Fully-automated microfluidic system for the synthesis of radiolabeled biomarkers for positron emission tomography

• US 20080233018A1
• Filed: 01/23/2008
• Published: 09/25/2008
• Est. Priority Date: 01/23/2007
• Status: Active Grant

• Current Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Original Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Inventors: Kolb, Hartmuth C., Ball, Carroll Edward, Elizarov, Arkadij M., van Dam, Robert Michael
• Granted Patent: US 7,829,032 B2
• Time in Patent Office: Days
• US Class Current: 422/159
• CPC Class Codes: B01J 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00783 Laminate assemblies, i.e. the reactor comprising a stack of plates
• CPC Class Codes: B01J 2219/00826 Quartz
• CPC Class Codes: B01J 2219/00831 Glass
• CPC Class Codes: B01J 2219/00833 Plastic
• CPC Class Codes: B01J 2219/0086 Dimensions of the flow channels
• CPC Class Codes: B01J 2219/00873 Heat exchange
• CPC Class Codes: B01J 2219/00891 Feeding or evacuation
• CPC Class Codes: B01J 2219/00907 using membranes
• CPC Class Codes: B01J 2219/00909 using filters
• CPC Class Codes: B01J 2219/00952 Sensing operations
• CPC Class Codes: B01J 2219/00959 Flow
• CPC Class Codes: B01J 2219/00961 Temperature
• CPC Class Codes: B01J 2219/00963 Pressure
• CPC Class Codes: B01J 2219/00986 Microprocessor
• CPC Class Codes: B01J 2219/0099 Cleaning
• CPC Class Codes: C07B 59/005 Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids

Abstract

The present application relates to microfluidic devices and related technologies, and to chemical processes using such devices. More specifically, the application discloses a fully automated synthesis of radioactive compounds for imaging, such as by positron emission tomography (PET), in a fast, efficient and compact manner. In particular, this application describe an automated, stand-alone, microfluidic instrument for the multi-step chemical synthesis of radiopharmaceuticals, such as probes for PET and a method of using such instruments.

Claims

1. A portable system for the automated radiosynthesis of a radiolabeled compound comprising:

a microfluidic synthesis chip comprising a reaction chamber of fixed volume, a membrane, at least one flow channel and at least one valve;

a reagent source comprising at least one reagent in fluid communication via a flow channel with said synthesis chip, wherein said reagent is conveyed in a metered amount to said reaction chamber via pneumatic actuation; and

at least one external input device coupled to at least one controller which is coupled to and controls the function of at least one component selected from the group consisting of an inert gas delivery source, a vacuum system, a temperature control system and a valve on said synthesis chip.

2. The system of claim 1 further configured for priming said flow channel, wherein said priming comprises conveying said reagent from said reagent source to said valve on said synthesis chip, wherein said valve is closed and said reagent is conveyed to a waste receptacle in fluid communication thereto.

3. The system of claim 1 wherein said reagent is conveyed from a pre-filled individual vial or from a pre-packaged cartridge.

4. The system of claim 1 wherein said system further comprises radiation shielding.

5. The system of claim 4 wherein said radiation shielding shields one or more of:

a) a radiolabel source in fluid communication via a flow channel with said reaction chamber;

b) said flow channel of said radiolabel source;

c) said synthesis chip;

d) a purification system in fluid communication with said synthesis chip; and

e) a product receptacle in fluid communication with said purification system.

6. The system of claim 4 wherein said system does not require a separate hot cell.

7. The system of claim 1 further comprising a heat-exchanger.

8. The system of claim 7 wherein said heat-exchanger heats said reaction chamber via a resistive heater and cools said reaction chamber by air in a vortex cooler.

9. The system of claim 1 wherein said radiolabeled compound is radiolabeled with F-18, C-11, N-13, O-15 or I-124.

10. The system of claim 9 wherein said radiolabeled compound is radiolabeled with F-18.

11. The system of claim 10 wherein said radiolabeled compound is selected from the group consisting of:

2-deoxy-2-[F-18]-fluoro-D-glucose (¹⁸F-FDG), 3′

-deoxy-3′

-[F-18]-fluorothymidine (¹⁸F-FLT), 9-[4-[F-18] fluoro-3-(hydroxymethyl)butyl]guanine (¹⁸F-FHBG), 9-[(3-[F-18] fluoro-1-hydroxy-2-propoxy)methyl]guanine (¹⁸F-FHPG), 3-(2′

-[F-18] fluoroethyl)spiperone (¹⁸F-FESP), 4-[F-18] fluoro-N-[2-[1-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (¹⁸F-p-MPPF), 2-(1-{6-[(2-[F-18]fluoroethyl)-(methyl)amino]-2-naphthyl}ethylidine)malononitrile (¹⁸F-FDDNP), 2-[F-18] fluoro-α

-methyltyrosine, [F-18] fluoromisonidazole (¹⁸F-FMISO), and 5-[F-18] fluoro-2′

-deoxyuridine (¹⁸F-FdUrd).

12. The system of claim 11 wherein said radiolabeled compound is 2-deoxy-2-[F-18]-fluoro-D-glucose ([F-18]FDG).

13. The system of claim 12 wherein said reagent is target water, [O-18]H₂O containing F-18, and isolation of said F-18 from said target water relies on electrochemical trapping.

14. The system of claim 12 wherein said reagent is target water, [O-18]H₂O containing F-18, and isolation of said F-18 from said target water relies on an ion-exchange column.

15. The system of claim 12 wherein the concentration of said [F-18]FDG is at least about 100 times that of the concentration of F-18 in said target water.

16. The system of claim 15 wherein the concentration of said [F-18]FDG is at least about 400 times that of the concentration of F-18 in said target water.

17. The system of claim 1 wherein said flow channel connecting said reagent source with said synthesis chip further comprises a check valve and/or a 3-way valve.

18. The system of claim 1 further comprising an inert gas inlet wherein the system is pressurized by inert gas from said inlet and the speed with which said reagents are conveyed from said source to said reaction chamber is controlled by pressure of an inert gas.

19. The system of claim 18 wherein said inert gas is split into various pressures.

20. The system of claim 1 wherein the speed with which said reagents are conveyed from said reagent source to said reaction chamber is controlled by the thickness and/or composition of said membrane.

21. The system of claim 1 wherein said system can be cleaned without requiring disassembly of the system, wherein said cleaning step comprises conveying a solvent from a solvent source via a flow channel through said reaction chamber to a waste receptacle and optionally conveying an inert gas from said inert gas delivery source through said reaction chamber.

22. The system of claim 1 wherein said isolated radiolabeled compound is collected in a product vial, wherein said product vial is shielded from said microfluidic synthesis chip and/or said reagent source.

23. The system of claim 1 wherein said vacuum system comprises pump, a trap, a valve and an electronic pressure gauge readable by said external input device.

24. The system of claim 23 further comprising a pressure controller.

25. The system of claim 1 further comprising at least one internal filter.

26. The system of claim 25 wherein the system can safely operate outside a fume hood.

27. The system of claim 1 wherein said radiolabeled compound is formed via a process occurring in said reaction chamber and is conveyed to a purification system via pneumatic actuation.

28. The system of claim 27 wherein said purification system comprises a column.

29. The system of claim 27 wherein said process is monitored using a borescope inserted through an actuation plate positioned adjacent to said microfluidic device.

30. The system of claim 1 wherein said at least one controller controls the function of an inert gas delivery source, a vacuum system, a temperature control system and a valve on said synthesis chip.

32. A method for the synthesis of purified [F-18]-FDG comprising the use of the system of claim 1 wherein one reagent is target water, [O-18]H₂O containing F-18, one solvent is water and said [F-18]FDG is collected in a product receptacle.

33. The method of claim 32 wherein an operator inputs into said external input device a value for one or more variables selected from the group consisting of:

reactor temperature, reaction time, reagent pressure, times of reagent filling, evaporation, elution;

vacuum on/off time, and inert gas pressure.

34. The method of claim 32 wherein said operator inputs into said external input device said value before implementation of said system and does not input another value into said external input device at least until said radiolabeled compound is synthesized.

35. The method of claim 33 wherein an operator inputs into said external input device a value for each of reactor temperature, reaction time, reagent pressure, times of reagent filling, evaporation, elution;

vacuum on/off time, and inert gas pressure.

36. The method of claim 35 wherein said operator inputs into said external input device each of said values before implementation of said system and does not input another value into said external input device at least until said radiolabeled compound is synthesized.

37. The method of claim 32 comprising removing [F-18]FDG from the system;

cleaning said system with water and drying said system with an inert gas.

38. A machine-readable computer program code, the program code including instructions for causing a controller to implement a method for the synthesis system of claim 1, said method comprising:

introducing one or more reagents into said reaction chamber;

operating the synthesis system to process said reagent(s) responsive to a predetermined algorithm to generate a radiolabeled compound; and

collecting said radiolabeled compound.

39. The machine-readable computer program code of claim 38, wherein said algorithm includes parameters for one or more variables selected from the group of reactor temperature, reaction time, reagent pressure, times of reagent filling, evaporation, elution;

vacuum on/off time, and inert gas pressure.

40. The machine readable computer program code of claim 38 wherein at least one parameter is input before implementation of said synthesis system.

31. A portable system for the automated radiosynthesis of a radiolabeled compound comprising:

a microfluidic synthesis chip comprising a reaction chamber of fixed volume, a membrane, at least one flow channel and at least one valve;

a reagent source comprising at least one reagent in fluid communication via a flow channel with said synthesis chip, wherein said reagent is conveyed in a metered amount to said reaction chamber via pneumatic actuation;

radiation shielding;

a heat-exchanger, wherein said heat-exchanger heats the reaction chamber via a resistive heater and cools said reaction chamber by air in a vortex cooler

at least one external input device coupled to at least one controller which is coupled to and controls the function of at least one component selected from the group consisting of an inert gas delivery source, a vacuum system, a temperature control system and said valve on said synthesis chip.