3 or taken from this.

According to FIG. 1, the device 1 furthermore has a dosing module 8. The dosing module 8 comprises a pipetting head 9, which by means of a robotics, which part of the dosing module 8, are relatively and channel-selectively movable in the z-axis to the reaction vessel. In the embodiment shown in FIG. 1, the pipetting head 9 is movable as a whole in the x, y axes, with the x and y axes in the plane of the paper, while the z axis is perpendicular to the plane of the paper runs. The movement of the pipetting head 9 is controlled by software. The robotics are controlled via a control module (not shown).

In Fig. 1, the pipetting head 9 carries four dosage units 10a, 10b, 10c and 12. Of course, the number of dosage units smaller or larger than four, as long as at least one dosage unit is provided. A dosage unit 10 is a device that can receive, transport and release a substance. In Fig. 1, the pipetting head 3 carries the following dosage units: three dosing tips 11 and a powder pipette 12. Each of the dosing tips 11 is connected to a syringe pump disposed in the dosing module 8. The powder pipette 12 is connected to a vacuum-compressed air unit disposed in the dosing module 8. By means of the syringe pump and the vacuum-compressed air unit of the dosing module 8, the uptake and release of a substance by the dosage units 10 is controlled. At least one of the metering syringes 11 (for example metering syringe 11b of the dosage unit 10b) has two channels for receiving, transporting and delivering a substance which is required for the synthesis of the radiochemical compound and for supplying a gas into the reaction module and a third channel for the removal of gaseous reaction products. For this purpose, vacuum may be applied to the third channel. For example, acetonitrile (ACN) or an Acetnotril solution can be fed, transported and removed via the first channel. For example, nitrogen can be supplied via the second channel.

The apparatus 1 further comprises a storage module 13 containing a reservoir 14 for the substances needed for the synthesis of the desired radiochemical compound. In the embodiment shown in Fig. 1 are two Types of storage containers 14 are provided, on the one hand a storage container 15 for receiving a powdery substance (for example Mannose triflate as shown in Example 2) and on the other hand a storage module 16 for receiving liquids. The storage module 16 may comprise a plurality of reservoirs 17 for receiving different liquids. The number of reservoirs 17 should be equal to or greater than the number of liquid substances needed for the synthesis of the radiochemical compound. In Fig. 1, a storage module 16 with six reservoirs 17 is shown. Fig. 1 shows a washing station 18, which may be formed separately from the storage module 13. The washing station has reservoirs 18 which contain cleaning substances for the dosage units 10.

The mode of operation of the device shown in FIG. 1 is described in the following Example 2 with reference to the production of [ ¹⁸ F] -FDG.

Example 2: Synthesis of | ^"18 F1 FDG

The synthesis of [ ¹⁸ F] -FDG using the apparatus shown in FIG. 1 will now be described.

Basic principles of the production of [FJ-FDG

As precursor for the production of [ ¹⁸ F] -FDG, anhydrous 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-beta-D-mannopyranose (also referred to as mannose triflate or TATM) is used , Fluorination of the precursor is accomplished by introducing ¹⁸ F by nucleophilic substitution to give 2- [ ¹⁸ F] fluoro-1,3,4,6-tetra-O-acetyl-D-glucose in acetonitrile under a nitrogen atmosphere. Subsequently, the protecting groups are removed by basic hydrolysis. The basic hydrolysis is typically carried out with sodium hydroxide at temperatures of 80 ° C. Subsequently, the reaction solution is neutralized with hydrochloric acid and finally diluted with water. The crude product thus obtained is purified by liquid chromatography, for example, using a cleaning cartridge to obtain [ ¹⁸ F] FDG. Further details on the preparation of [ ¹⁸ F] -FDG can be found in Coenen HH et al., Recommendation for a practical production of 2- [ ¹⁸ F] fluoro-2-deoxy-D-glucose. Appl. Radiat. Iseult. (38) 1997, 605-610.

starting materials

For the production of [ ¹⁸ F] -FDG by means of the apparatus shown in FIG. 1, the following substances are required as starting materials. Also indicated are the location of delivery in the apparatus 1 prior to the start of the synthesis and the amount that is provided. Both the place and the crowd have only exemplary character. (1) mannose triflate: powdery; Reservoir 1 of reservoir 13; 20 mg

(2 [ ¹⁸ F] 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 μl water / acetonitrile ( Volume ratio of 1/1); reservoir 14a of supply module 13;

(4) Ethanol, 200 μΐ, second reservoir 14b of supply module 13

(5) sodium hydroxide: 0.2 M aqueous solution; Reservoir 14c of supply module 13; 200 μΐ

Hydrochloric acid: 0.2 M aqueous solution; Reservoir 14d of supply module 13; 200 μΐ (5) water, reservoir 17a of supply module 16; 15 ml

(6) acetonitrile, reservoir 14e of stock module 13, 1 ml (7) citrate buffer solution consisting of: 25.2 mg di-sodium hydrogen citrate-1, 5-hydrate, 144.4 mg trisodium citrate 2-hydrate, 86.9 mg sodium chloride, 2.9 ml water for injections; 0.1 ml hydrochloric acid (2 M), reservoir 14f of storage module 13, (8) 0.9% NaCl solution, reservoir 17c of storage module 16

Stock module 13 and stock module 16 are each prefabricated kits. Both kits include a kit plate. Supply module 13 further comprises a QMA cartridge for separating the enriched water from the [ ¹⁸ F] fluoride. Stock module 16 includes substances needed in the majority of methods for making radiochemical compounds, while stock module 13 includes the substances needed specifically for the preparation of the given radiochemical compound. The aqueous [ ¹⁸ F] fluoride solution is housed in a separate storage module.

Step 1

The dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the reservoir 19. By means of the syringe pump, l, 2 ml of [ ¹⁸ F] fluoride are taken up by the dosing syringe 11a. The pipetting head 9 moves the syringe I Ia, containing the ^[18 F] fluoride, then to the supply module 13, which is present as a kit, with the QMA cartridge and outputs the ^[18 F] fluoride on the QMA cartridge. The continuous aqueous solution is taken up with a metering syringe 11c of the dosage unit 10b and discharged again in the storage container 21. The eluent solution from stock module 13 (kit) is taken up with the metering syringe 11a and added to the QMA cartridge. The continuous eluent solution with the [ ¹⁸ F] fluoride becomes received by the second metering syringe I Ib of the second dosage unit 10b and filled in the reaction vessel 3.

step 2

Subsequent to step 1, the dosing module 8 moves the pipetting head 9 with the second dosing syringe 11b to the reaction vessel 3. Dosage syringe 1b is a three-lumen dosing syringe with a first inner channel 21 for supplying nitrogen, a second inner channel for the addition of Acetonitrile for azeotropic drying and a third inner channel for vacuum extraction. The channel for vacuum extraction 23 is used to remove the nitrogen supplied and any waste products. When inserting the pipetting tip of the dosing syringe 11.b into the reaction vessel 3, the closure 7 of the opening 6 of the reaction vessel 3 is opened, the penetrating dossier tip 11 at this moment closes the opening 6 of the reaction vessel 3 airtight. After penetration of the dosing tip l l .b, nitrogen and acetonitrile are alternately introduced via channel 21 and channel 22 into the reaction vessel 3, thereby realizing azeotropic drying. By means of the cooling and heating device 5, the temperature of the eluent mixture in the reaction vessel 3 is raised to 95.degree. The supplied nitrogen, the water and the acetonitrile are removed from the reaction vessel 3 by means of the second channel 23 of the metering syringe 1 lb under vacuum. After completion of the drying, the metering syringe 11 b is removed from the reaction vessel 3, wherein the opening 6 of the reaction vessel 3 is closed by the closure 7.

step 3

The dosing module 8 moves the pipetting head 9 with the powder pipette 12 from its starting position to the powdered substance reservoir 15. The powder pipette 12 receives by means of a vacuum-compressed air unit 20 mg of mannose triflate from the reservoir 15. The pipetting head 9 then moves the powder pipette 12 containing the mannose triflate to an empty vial 22 placed on the storage module 13 (kit). After penetrating the dossier tip of the powder pipette 12, the discharge of the mannose is released by means of the vacuum-compressed air unit. Triflats into the empty vial 22 causes. The metering module 8 moves the pipetting head 9 with the first metering syringe 11a to the second reservoir 14 in the storage module 13. By means of the syringe pump, 1000 μl of acetonitrile are taken up by the metering syringe 11a and moved to the vial 22 to dissolve the 20 mg mannose triflate and the Solution again with the same dossier I Ia record. Subsequently, the pipetting head 9 moves the dosing syringe 11a containing the precursor solution to the reaction vessel 3. When the dosing syringe is introduced into the reaction vessel 3, the closure 7 is removed from the opening 6 of the reaction vessel 3, with the penetrating dossier tip opening 6 hermetically seals. After the penetration of the metering syringe 11a, the delivery of the precursor solution into the reaction vessel 3 is effected by means of the syringe pump. When introducing the metering syringe 1 la in the reaction vessel 3, the closure 7 is removed from the opening 6 of the reaction vessel 3, wherein the penetrating dossier tip closes the opening 6 airtight. After penetration of the metering syringe 11a, the delivery of the precursor solution into the reaction vessel 3 is effected by means of the syringe pump. By means of the cooling and heating device 5, the temperature of the reaction mixture located in the reaction vessel 3 is raised to 100 ° C. The metering syringe 11a is then removed from the reaction vessel 3, the opening 6 of the reaction vessel being closed by the closure 7. The dosing module 8 then moves the pipetting head 9 with the dosing syringe 1 la to the washing station 18, the dosing syringe 11a being washed with acetone.

Step 4

After a reaction time of 5 minutes, nitrogen is introduced via channel 21 into the reaction vessel for the evaporation of the acetonitrile by penetration of the three-lumen metering syringe 11b into the closure of the reaction vial. After complete evaporation of the acetonitrile and the cooling of the reaction vessel to 50 ° C, the dosing 8 moves the pipetting head 9 with the first metering syringe I Ia to the second storage vessel 14 in the storage module 13. By means of the syringe pump 200μ1 ethanol are taken up by the metering syringe I Ia. The pipetting head 9 then moves the dosing syringe with the ethanol to the reaction vessel 3. When the pipetting tip of the dosing syringe 11a is introduced into the reaction vessel 3, the closure 7 is opened from the opening 6 of the reaction vessel 3, wherein the penetrating Dossierspitze closes the opening 6 airtight. After the penetration of the pipetting tip of the metering syringe 11a, the delivery of the ethanol into the reaction vessel 3 is effected by means of the syringe pump. Then, the dosing module 8 moves the pipetting head 9 with the dosing syringe 11a to the washing station 18, the dosing syringe 11a being washed with acetone.

Step 5

Following this, the dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the second storage vessel 14 in the supply module 13 (kit). By means of the syringe pump 500 μΐ 2N sodium hydroxide are taken up by the metering syringe I Ia. The pipetting head 9 moves the dosing syringe l la.l containing the sodium hydroxide solution, then the reaction vessel 3. When inserting the pipette tip of the dosing I Ia in the reaction vessel 3, the closure 7 is removed from the opening 6 of the reaction vessel 3, wherein the penetrating Dossierspitze the opening 6 closes airtight. After the penetration of the pipetting tip of the metering syringe 11a, the delivery of the sodium hydroxide solution into the reaction vessel 3 is effected by means of the syringe pump. By means of the cooling and heating device 5, the temperature of the reaction mixture in the reaction vessel 3 is raised to 80 ° C. The metering syringe 11a is then removed from the reaction vessel 3, the 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 the washing station 18, the dosing syringe 11a being washed with acetone. Step 6

After hydrolysis with a reaction time of 5 min, the dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the third supply container in the storage module 13. By means of the syringe pump, 500 .mu.l of 2N hydrochloric acid are taken up by the dosing syringe 11a. The pipetting head 9 moves the dosing syringe 11a containing the hydrochloric acid, then to the reaction vessel 3. The dossier tip is introduced into the reaction vessel 3 as soon as the temperature is reached by means of the cooling and heating direction 5 of the reaction mixture located there has reached room temperature. When inserting the metering syringe 1 la into the reaction vessel 3, the closure 7 is removed from the opening 6 of the reaction vessel 3, the penetrating pipetting tip sealing the opening 6 airtight. After the penetration of the pipetting tip of the metering syringe 11a, the delivery of the hydrochloric acid into the reaction vessel 3 is effected by means of the syringe pump. The dosing syringe 11a is then removed from the reaction vessel 3, the 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 the washing station 18, the dosing syringe 11a being seen with acetone.

Step 7

Subsequent to step 6, the dosing module 8 moves the pipetting head 9 with the first dosing syringe 11a to the reservoir 17a in the reservoir 16. By means of the syringe pump, 15 ml of water are taken up by the dosing syringe 11. The pipetting head 9 moves the dosing syringe 11a, which contains the water, then to the reaction vessel 3. The dossier tip is introduced into the reaction vessel 3. When introducing the metering syringe 1 la in the reaction vessel 3, the closure 7 is removed from the opening 6 of the reaction vessel 3, wherein the penetrating dossier tip closes the opening 6 airtight. After the 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, so that the entire 15 ml of water and the reaction mixture are mixed in a reservoir of the syringe pump. The metering syringe 11a is then removed from the reaction vessel 3, the 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 for cleaning (cartridge) to the kit 13 and presses the entire aqueous solution with the radiotracer 18F-FDG over the cartridge. The continuous aqueous solution is taken up with a second dossier tip 11c of the dosage unit 10b and transported to the end vial 20 with attached sterile filter. The aqueous solution is filled through the sterile filter into the end vial 20. The end vial 20 already contains a citrate Buffer solution, which was filled during the hydrolysis of Radiotracers of the free Dossierspitze I Ia on the sterile filter.

Example 3

Example 3 corresponds to Example 2, except that an additional step, step 8, is provided for the distribution of patient doses.

Step 8

After cleaning the dossier tip 11a in the wash station, the isotonic saline solution (0.9%) is removed from the reservoir 17c and distributed to several vials with attached sterile filter, in position 23 on the device 1. The individual patient doses can then be removed from the end vial 20 with the dosing module 8 and distributed to the individual isotonic saline solutions by means of the dossier tip 11a.

LIST OF REFERENCE NUMBERS

1 device

2 reaction module

3 reaction vessel

4 housing

5 cooling and / or heating device

6 Opening of the reaction vessel

7 Closure of the reaction vessel

8 dosing module

9 pipetting head

10 dosage units

11 dosing syringes

12 powder pipette

13 kit / storage module

14 storage container for chemicals to be used

15 reservoir for powdered substances

16 supply module for liquid substances

17 reservoirs in the storage module 16

18 wash station

19 fluoride reservoir

20 endvial

21 ¹⁸ 0-water

22 empty vial

23 vials for patient doses

24 Hotcell

Claims

claims

A device for producing radiochemical compounds, comprising at least one reaction module, a dosing module and a storage module, wherein

- The reaction module has at least one reaction vessel with a closable opening, via the substances required for the preparation of a given radiochemical compounds into which the reaction vessel of the reaction module can be introduced and over which the radiochemical compound prepared are removed from the reaction vessel of the reaction module can;

the dosing module has at least one pipetting head which is movable relative to the supply module and the reaction module and in the x, y and z directions and has at least one dosing unit, and

- In the storage module at least one reservoir for one of the substances that are required for the preparation of the respective radiochemical compound, is formed.

2. Apparatus according to claim 1, characterized in that the reaction vessel of the reaction module has an internal volume of 10 nl to 20,000 μΐ.

3. Apparatus according to claim 1 or claim 2, characterized in that the reaction module has a heating and / or cooling device and / or microwave.

4. Device according to one of the preceding claims, characterized in that the reaction vessel has a closure, wherein the opening is opened when a substance which is used for the production of the respective radiochemi- see compound is required, introduced into the reaction vessel or the reaction mixture or a part thereof is discharged from the reaction vessel, and the opening is closed by means of the closure after completion of the supply or discharge of the substance.

Apparatus according to claim 4, characterized in that the dosage unit closes the opening, while the substance required for the preparation of the respective radiochemical compound is introduced into the reaction vessel or the reaction mixture or a part thereof is discharged from the reaction vessel.

Device according to one of the preceding claims, characterized in that it at least one dosage unit, which removes a pul- deformable substance from the storage module, transported to the reaction module and can introduce into the reaction vessel via the opening, and / or at least one further dosage unit, the remove a liquid substance from the storage module, transport it to the reaction module and can introduce it into the reaction vessel via the opening.

Device according to one of the preceding claims, characterized in that at least one dosage unit has two or more channels for the supply and removal of liquid and gaseous substances from a reaction vessel.

Device according to one of the preceding claims, characterized in that at least one dosage unit is a dreilumige dosage unit having a first channel for receiving, transporting and delivering a substance which is required for the synthesis of the radiochemical compound, a second channel for supplying a Gas into a reaction vessel and an NEN third channel for removing gaseous reaction products from the reaction vessel.

9. Device according to one of the preceding claims, characterized in that it further comprises a dispensing module for the produced radiochemical compound.

10. A process for the preparation of radiochemical compounds by means of a device according to one of claims 1 to 9, characterized in that by means of dosage units, the substances required for the preparation of the respective radiochemical compound are introduced into a reaction vessel of the reaction module, wherein the dosage units on a pipetting head in x-, y-direction or in the x-, y- and z-direction are movable.

11. The method according to claim 10, characterized in that the substances which are required for the preparation of the respective radiochemical compound are introduced successively into the reaction vessel of the reaction module.

12. The method according to claim 10 or claim 11, characterized in that the produced radiochemical compound is removed by means of a dosage unit from the reaction vessel.

13. The method according to claim 12, characterized in that the produced radiochemical compound is transferred by means of the dosage unit to a cleaning module.

14. The method according to any one of claims 10 to 13, characterized in that the dosage units are rinsed after receiving and delivering a substance in a washing unit.

15. Use of a device according to one of claims 1 to 9 for the preparation of radiochemical compounds.

16. Kit comprising (i) a support plate with reservoirs for receiving subtances, which are required for the preparation of a radiochemical compound, (ii) one or more cartridges for the purification of the substances and / or the radiochemical compound and (iii ) Substances required for the preparation of a radiochemical compound.