EP2183202A2 - Radiosynthèse microfluidique d'un composé radioétiqueté en utilisant un piégeage et une libération électrochimiques - Google Patents

Radiosynthèse microfluidique d'un composé radioétiqueté en utilisant un piégeage et une libération électrochimiques

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Publication number
EP2183202A2
EP2183202A2 EP20080796340 EP08796340A EP2183202A2 EP 2183202 A2 EP2183202 A2 EP 2183202A2 EP 20080796340 EP20080796340 EP 20080796340 EP 08796340 A EP08796340 A EP 08796340A EP 2183202 A2 EP2183202 A2 EP 2183202A2
Authority
EP
European Patent Office
Prior art keywords
electrodes
trapping
reactor
radioactive isotope
reactant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP20080796340
Other languages
German (de)
English (en)
Inventor
Arkadij M. Elizarov
Hartmuth C. Kolb
R. Michael Van Dam
James R. Heath
Brian Edgecombe
Farshad Motamedi
Anthony Stephen
Michael A. Giardello
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
California Institute of Technology
Materia Inc
Siemens Medical Solutions USA Inc
Original Assignee
California Institute of Technology
Materia Inc
Siemens Medical Solutions USA Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by California Institute of Technology, Materia Inc, Siemens Medical Solutions USA Inc filed Critical California Institute of Technology
Publication of EP2183202A2 publication Critical patent/EP2183202A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se

Definitions

  • the present invention relates generally to microfluidic devices and related technologies. More specifically, the invention relates to methods and devices for microfluidic radiosynthesis of radiolabeled compounds.
  • Microfluidic devices have been used for the preparation of a number of radiopharmaceutical compounds. These compounds may be used in medical imaging applications, such as Positron Emission Tomography (PET) systems, that create images based on the distribution of positron-emitting isotopes in the tissue of a patient.
  • PET Positron Emission Tomography
  • the isotopes are typically administered to a patient by injection of probe molecules that comprise a positron-emitting isotope, such as fluorine- 18, covalently attached to a molecule that is readily metabolized or localized in the body or that chemically binds to receptor sites within the body.
  • probe molecules that comprise a positron-emitting isotope, such as fluorine- 18, covalently attached to a molecule that is readily metabolized or localized in the body or that chemically binds to receptor sites within the body.
  • Microfluidic devices offer a variety of advantages over macroscopic reactors, such as reduced reagent consumption, high concentration of reagents, high surface- to-volume ratios, and improved control over mass and heat transfer. These devices are capable of processing small quantities of molecular probes, as well as expediting chemical processing that reduces the overall processing or cycle times, simplifies the chemical processing procedures, and at the same time, provides the flexibility to produce a wide range of probes, biomarkers and labeled drugs or drug analogs, inexpensively. [0005] All known microfluidic reactors used for radiosynthesis reported to date have relied on ion exchange columns as their source of concentrated F- 18. Release of F- 18 from such columns requires aqueous solutions Of K 2 CO 3 .
  • the present invention relates generally to microfluidic devices and related technologies. More specifically, embodiments of the present invention relate to trapping and release of radioactive isotopes inside a microreactor, a vial, a channel, or similar device, thus eliminating the need for azeotropic drying and several dead-end filling steps, as well as the necessity to move concentrated radioisotopes from one compartment of the device to another.
  • radioisotope enrichment is carried out internally within a radiochemical synthesis chip, allowing faster and more robust operation.
  • radiolabeled compounds that may be prepared according to the process described herein include compounds selected from the group consisting of 2-deoxy-2-[ 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), 9-[4-[ 18 F] fluoro-3-(hydroxymethyl)butyl] guanine ([ 18 F]FHBG), 9-[(3-[ 18 F] fluoro-l-hydroxy-2-propoxy)methyl]guanine ([ 18 F]FHPG), 3-(2'-[ 18 F] fluoroethyl)
  • One embodiment of the present invention relates to a method for the synthesis of a radiolabeled compound comprising a radioactive isotope using a micro fluidic device, the method comprising: introducing a composition comprising a radioactive isotope to the microfluidic device, electrochemically trapping the radioactive isotope using an electrode, adding a composition comprising a reactant to the reactor, electrochemically releasing the radioactive isotope from the electrode, and contacting the reactant with the radioactive isotope to form the radiolabeled compound. While the various aspects of the present application are applicable to any radioactive (or non-radioactive) material with dilute charged ions, in one aspect, the radioactive isotope is F- 18.
  • the reactant comprises mannose triflate.
  • the composition comprising the reactant is mannose triflate/K 2 CO 3 /K222; and MeCN is used as a solvent.
  • the reactant is N-dimethoxytrityl-5'-O-dimethoxytrityl-3'-O-nosyl-thymidine (also known as "BOC-BOC-Nosyl") and the radiolabeled compound is FLT.
  • a step of blowing an inert gas and a heating of the reactor is performed to dry the trapped F- 18 before adding the composition comprising the reactant to the reactor.
  • the inert gas is nitrogen or argon.
  • the reactor is a coin-shaped reactor in a radio- synthesis chip.
  • the trapping and releasing is carried out by one or more electrodes.
  • the electrodes are located in or on at least one of a floor, a ceiling, and a side of the reactor or combinations thereof.
  • the electrodes are located in a channel in fluid communication with the reactor.
  • the electrodes are non-metal electrodes.
  • the electrodes are made of a material selected from the group consisting of a graphite, a composite graphite, and silicon and combinations thereof.
  • the electrodes are graphite polymer electrodes.
  • the polymer is selected from the group consisting of a DCPD, a polyethylene, and a glass.
  • the electrodes are metal electrodes while in a different aspect, the electrodes are covered with a protective coating.
  • At least one of the electrochemical trapping and the releasing is carried out in accordance with an in-reactor feature. This feature is located inside of the reaction chamber.
  • the trapping, the releasing and the radiolabeled compound formation are carried out within the same microreactor.
  • a radiochemical labeling yield of at least 55% is produced. In one aspect, the yield is 55%, 65%, 75%, 85%, 95% or 99%.
  • the radioactive isotope is released into a non-aqueous solution. In yet another aspect, the non-aqueous solution is an organic solution.
  • the organic solution comprises at least one of acetonitrile, THF, dichloromethane, DMF, acetone, alcohols such as ethanol, methanol and t-amyl alcohol, DMSO, fluorous solvents, and mixtures thereof.
  • the reaction to form the radiolabeled compound is a substitution reaction.
  • the releasing is carried out simultaneously or concurrent with the substitution reaction.
  • the reactant is in a solvent.
  • the electrochemical trapping is carried out in one or more passes, and in another aspect, the electrochemical releasing is carried out in accordance with one or more reversals of a voltage bias.
  • Another embodiment of the present application relates to a method for the synthesis of a radiolabeled compound using a micro fluidic trap-release device, the method comprising introducing a composition comprising a radioactive isotope to the device, electrochemically trapping of the radioactive isotope, adding a composition comprising a reactant to the device, and electrochemically releasing the radioactive isotope into the trap- release device.
  • the trap-release device is a radiochemical microreactor.
  • a microfluidic radiosynthesis apparatus comprising a first electrode configured to electrochemically trap a radioactive isotope, a chamber, and a second electrode configured to electrochemically release the radioactive isotope into the chamber.
  • the apparatus is further configured for preparing a radiolabeled compound by performing a reaction of a reactant with the radioactive isotope.
  • the radioactive isotope is F-18.
  • the chamber is filled with a composition comprising a reactant.
  • the reactant comprises mannose triflate.
  • the reactant is N-dimethoxytrityl-5'-O-dimethoxytrityl-3'-O-nosyl-thymidine and the radiolabeled compound is FLT.
  • the apparatus is further configured to blow an inert gas and heat the chamber before adding the composition comprising the reactant.
  • the chamber is part of a coin-shaped reactor in a radio-synthesis chip.
  • the electrodes are located in or on at least one of a floor, a ceiling, and a side of the chamber or combinations thereof, while in another aspect, the electrodes are located in a channel in fluid communication with the chamber.
  • the electrodes are non-metal electrodes.
  • the electrodes are made of a material selected from the group consisting of graphite, a composite graphite, and silicon and combinations thereof.
  • the electrodes are graphite polymer electrodes.
  • the polymer is selected from the group consisting of a DCPD, a polyethylene, and a glass, and in yet a different aspect, the electrodes are metal electrodes.
  • the electrodes are covered with a protective coating, and according to a different aspect, at least one of the first and the second electrodes is configured as an on-chip feature or as an in- reactor feature.
  • the electrochemical trapping is carried out in one or more passes, while in a different aspect, the electrochemical releasing is carried out in accordance with one or more reversals of a voltage bias.
  • the trapping, the releasing and the radiolabeled compound formation are carried out within the same microreactor.
  • the radiochemical labeling yield of at least 55% is produced. In certain variations, the yield is 55%, 65%, 75%, 85%, 95% or 99%.
  • the radioactive isotope is released into a non-aqueous solution.
  • the nonaqueous solution is an organic solution, and the reaction to form the radiolabeled compound is a substitution reaction.
  • the releasing is carried out simultaneously with the substitution reaction.
  • the reactant is in a solvent.
  • Fig. 1 illustrates exemplary steps for synthesis of a radioactive isotope using an ion exchange column
  • Fig. 2 illustrates exemplary steps for synthesis of a radioactive isotope in accordance with an embodiment of the present application
  • Fig. 3(A) illustrates an exemplary apparatus used for electrochemical trapping and release in a vial in accordance with an embodiment of the present application
  • FIG. 3(B) illustrates an exemplary apparatus used for on-chip electrochemical trapping and release in accordance with an embodiment of the present application
  • FIG. 4(A) illustrates a cross-sectional view of an exemplary trap-release chip in accordance with an embodiment of the present application
  • FIG. 4(B) illustrates a top view of an exemplary coin-chamber apparatus in accordance with an embodiment of the present application
  • FIG. 4(C) illustrates a top view of an exemplary channel-based apparatus in accordance with an embodiment of the present application
  • Fig. 5(A) illustrates an exemplary coin-shaped microreactor apparatus in accordance with an embodiment of the present application
  • Fig. 5(B) illustrates a top view of the bottom section of the exemplary apparatus of Fig. 5(A) in accordance with an embodiment of the present application
  • Fig. 6(A) illustrates a top view of an exemplary electrochemical trap-release channel apparatus in accordance with an embodiment of the present application
  • Fig. 6(B) illustrates a bottom view of the exemplary apparatus of Fig. 6(A) in accordance with an embodiment of the present application
  • FIG. 6(B) illustrates a bottom view of the exemplary apparatus of Fig. 6(A) in accordance with an embodiment of the present application
  • FIG. 7 illustrates a cross-sectional view of an exemplary trap-release chip in accordance with an embodiment of the present application
  • FIG. 8(A) illustrates a top and side view of an exemplary electrochemical trap-release chip apparatus in accordance with an embodiment of the present application.
  • FIG. 8(B) illustrates a bottom and side view of the exemplary apparatus of
  • FIG. 8(A) in accordance with an embodiment of the present application.
  • a "microfluidic device” or “microfluidic chip” or “synthesis chip” or “chip” is a unit or device that permits the manipulation and transfer of small amounts of liquid (e.g., microliters or nano liters) into a substrate comprising micro-channels and micro- compartments.
  • the device may be configured to allow the manipulation of liquids, including reagents and solvents, to be transferred or conveyed within the micro channels and reaction chamber using mechanical or non-mechanical pumps.
  • the device may be constructed using micro-electromechanical fabrication methods as known in the art. Alternatively, the devices can be machined using computer numerical control (CNC) techniques.
  • substrates for forming the device include glass, quartz, silicon, ceramics or polymer. Such polymers may include PMMA (polymethylmethacrylate), PC (polycarbonate), PDMS (polydimethylsiloxane), DCPD (polydicyclopentadiene), PEEK and the like.
  • Such device may comprise columns, pumps, mixers, valves and the like.
  • the microfluidic channels or tubes (sometimes referred to as micro-channels or capillaries) have at least one cross-sectional dimension (e.g., height, width, depth, diameter), which by the way of example, and not by limitation, may range from 1 ,000 ⁇ m to 10 ⁇ m.
  • the micro-channels make it possible to manipulate extremely small volumes of liquid, for example on the order of nL to ⁇ L.
  • the micro reactors may also comprise one or more reservoirs in fluid communication with one or more of the micro-channels, each reservoir having, for example, a volume of about 5 to about 1 ,000 ⁇ L.
  • the term "radioactive isotope" refers to isotopes exhibiting radioactive decay
  • Radioactive isotopes or the correspond ions such as the fluoride ion, are named herein using various commonly used combinations of the name or symbol of the element and its mass number and are used interchangeably (e.g., 18 F, 18F, [F-18], fluorine- 18).
  • Exemplary radioactive isotopes include 1-124, F-18, C-I l, N-13, and 0-15, which have half-lives of 4.2 days, 110 minutes, 20 minutes, 10 minutes, and 2 minutes, respectively.
  • FLT precursor may be used to refer to "N- dimethoxytrityl-5'-O-dimethoxytrityl-3'-O-nosyl-thymidine” (also known as "BOC-BOC-
  • Column means a device that may be used to separate, purify or concentrate reactants or products. Such columns are well known in the art, and include, but are not limited to, ion exchange and affinity chromatography columns.
  • channel means a microfluidic channel through which a fluid, solution, or gas may flow. It is also a channel through which vacuum can be applied.
  • such channels may have a cross section of about 0.1 mm to about 1 mm.
  • the flow channels of embodiments of the present application may also have a cross section dimension in the range of about 0.05 microns to about 1,000 microns.
  • the particular shape and size of the flow channels depend on the particular application required for the reaction process, including the desired throughput, and may be configured and sized according to the desired application.
  • electrochemical trapping refers to of the process of separating charged ions from a solution by applying a voltage across a pair of electrodes that are in contact with the solution, thereby causing some, or substantially all, of the charged ions to be deposited onto, accumulated on, or collected in the vicinity of one of the electrodes.
  • electrochemical releasing refers to the process of releasing the trapped ions that have been deposited onto, accumulated on, or collected in the vicinity of one of the electrodes, by applying a voltage across the pair of electrodes that are in contact with a solution.
  • the voltage applied to carry out the electrochemical releasing may, for example, be in the opposite direction of the voltage applied to effect the electrochemical trapping.
  • Fig. 1 outlines a series of exemplary steps involved in the synthesis of F- 18 using a micro fluidic device, from taking F- 18 from cyclotron target water to fluorination reaction in a coin-shaped reactor chip using an ion exchange column.
  • Step 1 with valves 102 and 108 closed and valves 104 and 106 open, target water is passed through the ion exchange cartridge 110 to trap the F-18 out of a dilute solution.
  • Step 2 with valves 104 and 106 closed and valves 102 and 108 open, K 2 CO 3 is released into a concentrated solution that enters the reactor. After that delivery has taken place, the valve 108 controlling the F- 18 inlet closes, and in Step 3 water evaporation takes place.
  • Step 4 K222/MeCN solution is delivered from channel 112. This procedure also requires a significant amount of processing time because of dead end filing.
  • Step 5 drying, solvents are evaporated, leaving behind a residue containing [F-18]KF/K222 complex. This drying step also consumes a significant amount of processing time because of the need to move solvent vapors across a membrane, and the need for complete dryness.
  • Step 6 the precursor or reactant (such as mannose triflate) is delivered to the reactor through channel 116. This step is also time consuming because of dead end filling. Finally, in Step 7, the fluorination reaction takes place.
  • a micro fluidics approach in accordance with the various embodiments of the present application, allows the distance between the electrodes to be made very small both on the absolute scale (e.g., tens to hundreds of microns) and on relative scale (i.e., compared to path length of the fluid).
  • the trapping from a moving solution in accordance with exemplary techniques and devices of the present invention, may be carried out in less than one minute, as opposed to a five-minute trapping time that is typical for the conventional systems.
  • any F- 18 that was not initially trapped may be passed through the microfluidic device one or more times in order to allow trapping of additional F- 18.
  • This multiple-pass and/or recirculation capability enables 100% trapping of F- 18.
  • example embodiments of the microfluidic methods, systems and apparatus of the present application enable a precise temperature control over a wide range of temperatures, which is crucial for most radiosynthesis reactions.
  • Fig. 2 illustrates a series of exemplary steps for electrochemical trapping and release of F- 18 in a fully operational synthesis chip in accordance with an embodiment of the present application. As illustrated in Fig. 2, both a positive electrode 202 and a negative electrode 204 are placed within a reactor 200. In Step 1, electrochemical trapping of F- 18 on the inner surface or floor of the reactor 200 takes place.
  • Step 1 may be carried out as a fast unobstructed flow-through of dilute F " in H 2 O, followed by blowing N 2 while heating to dry the trapped fluoride.
  • the reactor 200 can be flushed with N 2 for drying purposes. If the dryness is not achieved to a desired level, the reactor 200 can be flushed or rinsed, for example, by MeCN, to remove the residual moisture, thus expediting the completion of this step and avoiding heating altogether when necessary.
  • Step 2 the reactor 200 is filled with the solution.
  • electrochemical release of F- 18 takes place.
  • the reactor 200 As the reactor 200 is filled with, for example, K 2 CO 3 /K222/mannose triflate/MeCN solution, it has sufficient ionic strength for the release of F- 18 upon reversing the bias. Since F- 18 gets released into the triflate solution it engages in reaction immediately. The release procedure, however, does not have to be immediate. The release can be controlled to be completed within the time period allowed for the fluorination, thus maximizing its yield. On the other hand, the overall process is expedited since the fluorination reaction is not postponed until the end of release and [F-18]fluoride transfer. As evident from the comparison of Figs.
  • an electrochemical trapping and release device may be coupled with the reactor but not as part of the reaction chamber itself.
  • Fig. 3(A) illustrates an example vial containing target water that is used for evaluation of electrodes made from different materials for the trapping/release applications in accordance with various embodiments of the present application.
  • Fig. 3(B) illustrates an example microfluidic chip that is implemented with trapping and release capabilities in accordance with various embodiments of the present application.
  • Both the vial and the chip of Figs. 3(A) and 3(B) are example embodiments of trap-release devices that may be implemented in accordance with the various embodiments of the present application.
  • the following provides an exemplary set of test results for two different sets of electrodes:
  • Copper electrodes may provide up to 75% trapping (@500V, and 5 min), up to 79% release into 0.5M KHCO 3 solution (@500V, and reverse bias pulsing). Some F- 18 may be released into pure water, and significant copper contamination of solution may occur.
  • Graphite and graphite/DCPD composite electrodes may provide up to 97% trapping, up to 96% release into 0.5M KHCO 3 solution. No solution contamination may occur.
  • Graphite/DCPD can be molded/machined into very complex and precise shapes.
  • composite electrodes When the electrodes are fabricated using such composite material, they produce trapping and release efficiencies that are comparable to those of pure graphite electrodes of the same size and shape.
  • Other exemplary material which may be used in construction of composite electrodes include, but are not limited to, graphite blends with glass, quartz or other polymer material such as PMMA (polymethylmethacrylate), PC (polycarbonate), PDMS
  • the electrodes of the various embodiments of the present application may be advantageously fabricated using such composite material since they can be easily machined and molded, are thermally and chemically resistant, and are very tough. See, for example, US Patent No. 7,339,006, the disclosure of which is incorporated herein by reference in its entirety.
  • bare electrodes may drive a current through the solution. This approach relies on F " being attracted to the positive electrode, where it gets attached to the electrode forming ionic bonds. Using this method, and given enough time, substantially all fluoride may be taken out of the solution since there is no equilibrium to maintain and no repulsion. When the bias is reversed, adsorbed [F-18]F " is released into the solution. Again, given sufficient amount of time, substantially all F- 18 may be released. Experimental results have confirmed proper release of suitable F- 18, and its reactivity towards mannose triflate.
  • the trapping and release of F- 18 may be carried out using insulated electrodes so that F- 18 is attracted to the positive electrode by the electric field alone.
  • This approach is advantageously designed to assure that F- 18 does not undergo any transformations and/or reactions between the trapping and the release stages, and that it does not pick up any counter ions (such as Cu 2+ ) (or to minimize any such transformations or reactions) that may hinder fluorination reactions.
  • F " is attracted towards the positive electrode and is held on its surface electrostatically until the bias is reversed. This method involves high concentration aggregation of 18 F " on the positive electrode surface.
  • Concentration of negative charges may start to repel further fluoride adsorption at a certain point when equilibrium is reached since the attraction is much weaker than with bare electrodes.
  • the adsorption of F-18 may be improved by increasing the surface area of the positive electrode. This approach has been demonstrated experimentally using both test vials and on-chip implementations.
  • Fig. 4(A) illustrates a cross-sectional view of an example microfluidic chip for implementing a trap/release procedure in accordance with an embodiment of the present application.
  • the example chip of Fig. 4(A) is specially designed to allow evaluation of the trapping efficiency separately from other variables, without performing subsequent reactions. In addition, it allows a wide range and variations of shape and volume of the trapping feature to be studied.
  • the positive electrode 406 is positioned in the floor of trapping chamber/channel 402 and the negative electrode 404 is positioned in the ceiling of the trapping chamber/channel 402.
  • FIG. 4(A) also illustrates the loading channel 412, the insulating/sealing gasket 408 that is used to ensure proper sealing between the top and bottom sections of the chip, and the screws 410 that are used to firmly hold the top and bottom sections of the chip together.
  • both electrodes are constructed using aluminum, with the bottom electrode being a machined block and the top electrode being foil pressed between DCPD and the soft gasket.
  • the same architecture may be implemented to make devices with coin-shaped chambers, as well as long channel trap devices.
  • Fig. 4(B) illustrates a top view of a coin-chamber based device
  • Fig. 4(C) illustrates a top view of a channel based device.
  • both electrodes may be constructed using a graphite -DCPD blend.
  • Figs. 5(A) and 5(B) illustrate one such exemplary chip with a coin- shaped reactor 502 that has been successfully fabricated and tested. This configuration is comprised of two sections: a top section 504 and a bottom section 506 that are firmly held together using a plurality of screws 508 and a thin gasket around the reactor.
  • a coin-shaped reactor 502 is located within the center of the chip assembly, and graphite-DCPD electrodes 510 are placed in the floor and ceiling of the reactor. As depicted in Fig. 5(A), the two electrodes 510 protrude from the top and the bottom sections of the assembled chip.
  • Fig. 5(A) the two electrodes 510 protrude from the top and the bottom sections of the assembled chip.
  • Fig. 6(A) illustrates the top view of an electrochemical trap with a 4-cm channel, with liquid ports 604, electrode leads 602 and a valve actuator 606 clearly visible.
  • Fig. 6(B) the bottom view of the same device is depicted, with the embedded graphite electrodes 608 clearly visible.
  • the chips with long channel trap configurations such as the ones illustrated in Figs. 4(C), 6(A) and 6(B)
  • coin-shaped chips have the following advantages: (a) their evaluation allows easy transformation to in-reactor trapping, (b) such test devices can be easily fabricated using existing parts, and (c) they do not involve transferring of concentrated F- 18 solutions.
  • the F- 18 solution can be passed through the trap multiple times until all F- 18 has been extracted.
  • the efficiency of release may be improved by reversing the bias several times in order to release all F-18, even that portion that is adsorbed onto the new positive electrode (i.e., the negative electrode during trapping).
  • metal electrodes may be replaced by a composite material such as graphite/DCPD.
  • the trapping device may be separated from the radio-synthesis micro-reactor or the entire chip.
  • the advantage of such an arrangement is that the reactor operation is not jeopardized by the integration of electrodes, and that of the trap is not jeopardized by high temperatures and various reagents used in the reaction chamber.
  • F- 18 may have to be released with extremely high efficiency to make its transport from one place to the next feasible.
  • multiple passes of the same F- 18 solution may be performed. This technique may further minimize the path length and allow easier integration of electrodes.
  • electrochemical trapping and release may be carried out from one solution into another, where the two solutions form a laminar flow in a microchannel.
  • Fig. 7 illustrates an alternative design for an in-reactor trapping process in accordance with an example embodiment of the present application.
  • one electrode for example the positive electrode 706, as well as the other electrode, for example, the negative electrode 704, are positioned in the floor of the trapping chamber/reactor 702, with the positive electrode 706 having a significantly larger surface area than the negative electrode 704.
  • Fig. 7 also illustrates the loading channel 712 and the insulating/sealing gasket 708 to ensure proper sealing between the top and bottom sections of the chip.
  • the positive electrode 706 may be a block similar to the configuration shown in Fig.
  • the negative electrode 704 may be constructed by drilling a hole in the positive electrode block 706 that is filled with, for example, a DCPD-insulated negative electrode wire.
  • This configuration allows the current to be still driven through the solution while clearing the top surface of the reactor for implementation of functional vents 710.
  • this configuration is still advantageous since it allows the vents to be located in the ceiling, where they do not touch the liquid within the reaction chamber.
  • the transparent reactor ceiling allows monitoring of the reaction chamber and progress tracking. In an in-reactor trapping process, this design allows F- 18 to react immediately upon release, and allows residual F- 18 to be released after the reaction has started. Fig.
  • FIG. 8 illustrates an exemplary trap with a 5 -mm channel that has been successfully fabricated and tested in accordance with design principles that are depicted in Fig. 7.
  • Fig. 8(A) illustrates a top and side view of the chip with a liquid port 802, electrode leads 804 and vent ports 806 clearly visible.
  • Fig. 8(B) illustrates a bottom-and-side view of the same chip with electrode leads 804 and vent ports 806 clearly visible.
  • Fig. 4 and Fig. 7 illustrate two exemplary electrode configurations
  • other electrode geometries may be implemented in accordance with various embodiments of the present application.
  • both or either electrodes may be placed within any one of the following elements: floor, ceiling, and sides of the reactor, as well as the channels leading up to the reactor.
  • Table 1 illustrates the various exemplary results obtained from evaluating F-
  • Table 2 illustrates the various exemplary results obtained from evaluating F-

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Abstract

L'invention concerne des procédés et un appareil permettant une radiosynthèse de composés radioétiquetés en utilisant un piégeage et une libération électrochimiques. Le piégeage et la libération d'isotopes radioactifs surviennent tous à l'intérieur d'un microréacteur, d'un flacon ou d'un dispositif similaire, en éliminant ainsi le besoin d'un séchage azéotrope et plusieurs étapes de remplissage d'extrémité, de même que la nécessité de déplacer des radio-isotopes concentrés depuis un premier compartiment de la plaquette vers un autre. Ces caractéristiques ainsi que d'autres permettent à un enrichissement de radio-isotopes d'être effectué intérieurement dans une plaquette de synthèse radiochimique, en fournissant un fonctionnement plus rapide et plus robuste, de même qu'en produisant des rendements d'étiquetage radiochimique très élevés.
EP20080796340 2007-07-20 2008-07-18 Radiosynthèse microfluidique d'un composé radioétiqueté en utilisant un piégeage et une libération électrochimiques Withdrawn EP2183202A2 (fr)

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