JP2010531295A - Microfluidic Radiosynthesis System for Positron Emission Tomography Biomarkers (Related Application) This application is a US Provisional Application No. 60 / 923,086 filed Apr. 12, 2007, April 2007. U.S. Provisional Application No. 60 / 923,407 filed on Jan. 13, U.S. Patent Provisional Application No. 11 / 895,636, filed Aug. 23, 2007, and Jan. 2008 Claims priority based on US Provisional Patent Application No. 61 / 010,822, filed on Jan. 11, the contents of each of which are incorporated herein by reference in their entirety. - Google Patents

Abstract

Disclosed are methods and apparatus for fully automated synthesis of radioactive compounds for imaging in a rapid, efficient and precise manner, for example by positron emission tomography (PET). In particular, the various embodiments of the present invention are PET radioactivity purified within a shorter period of time than a conventional chemical system starting from target water on a microfluidic device with an unlimited flow of gas through the reactor. Provides an automated, independent, hands-free operation of the entire radiosynthesis cycle to produce a tracer Accordingly, one aspect of the present invention provides a reaction chamber, one or more flow channels connected to the reaction chamber, one or more vents connected to the reaction chamber, and the inside and outside of the reaction chamber. The invention relates to a microfluidic chip for radiosynthesizing radiolabeled compounds comprising one or more integrated valves for performing flow control.
[Selection] Figure 3

Description

  The present invention relates generally to microfluidic devices and related technologies, and chemical processes using such devices. More particularly, the invention relates to a fully automated synthesis of radioactive compounds for imaging in a rapid, efficient and precise manner, for example by positron emission tomography (PET). In particular, embodiments of the invention relate to automated stand-alone microfluidic devices for multi-step chemical synthesis of radiopharmaceuticals, such as PET probes, and methods of using such systems.

  This section is intended to provide a background or context to the invention that is recited in the claims. The description set forth herein may include concepts that could be accomplished, but not necessarily previously envisioned or accomplished. For this reason, unless stated otherwise in this specification, the content described in this section is not prior art to the specification and claims in this application, but is deemed to be prior art by inclusion in this section. is not.

  Positron emission tomography (PET) is a molecular imaging technique that is increasingly being used to detect diseases. A PET imaging system creates an image based on the distribution of positron emitting isotopes in patient tissue. These isotopes are typically covalently bonded positron emitting isotopes (for example, molecules that are readily metabolized or localized in the body or chemically bound to receptor sites in the body) , Carbon 11, nitrogen 13, oxygen 15 or fluorine 18) is administered to the patient by injection of a probe molecule comprising. For PET probes, the positron emitter's half-life is short, so the probe synthesis, analysis and purification must be completed quickly.

So far, large capacity synthesis modules have been developed and used for the preparation of numerous radiopharmaceutical compounds. Common drugs radiolabeled with F-18 include 2-deoxy-2- [F-18] -fluoro-D-glucose ( ¹⁸ F-FDG), 3′-deoxy-3 ′-[F- 18] -fluorothymidine ( ¹⁸ F-FLT), 9- [4- [F-18] fluoro-3- (hydroxymethyl) butyl] guanine ( ¹⁸ F-FHBG), 9-[(3- [F-18 ] fluoro-1-hydroxy-2-propoxy) methyl] guanine ^{(18 F-FHPG), 3-} (2 '- [F-18] fluoroethyl) spiperone ^{(18 F-FESP), 4-} [F-18] Fluoro-N- [2- [1- (2-methoxyphenyl) -1-piperazinyl] ethyl] -N-2-pyridinyl-benzamide ( ¹⁸ Fp-MPPF), 2- (1- {6-[( 2- [F-18] fluoroethyl)-(methyl) Amino] -2-naphthyl} ethylidine) malononitrile ^{(18 F-FDDNP), 2-} [F-18] fluoro -α- methyl tyrosine, [F-18] fluoro-miso NIDA tetrazole ^{(18 F-FMISO), 5-} [ F-18] fluoro-2′-deoxyuridine ( ¹⁸ F-FdUrd) is included. Other common radiolabeled compounds include ¹¹ C-methionine and ¹¹ C-acetic acid. Large capacity synthesis modules occupy a large amount of space and chemical processes require longer reaction time cycles than are desired to prepare the labeled compound. Such modules are also difficult to modify for research and development of new compounds and probes. In general, reactions in such modules are performed with reduced efficiency due to the tremendous large reagent dilution required for large scale liquid operations.

The synthesis of [F-18] -labeled molecular probe 2-deoxy-2- [F-18] -fluoro-D-glucose ( ¹⁸ F-FDG) is based on three major sequential synthesis processes. (I) Concentration of dilute [F-18] fluoride solution (1-10 ppm) obtained from bombardment of target water [O-18] H ₂ O in a cyclotron; (ii) [F− of mannose triflate precursor 18] fluoride substitution; and (iii) acid hydrolysis of the fluorinated intermediate. Currently, [F-18] FDG is produced on a routine basis using a large commercial synthesizer with a processing time (or cycle time) of about 50 minutes. These synthesizers consist in part of mechanical valves, glass based reaction chambers and ion exchange columns. The physical dimensions of these devices are typically approximately 80 cm × 40 cm × 60 cm. Descriptions of a large-scale synthesis apparatus can be found in, for example, International Publication No. 2007/066089, International Publication No. 2005/057589, US Patent Application Publication No. 2007/0031492, and US Patent Application Publication No. 2004/022696. Can be found in the issue description.

Due to the long processing time, the low reagent concentration of the large scale synthesizer and the short half-life of [F-18] fluorine (t _1/2 = 109.7 min), the resulting probe radiochemical yield is A considerable decrease is inevitable. In addition, since many commercial automated systems are built for large scale synthesis, the process requires large consumption of valuable reagents (eg, precursors or Kryptofix 2.2.2) This is inefficient and uneconomic for both clinical and research studies. For example, the radioactivity required for single patient [F-18] FDG PET imaging is about 20 mCi, which corresponds to about 240 ng of FDG. For small animal imaging applications such as mice, only [F-18] FDG of about 200 μCi or less is required. The same is true for FLT.

  Therefore, there is a need to develop smaller or microminiaturized systems and devices that can handle such small amounts of molecular probes. In addition, the chemical processing can be facilitated to reduce the total processing time or cycle time while simplifying the chemical processing procedure, while at the same time inexpensively producing a wide range of probes, biomarker labeled drugs or drug analogs There is a need for a system that provides the flexibility to do so.

  Microfluidic devices offer various advantages over large scale reactors, such as reduced reagent consumption, high concentration of reagents, high area to volume ratio and improved control of mass and heat transfer ( For example, K. Jahnisch, V. Hessel, H. Lowe, M. Baerns, Angew. Chem. 2004, 116: 410-451, Angew. Chem. Int. Ed. Engl. See Watts, S. J. Haswell, Chem. Soc. Rev. 2005, 34: 235-246, G. Jas, A. Kirschning, Chem. Eur. J. 2003, 9: 5708-5723).

  The present invention relates generally to microfluidic devices and related techniques, and to chemical processes using such devices. More particularly, embodiments of the invention relate to fully automated synthesis of radioactive compounds for imaging in a rapid, efficient and precise manner, for example by positron emission tomography (PET). In particular, the various embodiments of the present invention are PET radioactivity purified within a shorter period of time than a conventional chemical system starting from target water on a microfluidic device with an unlimited flow of gas through the reactor. It provides an automated, independent, hands-free operation of the entire radiosynthesis cycle that produces a tracer, exhibits a significantly higher reaction yield, and requires only a significantly smaller amount of precursor. Accordingly, one aspect of the present invention provides a reaction chamber, one or more flow channels connected to the reaction chamber, one or more vents connected to the reaction chamber, and the inside and outside of the reaction chamber. A microfluidic chip for radiosynthesizing radiolabeled compounds comprising one or more integrated valves for performing flow control. The terms “device”, “apparatus” and “equipment” are used interchangeably herein and are not intended to limit the scope of the present invention.

  In one embodiment, the reaction chamber is located inside the reactor (reactor) portion and the lid portion of the chip that are fitted with pressure. In another embodiment, at least a portion of the lid is transparent. In another embodiment, the lid consists of a glass window in a frame. In another embodiment, the chip is monolithic and the reaction chamber is completely enclosed within the chip. According to another embodiment, the chip further includes an interface configured to deliver reaction chamber products. According to yet another embodiment, the interface is connected to the reactor part of the chip. Another embodiment provides that the reaction chamber floor comprises a bend. In another embodiment, the tip has a hexagonal shape.

  According to another embodiment, the chip further comprises a heater for heating the reaction chamber. According to one embodiment, the heater comprises at least one of a heating element, a resistance heater, a radiator, a microwave heater, and a laser device for remotely delivering heat to the reaction chamber. In yet another embodiment, the heater is coupled to the chip through an opening in the bottom surface of the chip. In one embodiment, the heater is separated from the sidewall of the opening by a gap, while in another embodiment, the heater is separated from the reaction chamber by a 250 micron portion. In one embodiment, this portion comprises doped DCPD material.

  According to another embodiment of the invention, the valve is controlled by a pneumatic actuator. In different embodiments, the valve is controlled by a solenoid. According to another embodiment, the valve comprises a dual port plunger with one or more narrow sections separated by one or more ridges. In a different embodiment, the valve comprises a plunger with a thin metal part, a tip, and one or more o-rings modified to prevent gas leakage from the reaction chamber.

  In another embodiment, the chip further comprises one or more reaction chambers. In another embodiment, the tip comprises an ion exchange column integrated on the tip. In one embodiment, the chip comprises an HPLC integrated within the chip, while in a different embodiment, the chip comprises an HPLC integrated within the interface portion of the chip. In another embodiment, the chip comprises one or more internal filters for removing exhaust. According to another embodiment, the reaction chamber has a cylindrical shape and a volume of 60 μL (microliter), and in a different embodiment, the tip is configured as a closed system with no pipe extension.

  According to another embodiment of the invention, the chip is further modified to communicate with a fluid and gas delivery and removal network. In one embodiment, one or more syringes are used to deliver at least one fluid or gas to the chip. In one embodiment, a syringe is placed below one or more vials with liquid contents to perform efficient delivery of liquid to the tip. In another embodiment, a syringe is used to deliver gas to the tip. In different embodiments, the network is modified to work with at least one of prefilled individual vials and prepackaged cartridges. In one embodiment, the cartridge contains a pre-metered amount of reagent sufficient for a single use with the chip. In different embodiments, the controlled delivery of liquid is performed by a gradual increase in pressure to the closed vent.

  According to another embodiment of the invention, solvent evaporation and vapor removal is performed by flowing a gas over the solution in the reaction chamber. In one embodiment, the gas is nitrogen. According to a different embodiment, the reaction chamber contents are superheated by closing the vent and heating the reaction chamber with a heater. Another embodiment comprises pressurizing the reaction chamber prior to applying heat. According to a different embodiment, the chip further comprises an integrated solvent removal module.

  Another aspect of the present invention controls a microfluidic chip, a reagent source in fluid communication with the chip and comprising at least one reagent, a gas and fluid delivery and removal network, and operation of the network. A portable device for the automatic radiosynthesis of radiolabeled compounds comprising a controller modified in this way and a local radiation shield for shielding one or more radiation-critical components of the device. In one embodiment, the device further comprises a camera for monitoring the reaction chamber in the microfluidic chip. According to another embodiment, the device further comprises a machine vision system that is modified to recognize completion of one or more steps according to information received from the camera. In one embodiment, the second step is started as soon as the first step is completed.

  According to another embodiment of the invention, the device is configured to operate in batch mode. In one embodiment, the device is configured to operate in a flow-through mode, while in a different embodiment, the device is configured to operate in a batch-flow hybrid mode. Yes. In different embodiments of the present invention, local shielding is performed on at least one of the ion exchange column and the F-18 source. In another embodiment, the controller comprises a programmable logic controller and a user interface. In one embodiment, the user interface is configured to perform at least one of manual operation and automatic operation of the device.

  In another embodiment, the device further comprises one or more internal filters for removing exhaust. In another embodiment, local occlusion prevents exposure of the user to radiation in multiple composite runs performed by the user. In one embodiment, all of the packed reagents are consumed by the zero waste system, and in different embodiments, the device allows the [f-18] fluoride to be efficiently eluted from the ion exchange column. Further modifications have been made. In another embodiment, the device further comprises self-metering of the reagent, and in another embodiment, the device is further modified to operate fully automatically.

  A different aspect of the invention introduces one or more reagents into a microfluidic chip (where the chip is a reaction chamber, one or more flow channels connected to the reaction chamber, and the reaction chamber). One or more connected vents and one or more integrated valves for controlling the flow into and out of the reaction chamber.), Treating the reagents to produce radiolabeled compounds And collecting the radiolabeled compound, and a method for radiosynthesising the radiolabeled compound.

  A different aspect of the present invention relates to program code implemented on a computer readable medium, which causes the controller to perform a method for radiosynthesising a radiolabeled compound using a microfluidic chip. The method comprises introducing one or more reagents into the reaction chamber and operating a synthesis system to process the reagents in response to a predetermined defined algorithm to produce a radiolabeled compound; And collecting the radiolabeled compound. In another embodiment, the entire process starting with the radionuclide received from the cyclotron and finishing to the purified product in the injectable formulation is performed automatically without user intervention.

Further, methods and devices according to various embodiments of the present invention provide the following additional features and advantages.
The device can perform multiple runs (including synthesis of different products) without exposing the user to radiation;
A “zero waste” microfluidic system using 100% of the packed reagents;
• Solvents can be evaporated below their boiling point without evacuating the microfluidic device;
The reaction can be carried out in a solution heated to a temperature of twice the boiling point of the solvent used (or above 100 ° C.);
The device may comprise an integral chip without a separate lid and reactor part;
The device can be used without an interface layer comprising pins fitted with pressure in a port connected to the tube;
The device allows ultra efficient fractional elution of "F-18" fluoride from an ion exchange column;
The reaction chamber floor may comprise any material with high thermal conductivity and inert surface;
The tip allows self-weighing of the reagent (eg by surface tension);
The chip allows reagents on the solid support (eg by placing beads in the reactor that can be held in the reactor while the solution enters and exits);
A dual syringe system that allows reagent separation (eg, reagent for one syringe and gas for the other);
-Local shielding that protects users and electronic devices simultaneously;
• Direct packing from the chip to the HPLC column;
-Automatic recognition and isolation of products;
-Desktop operation-does not require handling of exhaust devices such as drafts;
• Automatic organic solvent removal system; and • The entire process (from F-18 in the target water to the purified product formulated for injection into the patient) can be performed automatically with a single command.

  These and other advantages and features of various embodiments of the present invention, as well as their mechanism and method of operation, will become apparent from the following detailed description when taken in conjunction with the accompanying drawings.

Embodiments of the present invention will be described with reference to the accompanying drawings.
FIG. 2 shows a cross section of a representative microfluidic chip, according to one embodiment of the present invention. FIG. 2 is a view of an assembled exemplary microfluidic chip from different angles, according to one embodiment of the present invention. FIG. 6 shows an exemplary process for [F-18] -FDG synthesis, according to one embodiment of the present invention. FIG. 2 illustrates an exemplary microfluidic chip with a remote actuator, according to one embodiment of the present invention. FIG. 2 shows a fluid and gas network for a microfluidic device, according to an exemplary embodiment of the present invention. FIG. 2 illustrates an exemplary microfluidic chip with a solenoid, according to one embodiment of the present invention. FIG. 2 shows an exemplary microfluidic-based instrument according to one embodiment of the present invention. FIG. 2 shows an exemplary microfluidic-based instrument according to one embodiment of the present invention. FIG. 2 shows an exemplary microfluidic-based instrument according to one embodiment of the present invention. FIG. 2 shows an exemplary microfluidic-based instrument according to one embodiment of the present invention. FIG. 4 illustrates a user interface for a microfluidics-based instrument, according to an exemplary embodiment of the present invention. FIG. 4 illustrates a user interface for a microfluidics-based instrument, according to an exemplary embodiment of the present invention. FIG. 4 illustrates a user interface for a microfluidics-based instrument, according to an exemplary embodiment of the present invention. FIG. 3 shows a fluid and gas network for a microfluidics-based device, according to an exemplary embodiment of the present invention. FIG. 3 shows a fluid and gas network for a microfluidics-based device, according to an exemplary embodiment of the present invention. FIG. 3 shows a fluid and gas network for a microfluidics-based device, according to an exemplary embodiment of the present invention. FIG. 3 shows a fluid and gas network for a microfluidics-based device, according to an exemplary embodiment of the present invention. FIG. 3 shows a lid of an exemplary microfluidic chip, according to one embodiment of the present invention. FIG. 3 shows a reactor portion of a representative microfluidic chip, according to one embodiment of the present invention. FIG. 4 illustrates an interface portion of an exemplary microfluidic chip, according to one embodiment of the present invention. FIG. 4 illustrates a coupled microfluidic chip and interface assembly, according to an exemplary embodiment of the present invention. FIG. 5 illustrates an exemplary plunger valve actuation according to one embodiment of the present invention. FIG. 5 illustrates an exemplary plunger valve actuation according to one embodiment of the present invention. FIG. 3 illustrates an exemplary plunger valve according to one embodiment of the present invention. FIG. 3 illustrates an exemplary plunger valve according to one embodiment of the present invention. FIG. 3 illustrates an exemplary vent valve according to one embodiment of the present invention. FIG. 3 shows a lid of an exemplary microfluidic chip, according to one embodiment of the present invention. 2 is a product transfer and purification system diagram according to an exemplary embodiment of the present invention. 2 is a detection and isolation system diagram according to an exemplary embodiment of the present invention. 2 is a detection and isolation device diagram according to an exemplary embodiment of the present invention. 2 is a solvent removal diagram according to an exemplary embodiment of the present invention. 2 is a solvent removal diagram according to an exemplary embodiment of the present invention. FIG. 3 shows a vial fixture according to an exemplary embodiment of the present invention.

  In the following specification, for purposes of explanation and not limitation, details and descriptions are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to those skilled in the art that the present invention may be practiced in other embodiments that depart from these details and descriptions.

  "System for Purification and Analysis of Radiochemical Products Yield by Microfluidics Science", filed Aug. 23, 2007 US patent application Ser. No. 11 / 895,636 is hereby incorporated by reference in its entirety.

  In general, conventional automated synthesizers for synthesizing radiopharmaceuticals are inefficient and efficient microfluidic reactors identified to date require manual operation. Various embodiments of the present invention allow automatic operation of microfluidic reactors. Previous microfluidic reactors have been operated inside fixed leaded hot cells by various mechanical, pneumatic or very simple electronic controls, but this always required the operator's attention . These reactors show significant variability as a result. The automation enabled by one aspect of the present invention makes microfluidic devices autonomous and portable. In one embodiment, the microfluidic system of the present invention can be used by medical personnel in either clinical or R & D situations and does not require the constant presence of a technician or specially trained operator. Furthermore, microfluidic systems according to embodiments of the present invention allow various steps of synthesis to be performed in a controlled and traceable manner. In another aspect of the invention, a syringe driver can be used to more accurately deliver and meter reagents. In general, the use of sensors can monitor process completion, such as solvent evaporation. This arrangement results in a faster and more failsafe device.

  In particular, embodiments of the invention relate to microfluidic systems for fully automated synthesis of biomarkers or radiolabeled pharmaceuticals for positron emission tomography. Some of the advantages associated with various embodiments of the present invention include, for example, F-18, which reduces reagent usage (thus reducing chemical product costs), increases reaction efficiency and yield. Includes the ability to synthesize compounds in a flexible manner, as needed, and to increase radiolabel concentration. Another advantage of the various embodiments of the present invention is the continuous synthesis of multiple products without exposure to radiation to the user between runs (exposure is unavoidable in conventional systems). Capabilities and the ability to perform high pressure reactions (eg, several hundred psi) are included.

  The system disclosed herein provides additional reagent modules, waste modules to allow the system to be used for different biomarkers from one run to the next or even simultaneously. And a mechanism for adding a synthesis module. If the same number of steps are involved in the synthesis of different biomarkers, the instrument can be used as a single pre-filled reagent and / or solvent without hardware changes or for a single run. The used cartridge can be reused. Because of this ease of use, R & D requires the synthesis of biomarkers on demand, such as when several patients require different scans performed on the same day with different biomarkers Extreme flexibility is possible in environmental or special clinical situations.

  In one aspect, the present invention provides an automated instrument that is easy to use and flexible. Thus, the system allows non-experts to synthesize various PET biomarkers on demand for biomarker development, synthesis optimization and testing. In another aspect, the present invention provides an instrument that can be placed in a hospital remote from the currently available cyclotron. The devices disclosed herein require fresh product as opposed to the collapsed product associated with conventional systems that require delivery from a centralized (and possibly remote) synthesis facility. It is possible to synthesize accordingly. This type of field equipment makes PET scans more accessible to additional clinics, patients and laboratories, exceeding that available from local radio-pharmacies (with high specific activity). Provide additional flexibility in obtaining the desired biomarkers.

  To better understand the methods, systems and devices disclosed herein, the following lists terms and definitions used in the fields of organic synthesis, engineering and pharmacy.

  A “microfluidic device” or “microfluidic chip” or “synthetic chip” or “chip” can manipulate a small volume (eg, μL (microliter) or nL (nanoliter)) of liquid into a substrate containing microchannels A unit or device that enables their transfer. The device can be configured so that mechanical or non-mechanical pumps can be used to manipulate liquids, including reagents and solvents to be transferred or transported in the microchannels and reaction chambers. The device can be constructed using micro-electromechanical fabrication methods known in the art. Alternatively, the device can be machined using computer numerical control (CNC) technology. Examples of substrates for forming the device include glass, quartz or polymer. Such polymers may include PMMA (polymethyl methacrylate), PC (polycarbonate), PDMS (polydimethylsiloxane), DCPD (polydicyclopentadiene), PEEK, and the like. Such devices can include columns, pumps, mixers, valves, and the like. Generally, a microfluidic channel or tube (sometimes referred to as a microchannel or capillary) has at least one cross-sectional dimension (eg, height, width, depth, diameter), which is, for example, limited However, it may range from 1,000 μm to 10 μm. The microchannel makes it possible to manipulate very small amounts of liquid, for example at the level of nL to μL. The microreactor may further comprise one or more reservoirs in fluid communication with one or more microchannels, each reservoir having a volume of, for example, from about 5 to about 1,000 μL.

  A “reaction chamber” (sometimes referred to as a “reactor” or “microreactor”) is a microfluidic chip (here or for example US Pat. No. 11 / 514,396) where the reaction takes place. , U.S. Patent No. 11 / 540,344, or U.S. Patent No. 11 / 701,917, each of which is incorporated herein by reference in its entirety. Regarding the above functions. The reaction chamber may be cylindrical, for example. The reaction chamber is connected to one or more microchannels designed to deliver reagents and / or solvents or to remove products (eg, controlled by an on-chip valve or equivalent device) have. For example, without limitation, the reaction chamber may have a diameter to height ratio of greater than about 0.5: 10. For example, but not limited to, the height of the reactor may be from about 25 μm (micrometers) to about 20,000 μm.

  “Column” means a device that can be used to separate, purify or concentrate a reactant or product. Such columns are well known in the art and include, but are not limited to, ion exchange and affinity chromatography columns.

  “Flow channel” or “channel” means a microfluidic channel through which a fluid, solution, or gas can flow. For example, without limitation, such a channel may have a cross-section of about 0.1 mm to about 1 mm. For example, but not limited to, the flow channel of embodiments of the present invention may also have a cross-sectional dimension in the range of about 0.05 microns to about 1,000 microns. The particular shape and size of the flow channel will depend on the particular application required for the reaction process, including the desired throughput, and can be configured and dimensioned according to the desired application.

“Target water” is [ ¹⁸ O] H ₂ O after impact with high energy protons in a particle accelerator, such as a cyclotron. The target water contains [ ¹⁸ F] fluoride. In one embodiment of the present invention, target water preparation is contemplated separately from the system disclosed herein. Target water is supplied to the system from a cartridge in one embodiment of the invention and from an individual vial that is pre-filled in another embodiment.

  Microfluidic “valves” (or “microvalves”) are the various components of a microfluidic device, including the flow between flow channels, solvent or reagent reservoirs, reaction chambers, columns, manifolds, temperature control elements and devices. Means a device that can be controlled or actuated to control or regulate fluid, gas or solution flow between them. Examples include, but are not limited to, such valves include mechanical (or micromechanical) valves, (pressure actuated) elastomeric valves, pneumatic valves, solid valves, and the like. Examples of such valves and methods of making them are described, for example, in “The New Generation of Microvalves” Analytical Chemistry. In Felton, 429-432 (2003).

The term “radioisotope” means an isotope that exhibits radioactive decay (eg, emits positrons). Such isotopes are also referred to in the art as radioisotopes or radionuclides. Radioisotopes are named herein using various combinations of commonly used element names or symbols and their mass numbers (eg, ¹⁸ F, [F-18], fluorine- 18). Exemplary radioisotopes include I-124, F-18, C-11, N-13 and O-, which have half-lives of 4.2 days, 110 minutes, 20 minutes, 10 minutes, and 2 minutes, respectively. 15 is included.

  The term “FLT precursor” refers to “N-dimethoxytrityl-5′-O-dimethoxytrityl-3′-O-nosyl-thymidine” (also known as “BOC-BOC-nosyl”); F-18] fluoromisonidazole can be used to represent and FHBG can be used to represent 9- [4- [18F] fluoro-3- (hydroxymethyl) butyl] guanine.

The term “reactive precursor” or “precursor” refers to an organic or inorganic non-reactant that is reacted with a radioisotope, typically by nucleophilic substitution, electrophilic substitution, or ion exchange, to form a radiopharmaceutical. Means a radioactive molecule. The chemical nature of the reactive precursor depends on the physiological process being tested. Typically, reactive precursors are used to generate radiolabeled compounds that selectively label target sites in the body, including the brain, which means that this compound is in a subject. It means that it may be reactive with the target site and, if necessary, can be transported across the blood brain barrier. Typical organic reactive precursors include sugars, amino acids, proteins, nucleosides, nucleotides, small molecule pharmaceuticals and their derivatives. One common precursor used in the preparation of ¹⁸ F-FDG is 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose.

  The phrase “reactor temperature” means the temperature observed, measured and / or maintained in the reaction chamber.

  “Reaction time” is the time during which the reaction can proceed before the next step occurs.

  The phrase “reagent pressure” or “solvent pressure” refers to a gas (usually nitrogen or argon, for example) applied to a reagent or solvent vial that drives the reagent or solvent into the flow channel, for example, into the reaction chamber. Means the pressure of the active gas).

  The phrase “reagent fill time” or “solvent fill time” refers to the reagent or solvent being placed in the microfluidic chip before the on-chip valve is closed, thereby preventing additional reagent or solvent from passing into the reaction chamber. It means time to enter.

  The term “evaporation” means a change in the solvent state from liquid to gas, usually followed by removal of the gas from the reactor. One method for removing gas is performed by applying a vacuum. Various solvents, such as acetonitrile and water, are evaporated during the synthetic route disclosed herein. As is known to those skilled in the art, each solvent, such as acetonitrile and water, may have a different evaporation time and / or temperature. In another embodiment, the evaporation is performed by heating the reaction chamber while flowing an inert gas over the reaction mixture to facilitate the removal of vapor from the reaction chamber.

  The term “elution” generally means the removal of a compound from a specific location. The elution of [F-18] fluoride from the ion exchange column means the transport of [F-18] fluoride by the eluent from the column to the reaction chamber. Product elution from the reaction chamber refers to the transfer of product from the reaction chamber to an off-chip product vial (or purification system), for example, by flushing the reaction chamber with a large amount of solvent, such as water. To do.

  The “off / on time” associated with the vacuum (or gas pressure) applied at a point in the system represents the time of radiosynthesis operation when the vacuum (or gas pressure) is started or stopped.

  “Inert gas pressure” including “nitrogen pressure” or “argon pressure” means the pressure of an inert gas such as nitrogen or argon that is allowed to pass through a predetermined regulator.

  The phrase “internal filter” refers to a vial, syringe or another container that is filled with an adsorbent material such as charcoal and has two ports. As the exhaust from the microfluidic chip passes through such a filter, radioactive and non-radioactive contaminants are generally captured and remain on the filter. After the reaction exhaust passes through the internal filter, the purified gas is released into the atmosphere. The use of a suitable internal filter reduces or eliminates the need for additional exhaust treatment for safe operation of the portable system. In one embodiment, it is not necessary to operate the portable system disclosed herein in a draft.

  The term “priming” when used in connection with a reagent flow channel means that the reagent is transported through the flow channel connecting the reagent source and the reaction chamber, but the reagent flow is closed on. Passes through the tip valve and through the open flow channel to the waste container. In this method, when a reagent is added to the reaction chamber, the corresponding on-chip valve is opened to deliver the reagent into the reaction chamber with minimal delay from the flow channel primed with pneumatic actuation. Alternatively, if the flow channel is not primed, the reagent must travel the entire length of the flow channel from the reagent source to the reaction chamber, which causes the gas in that path to flow over the reaction chamber and synthesis chip. Move through the open vent channel. This can cause loss of reagent or solvent, but this is avoided by priming the flow channel. Similarly, where appropriate, the term “priming” can be used in connection with solvent flow channels.

  The phrase “prepackaged disposable reagent cartridge” means a device designed to be removable and replaceable within or on the automated system described herein. Reagents held in the cartridge can be transported to the reaction chamber after the cartridge is fitted into the system described herein. Where appropriate for preparing the radiolabeled compound, the reagent cartridge may contain a solvent as well as a reagent. Alternatively, the solvent may be provided separately from the reagent.

  In one embodiment, the automated system disclosed herein includes a system with a disposable reagent cartridge. In one embodiment, the present invention relates to an automated system with the flexibility to create a variety of different radiopharmaceuticals while minimizing the risk of cross-contamination by simply replacing the cartridge. The use of such cartridges includes simplified setup, rapid changes between manufacturing operations, automatic diagnostic tests prior to cartridge and reagent operation, reagent traceability, single use, tamper-evident measures and abuse prevention There are a number of advantages, including a strategy. Reagent cartridge replacement eliminates the need to design a completely new automated synthesis system each time a different radiopharmaceutical is prepared. The system described herein allows cartridge replacement without opening the shield and exposing the user to radiation.

  Suitable heat sources for use in the synthesis system disclosed herein include, but are not limited to, resistive heating, local and non-local microwave heating, and Peltier devices. Various sensors (eg, flow sensors, liquid-gas interface sensors, radioactivity sensors, pressure sensors, temperature sensors, etc.) and other equipment components (eg, valves, switches, etc.) are integrated into the system, process control and Can be connected to a computer for monitoring purposes.

  The synthesis system disclosed herein includes a microfluidic synthesis chip in which, for example, reagents are mixed and heated, and solvents are exchanged to perform the desired chemical process.

  Conventional microfluidic chips are often too slow (even conceptually) to implement in practical applications. Embodiments of the present invention allow for rapid synthesis while at the same time increasing reaction yields that are critical for low yield biomarker production. Previously known microfluidic chips had to be operated manually or semi-manually, making them impractical for practical applications despite the advantages demonstrated on-chip. As a result, in the past, automated instruments were implemented using non-microfluidic engineering methods. In one aspect, the present invention is directed to a self-shielding fully automatic radiation synthesis instrument based on a batch mode microfluidic device.

  The microfluidic devices described herein can produce known biomarkers at higher speeds and in higher yields when used for radiochemical synthesis. In addition, such devices may be used, for example, in research and development efforts to develop new biomarkers that typically involve inactive reactions and / or reactions that cannot produce significant amounts of material by conventional methods. In addition, it enables the production of novel biomarkers that cannot be synthesized efficiently by conventional methods. Thus, an instrument that allows 10 to 20 syntheses to be carried out in a day (as opposed to 1-2 when using conventional instruments) allows researchers to quickly optimize reaction conditions Make it possible.

  Various embodiments of the present invention are performed in a fully automated (eg, one touch) method in which a fully automated radiosynthesis (eg, from target water to a purified product in an injectable composition) is performed in a single instrument. Or enabling individual process control. Various exemplary embodiments disclosed herein can be used for either producing known biomarkers in an automated mode as well as developing new biomarkers in a mode with individual process control. .

  The systems disclosed herein have demonstrated significant yield and reaction time improvements, particularly over conventional chemistry. One exemplary system automates chip operation with a visual basic program and a PLC (programmable logic controller). The automated process also provides automated product isolation capabilities.

  Previous closed microfluidic reactors contained fluoride and reaction intermediates in the reaction chamber with a gas permeable gasket. These gaskets must be composed of materials that are sufficiently inert, can withstand radiolabeling conditions, and at the same time exhibit significant gas permeability. Even when suitable gaskets are available, such closed devices that rely on gas movement through the membrane still suffer from long evaporation times and filling processes. On the other hand, one of the requirements for efficient radiosynthesis is often speed. In general, in the microreactors disclosed so far, the intermediate (handling) process rather than the reaction itself has been found to be the main source of delay. According to various embodiments of the present invention, these reaction steps are minimized in time because reaction efficiency and filling steps are significantly shortened by an unlimited gas path that does not include a membrane.

  The systems and devices disclosed herein achieve preventing leakage of reagents, products and intermediates without the need for membranes. Furthermore, they retain the ability to carry out superheat reactions. Embodiments of the present invention further relate to a microreactor piped for reagent delivery and solvent vapor removal. Reagent delivery according to exemplary embodiments of the present invention can be enabled by channels with specially designed valves that can withstand much higher pressures than previous systems without relying on elastomeric gaskets. Devices produced by exemplary embodiments of the present invention have proven to work successfully at hundreds of psi. In one exemplary embodiment, vapor removal occurs by flowing nitrogen over the surface of the liquid. This flow can be carried out in a controlled manner and therefore the evaporation rate can be determined or completely interrupted during the reaction process.

  Thus, according to embodiments of the present invention, loss of F-18 is avoided when various mechanisms are used for the production of F-18 labeled probes such as, for example, [F-18] FDG, Reduced or reduced. Furthermore, embodiments of the present invention provide the capabilities necessary to increase product diversity. In some embodiments of the present invention, the chips and their control systems disclosed herein exhibit improved capabilities, including but not limited to significant pressures. Performing the reaction, including active mixing, reagent concentration, heating and cooling rates, and the like.

  One embodiment of the present invention is a device that includes an integrated ion exchange column. The integration of the ion exchange column overcomes the F-18 loss during transport from the ion exchange column to the chip. In general, the column can be encased in a barrel made in a chip and covered with PEEK or other inert material frit. This column can also be located in the chip fluid adapter base.

  Another embodiment of the invention is a device that includes an on-chip integrated valve that controls the flow of gas (and vapor). In one variation, the on-chip valve controls liquid passage while the gas control valve is off-chip. In another variation, both the liquid control valve and the gas control valve are on-chip. The integration of the valve on-chip allows for better sealing of the reactor as well as better pressure control. This also prevents the loss of solvent and reagents into the extended off-chip vent piping. Thus, since the valve plunger can reach the reaction chamber exactly, a closed system is possible which eliminates the channel between the valve and the reaction chamber and thus does not have a piping extension. In one embodiment, these valves are configured to carry out the reaction at high pressure. Other mechanisms that ensure high pressure capability can be used to achieve pressures reaching or exceeding 300 psi. Such capability allows for a superheated reaction, which results in high yields and reaction rates guided by principles similar to microwave reactors.

  According to one embodiment of the present invention, a version of the reactor can be constructed without a pipe extension, but it is completely closed and unreacted material or uneluted product is retained. It has a standard coin shape or other shape with no pockets that could do. In addition to having a standard shape, the reactor surface can be very smooth to minimize surface area. Furthermore, the corners and grooves can be eliminated, reducing the portion of the reactor that can collect reaction residues or moisture and are difficult to access.

  In another embodiment of the present invention, for example, for reactors that can remain sealed at high pressure, microwave capability is incorporated into the chip. Concentrating the microwave on the reactor results in a very rapid reaction, as is known to those skilled in the art. Yet another variation can incorporate a built-in acoustic device on the chip to facilitate the reaction by rapid mixing of reagents. In another variation, surface acoustic waves are used to facilitate mixing in the reaction chamber. In yet another embodiment, a capillary channel is used to mix the reagents, which can aspirate liquid and release it into the reaction chamber in the form of a jet.

  Another embodiment of the present invention uses a fast response temperature control system to improve heating and cooling rates. In one aspect, the heating element is an integral on-chip. Another approach is an integrated radiator in close proximity to the reactor that carries a heat transfer “coolant” -like fluid, the temperature of which is controlled off-chip or another part of the chip. In general, it takes some time (e.g., 1 minute or more) to temperature equilibrate the heating block, but more time is required to reach a reactor that is 1 mm away from the block by 1 mm of material. It takes. As disclosed herein, remote heating can also be achieved using a laser positioned externally but focused in the reactor. Additionally or alternatively, the reactor floor thickness can be reduced to, for example, 250 μm for faster and more efficient heat transfer.

  To increase the heating and cooling rates disclosed herein, a chip material with better thermal conductivity than pure DCPD (polydicyclopentadiene) can be used. Such materials include, for example, DCPD doped with other materials. Another approach to tackling the increased heating / cooling rate involves thermal insulation from the rest of the reactor chip. In this case, heating and cooling is not slowed by the mass of the device acting as a heat sink.

  In one embodiment, the material for the chip is glass. Alternatively, similar materials such as quartz or silicon can be used. Other suitable materials can be identified by those skilled in the art. Similarly, appropriate fabrication methods should be incorporated based on the use of such materials. In another embodiment, the chip disclosed herein has the ability to pre-fill reagents, thereby providing a single use configuration. In a single use configuration, the instrument may not perform any liquid treatment, thus avoiding reagent waste. The on-chip reagent can be moved through the membrane by vacuum or drawn into the reactor. In one system, all the valves of the chip are closed and the reagents are retained in their individual reservoirs before the chip is inserted into the instrument.

  In another embodiment, the HPLC column / system is part of a chip or fluid based adapter. If the purification system is part of a fluid based adapter, the column may be a multi-use component. Incorporating various approaches described herein can reduce the loss of F-18 to insignificant numbers.

  Another variation disclosed herein is a flow reactor. Flow reactors include traditional types based on piping or long helical in-chip channels, or completely different structures. Such possibilities include Gillies et al., “Microfluidic technology for PET radiochemistry”, Applied Radiation and Isotopes (2006) 64: 333-336, Gillies et al., “Microfluidic reactor for the radiology of PET radiotracers”, Applied Radiation and Isotopes 3 (Applied Radiation and Isotopes 25). A cylindrical reactor similar to that reported by No. 32 is included, but is not limited thereto. As is known to those skilled in the art, additional novel mechanisms can be added to either type of reactor to increase the reaction rate. These additions may include, but are not limited to, a shape on the surface of the channel or reactor that introduces or simply directs turbulence to the moving liquid. The principle of jetting one fluid to another may also be used.

  As disclosed herein, it is also possible to create a hybrid batch flow reactor, where the first liquid is circulated in a low volume loop that continues to rotate. At one point in the loop, the first liquid contacts the second liquid, which is a reagent that flows through. The first and second liquids contact each other in a laminar flow mode, after which they are separated after traveling a predetermined distance. This approach allows important reagents and intermediates to be retained in a concentrate that does not leave the chip, while other (inexpensive and non-limiting) reagents can flow through. Furthermore, it is also possible to incorporate such a mechanism to capture the fluoride, in which case the fluoride is transferred from the dilute flowing liquid into the concentrated recirculating solution. Similar principles can be applied during some or all of the purification steps. Alternatively, other active mixing mechanisms can be created in either flow-through or static batch reactors.

  Another semi-batch approach is based on the “Hypervap” technology according to an exemplary embodiment of the present invention. The Hypervap method allows the reagent to be continuously injected into the reactor where it can be concentrated. The desired amount of reagent is brought into the reactor from a single concentration solution by changing the flow of reagents and gases. The particular reagent remains in the reactor at the same volume (which can also be controlled). Here, the reaction takes place in one chamber in a solution moving at high speed around the chamber. Although the product can be collected only once per run as a batch, the amount of reagent used can be varied during the run. This approach has significant value for both research and development as well as manufacturing applications.

  Another variation described herein provides additional beneficial features to address problems such as long distance material transfer, limited solvent exchange capacity and inefficient F-18 capture and release. Is done. A chip according to an exemplary embodiment of the present invention allows for efficient concentration of dilute solutions. These advantages are due, in part, to the fact that the loss associated with material transfer is reduced in an integrated device according to embodiments of the present invention. For example, incorporating capture and release systems that can function with efficiencies of about 99% or higher increases the overall yield observed with many disclosed systems. This efficiency is achieved by several factors. First, the volume of the ion exchange bed (eg, packed with AG1-X8 or another resin) is minimal (eg, 4 μL total volume and less than 2 μL void volume)-this is a multiple column volume This yields 15 μL of eluent containing Second, fluoride capture and release occurs in the opposite direction—most F-18 is concentrated at the beginning of the column during capture and does not need to be balanced with the rest of the column during release. Third, the release solution breaks down into small fractions (eg, less than about 1 μL), which causes most of the concentrated F-18 to move within the first fractional fraction without mixing with the rest. This allows each subsequent fraction to be wiped away with the fresh batch of eluent rather than the concentrated F-18 solution that is left behind after the previous fraction. A total capture and release efficiency of up to 99.8% has been observed. When using ion exchange columns, frit selection can be extremely important. For example, metal frits can have a detrimental effect on capture and release, Teflon frits can easily break down, and PEEK frits can become clogged despite easily filtering the solution. There is. According to one exemplary embodiment of the present invention, UHMWPE (ultra high molecular weight polyethylene) has been determined to be the optimal frit material. In some embodiments of the flow-through mode incorporated herein, the electrochemical capture and release mechanism is extremely beneficial. In other embodiments, the elution volume may be smaller, such as 10 μL, 5 μL, or 2 μL.

  For both flow-through and batch devices, optimized devices are prepared using highly inert state-of-the-art materials. Such materials may include, but are not limited to, PFPE-based materials (perfluoropolyether) or experimental ROMP. In another embodiment of the present invention, a device is disclosed that allows multiple reactions to be performed on the same chip, including reactions that are performed simultaneously when different regions of the chip are used.

  A number of novel biomarkers involve more complex synthesis with intermediate purification. To accommodate such pathways, devices according to exemplary embodiments of the present invention are designed with a fast activity enrichment mechanism that allows for HPLC purification of intermediates. Such a device can include multiple reactors with different capacities or functions adapted to different steps of the process. One advantage for such a system is that everything is integrated into one device, thereby minimizing material transfer and eliminating the need for dilution. Concentration devices that rely on principles similar to Hypervap can tolerate continuous concentration of the solution, in which case the solution is fed into a small chamber as the solvent evaporates. Alternatively, large containers / chambers can be designed on-chip, but in such instances it may be difficult to collect material from walls with high surface areas after evaporation.

  In one exemplary embodiment, a device / equipment combo is provided that allows multiple reactions to be performed simultaneously. In such a configuration, multiple batches can combine the products in the purification stage. Alternatively, several batches can be staggered to allow continuous operation of purification on the same column for reaction mixtures from different reactors.

  In one variation, a polymer such as pDCPD, which is a rigid and transparent polymer with excellent machining properties, is used in the devices disclosed herein. Furthermore, the use of alternative fabrication methods results in faster manufacturing and better chip characteristics. Such methods include, but are not limited to, hot embossing, injection molding or etching. It is also possible to incorporate a reaction on a solid support, in which case either a non-radioactive reagent is immobilized or the molecule is labeled (followed by post-purification cleavage). Is done).

  The instrument controlling the chip disclosed herein can be self-shielding and can accept a labeled probe either by tubing or a vial. In the latter case, the vial can be shielded and inserted into the instrument without exposure to the operator.

  In one exemplary embodiment, each reagent and / or solvent can be delivered from a separate reagent / solvent source to the synthesis chip. In this case, each reagent / solvent source may have two ports into which piping is inserted, an inlet and an outlet. The inlet piping may be located above the fluid surface and is in fluid communication with an electronically controlled three-way valve connected to a pressurized or quantified inert gas (eg, nitrogen or argon) source. ing. Each reagent / solvent may have its own independently controllable pressure, allowing flexibility by allowing different flow rates. Each reagent / solvent source outlet line (or outlet channel) may be a piece of tubing with one end at the bottom of the reagent vial and the tip towards the microfluidic chip. A three-way valve connected to the inlet can be opened so that the reagent / solvent vial is pressurized and the reagent / solvent is pushed into the outlet line, or evacuated so that the reagent / solvent vial is opened to the atmosphere and depressurized. can do.

  Lines (or channels) from reagent / solvent vials direct “washing” solvent and / or inert gas (nitrogen or argon) towards the synthesis chip to wash and clean one or more lines at the end of the synthesis run. An additional electronically controlled three-way valve can be passed on the way to the synthesis chip so that it can be dried. Drying the line helps to avoid liquid leakage when the chip is removed from the interface adapter and reinstalled. Drying also helps to avoid contamination of subsequent operations by previous operating components or dilution of the reagent by the wash solvent. In addition, the check valve is located in the inlet line on the way to the synthesis chip and can be used as a reagent / solvent by any leaky microfluidic chip valve (or a valve that is inadvertently switched on at the wrong time). Ensure that back flow into the vial never occurs.

In one embodiment, reagents / solvents are individually filled into prefilled vials and loaded into the system. These vials may be, for example, small v-vials placed between a syringe that moves N ₂ and the tip, filled with reagents that use their full volume on the tip in a single run. It may be. The fixtures holding these vials may have pins that reach the bottom of the v-vial and are connected to tubing leading to the tip. Another port in the fixture which holds the vial, may be connected to N ₂ syringes that can move the liquid into the tip in a controlled manner by pressing N _2. Reagents used in ng or mg quantities can be weighed out in these vials and the solvent added using a micropipette. FIG. 28 illustrates the shape of such a vial according to an exemplary embodiment of the present invention. The “zero waste” reagent vial shown in FIG. 28 is available for the precursor and Kryptofix 2.2.2 solution loaded into the system in the correct amount. There are two ways to deliver reagents from such vials to the chip. One is by opening the on-chip inlet valve and vent (to escape the displaced gas) and using a syringe to gently move N ₂ behind the reagent. Another method eliminates the use of a syringe. When the on-chip valve is opened and the vent is closed, a small amount of pressure is applied behind the liquid in the v-vial and the liquid is pushed toward the chip as the gas in the system compresses. As the pressure increases, the gas in front of the liquid is further compressed, moving the liquid toward the chip and eventually reaching the reaction chamber to fill it. This latter method can only be used when an off-chip vent valve is used.

  In another embodiment, these reagents / solvents can be packaged in a single reagent cartridge that can be installed in a single step, but can also be packaged in very small quantities using each synthesis chip to provide different biomarkers. Synthesis can be facilitated. Different sets of reagents / solvents and different chip configurations can then be used for each desired radiosynthesis. Alternatively, if the same reagent (such as HCl) is used in subsequent runs, they are filled in large quantities into the system and the metered amount can be dispensed to the tip by a syringe pump as needed. In another embodiment, the chip incorporates a metering mechanism that allows only a predetermined amount of reagent used in excess to be used in a single run. Such a mechanism may be based on surface tension or other characteristics.

In one exemplary system, a radiolabel such as F-18 is delivered from the cyclotron through a check valve into a temporary storage vial inside the instrument. In another exemplary system, the radiolabel is daily in a leaded vial that is easy to connect, or in some cases (eg, attached to an ion exchange column that is eluted in a temporary storage vial inside the instrument). Delivered in solid phase. It is not assumed that the operator will have their own cyclotron, and delivery of radiolabels as needed, eg once a day, will solve this deficiency. [F-18] In one example of FDG synthesis, F-18 is provided in a solution of target water. This solution is first passed through the exchange resin to capture and concentrate F-18; then F-18 is eluted into the microfluidic synthesis chip using K ₂ CO ₃ solution. In order to minimize the fluid volume transferred from the exchange column into the microfluidic synthesis chip, a trace (eg, 0.5 μL) rotary valve may be used in this portion of the fluid system.

  In one embodiment, the total loading of radionuclides (from the cyclotron or shielded container) delivered to the system is used in a single run, while in other embodiments, several consecutive or parallel It can be divided into fractions used in driving.

  Other methods for capturing fluoride ions (eg, US 60 / 950,976, "Microfluidic radiosynthesis device by electrochemical capture and release of F-18 in its concentration stage (Microfluidic radiosynthesis device relying). electrochemical trapping and release of F-18 in situ isotopic concentration step), as an alternative, can easily be integrated into the system according to embodiments of the present invention. Can do. Using electrochemical capture methods, the controller and the expanded computer can further control the high voltage supply required in this setup.

  The radiolabeled product created in the synthesis chip can be eluted with a solvent through a purification system such as a column into a final collection vial (or product container) and analyzed and / or patient Can be diluted to the volume required for injection. In one embodiment, the product container is placed in a leaded vial or syringe attached to the outside of the instrument for easy and rapid removal and delivery to the patient or for subsequent analysis. Alternatively, the product can be eluted into an injection loop from which the product can be loaded onto an HPLC column and then subjected to HPLC purification.

  An additional electronically controlled three-way valve can be placed in the path of the solvent, such as water, to the microfluidic synthesis chip. In one position, this valve allows solvent to flow into the chip. In other configurations, the liquid is allowed to flow from the synthesis chip to the waste. This valve can be used during the cleaning / cleaning phase. The cleaning solvent and gas (nitrogen or argon) may be passed through a synthesis chip to drain and clean it. In one embodiment, the entire system can be washed with solvent without disassembling the system and without removing the shield.

  The automated system according to one embodiment of the present invention also controls a valve integrated within the microfluidic chip. The pneumatic pistons that drive the mechanical actuating pins in these valves are driven by compressed air (or other gas) that is controlled by electronic valves as required.

  Many synthesizers known in the art use gas-operated elastomeric valves or pneumatic valves. Furthermore, there is important literature disclosing the control of microfluidic valves by various operating methods. See, for example, US Patent Application No. 2002/0127736, “Microfluidic devices and methods of use”, which is incorporated herein by reference in its entirety. In one aspect, microfluidic devices according to embodiments of the present invention are mechanical valves that can be operated efficiently under high pressure (eg, in US Patent Application No. 2007/0051412, which is hereby incorporated by reference in its entirety). Use the disclosed mechanical valves, etc.).

  Details of reagent delivery via a microfluidic chip and dead volume bypass mechanism that can be incorporated into the system disclosed in the present invention can be found in US Patent Publication No. 11 / 862,167, which is hereby incorporated by reference in its entirety. , “Systems and Methods for Interfacing with a Microfluidic Chip”.

  Each inlet bypass may be connected to a check valve and then to a single electronically controlled dead volume bypass valve. In one embodiment, system components that may be under automatic control include an inert gas delivery source, a temperature control system, a pressure control system, and one or more valves on the synthesis chip.

  The hardware disclosed herein can be controlled using a variety of electronic hardware equipment and devices. For example, a PC-104 based system can be used with 16 analog inputs, 10 analog outputs, 8 digital inputs, and 48 digital outputs. The controller can execute embedded Windows-NT software that communicates with a standard PC running FIX32 automatic software via an Ethernet connection. This software is, for example, an automated language that allows easy construction of a graphical interface for visualizing what is happening in hardware and controlling various valves and other components. The interface can accept various modes of operation, such as fully automatic, manual or stepped operation.

  In one embodiment, the control software provides individual digital outputs (eg, two-way and three-way valves, on-chip valves, temperature control systems, heater enable, cooler enable, vacuum system, rotary injector, and other system components. ) And analog outputs (e.g., temperature setpoints, and other outputs). Analog inputs (eg, reactor temperature, vent channel pressure, radiation level) can be scaled to engineering units for monitoring on the main screen.

  In addition to the interactive graphical interface described herein, dozens of scripts automate the process steps described herein. Each subprogram is a series of simple operations (for example, until the reactor reaches a specified temperature, such as changing the state of a valve, waiting for a certain amount of time, or waiting for an input specific value). Heating). A system according to embodiments of the present invention iteratively generates purified human-scale quantities of FDG, for example, in a semi-automatic manner (each step in radiosynthesis is initiated using a button on a computer screen). it can.

  In a fully automatic system, the required reaction time can be optimized, for example a simple script in FIX 32 can be written to execute all operations in sequence. One example can include automated unit operations such as filling, which include multiple sub-steps. “Unit activation” scripts can be designed to be “parameterized”. That is, in a single place, the operator can set the distribution time, reaction time and heating temperature. The automated script can then read all the information and adjust the synthesis operation accordingly. Automated driving can also be initiated, for example, by a user simply clicking on a “Start” icon that is part of the user interface. A system according to an embodiment of the present invention provides a fully automated hands-free operation of a full radiation synthesis cycle on a microfluidic device producing a purified PET radiotracer. In one embodiment, the device is portable, has no external components, is self-shielded, i.e. does not require a separate hot cell. In yet another embodiment, the device includes an internal filter that allows operation without any additional exhaust, i.e., true tabletop operation that does not require a draft.

  According to exemplary embodiments of the present invention, the hardware disclosed herein is controlled using a PC, a programmable logic controller (PLC), and a software control program written in Visual Basic. Can do. The PLC uses 6 analog outputs, 8 analog inputs, 24 relay outputs, 18 digital inputs, 17 digital outputs, and ladder logic program. All I / Os can be controlled. For example, a standard PC using visual basic control software can control the PLC and eight precision syringe pumps using serial communication. This provides a very detailed graphical interface, allows visualization of what is happening in the hardware, and controls various valves, pumps, heaters and other components. The interface can also accept various operating modes such as fully automatic, semi-automatic and manual.

  According to one exemplary embodiment, in manual operation mode, the control software allows individual control of all components and processes in the instrument through button clicks and text entry from the user interface screen.

  According to one exemplary embodiment, the semi-automatic mode of operation uses various subroutines adapted to automatically control initialization, priming, filling, evaporation, hydrolysis, fluorination and various other processes. it can. In addition, each of the automated processes can allow entry of specific values (eg, temperature, pressure, flow rate, volume and time).

  According to an exemplary embodiment, in a fully automatic mode of operation, the system is a fully automatic hands-free operation of a full radiosynthesis cycle on a microfluidic device producing a purified PET radiotracer product with a single button click. I will provide a. The required reaction value can be entered at the start of the reaction if desired. That is, the default values can be changed and the operator can set the flow time, reaction time, temperature, pressure and volume before starting the reaction. The automated script can read all the information and adjust the synthesis operation accordingly. In one embodiment, the device is portable, has no external components, and is self-shielded (ie, does not require a separate hot cell). In yet another embodiment, the device includes an internal filter that allows operation without any additional exhaust, i.e., true tabletop operation that does not require a draft.

  In one embodiment, one or more reagents may be delivered from individual prefilled vials or from pre-packaged disposable cartridges. In one embodiment, the portable system can be cleaned without disassembly. Thus, the reaction chamber and each of the reagent, product and waste channels can be cleaned by automated methods if desired. The identity of the generated radiotracer can be easily changed without requiring hardware changes. In one embodiment, the microfluidic synthesis chip is interchangeable. In one variation, synthetic chip replacement can be performed by opening a single door in the lead shield rather than disassembling the entire shield. In another embodiment, the final product vial can be placed in a separate shielded container so that the operator picking up the product is not exposed to the remaining radiation from the instrument.

Radiation shielding: Integrated shielding is one feature that makes the devices disclosed herein independent of traditional hot cells and radiopharmacies. In one embodiment, the shield consists of a box constructed from 18 connected 0.565 ″ thick lead panels (2,000 pounds total). According to another exemplary embodiment of the present invention, device shielding is performed in a localized manner. Thus, in contrast to coating the entire device, which increases the device weight and exposes the electronics to radiation, local shielding is useful for radiation handling components and detection, such as ion exchange columns, tips, and F-18 source vials. It may be performed to cover only the vessel. This arrangement uses significantly less shielding material while maintaining protection for the electronic components. Alternatively, the device may be designed to be sized to fit inside a properly shielded minicell, if desired. Some of the advantages associated with such local shielding can be summarized as follows.
• Portable and lightweight equipment (~ 300 pounds);
・ No need to build a laboratory using hot cells;
-Protection of electronic equipment from radiation damage;
・ "Insertion" bottles that allow placement of equipment away from the cyclotron;
-Transport of equipment without user exposure;
• Separate detectors from the rest of the system through the use of segmented designs. This allows removal of the product without exposing the user to other radiation sources inside the device;
The ability to perform multiple consecutive runs without having to open the shield, since the reagent vial can be placed outside the shield;
Easy on top, allowing access to internal (shielded) areas without requiring excessive force (to lift heavy shields) as segments are on rails that slide easily Hatching mechanism;
• Uniform shielding that provides protection from all angles.

  In another embodiment, the apparatus includes a heat exchanger that allows for rapid heating of the reaction chamber with a resistive heater and cooling of the reaction chamber with air from a vortex cooler.

  According to one embodiment of the present invention, a computer system or an external input device can be connected to a program storage device and a control device. The controller can be connected to at least one valve on the synthesis chip, an inert gas source, a temperature control system, a pressure monitor, and / or a vacuum system.

  A general-purpose computer system includes a processing device, a system memory, a system bus for connecting the system memory to the processing device, a storage device such as a hard disk drive, a magnetic disk drive for reading from and writing to a removable magnetic disk, and a CD-ROM disk, for example. Includes an optical disk drive for reading or writing to and from other optical media. The storage device can be connected to the system bus by a storage device interface, such as a hard disk drive interface, a magnetic disk drive interface, and an optical drive interface. This description of computer readable media relates to hard disks, removable magnetic disks and CD-ROM disks, but is readable by computer systems such as magnetic cassettes, flash memory cards, digital video disks, etc. and fits the desired end purpose. It should be understood that other types of media may also be used.

  A user can enter commands and information into the general purpose computer system or graphic information into the general purpose computer system. A display device having a display screen, such as a monitor, is connected to the system bus by an interface. In addition to the display screen, the general-purpose computer system can further include other peripheral output devices. A general purpose computer system can operate in a network environment using logical coupling to one or more remote computer systems, such as servers, routers, peer devices or other common network nodes, and such systems are Any or all of the elements described herein in connection with a general purpose computer system may be included.

  When used in a LAN (local area network) environment, the general-purpose computer system is connected to the LAN through a network interface. When used in a WAN network environment, a general purpose computer system typically includes a modem or other means for establishing communications over the WAN, such as the Internet. An internal or external modem can be connected to the system bus by a serial port interface. Within a network environment, program modules or portions thereof rendered in connection with a general purpose computer system can be stored in a remote storage device. It will be appreciated that the network connections shown herein are exemplary and other means of establishing a communications link between the computer systems can be used. It is also understood that the application module can be equally implemented on a host or server computer system other than a general purpose computer system, and can be equally transmitted to the host computer system by other means than a CD-ROM, for example, via a network connection interface. I want. Program modules stored in a computer system driver can control the manner in which a general-purpose computer system functions and interacts with users, I / O devices, or other computers. Program modules can include routines, operating systems, target application program modules, data structures, browsers, and other components.

  The operations, steps, and procedures described herein are considered to be well disclosed to enable those skilled in the art to carry out exemplary embodiments of the invention, and thus are described in the detailed description. It should be understood that no particular programming language is described for performing the various methods described. In addition, there are a number of computers and operating systems that can be used in implementing the exemplary embodiments, and thus it is not possible to provide a detailed computer program that can be applied to all of these many different systems. Each user of a particular computer must know the language and tools that are most useful for that user's needs and purposes.

Furthermore, the method can be implemented in the form of computer-implemented processes and apparatuses for performing those processes. The above may also be implemented in the form of computer program code including instructions implemented on a tangible medium, such as a floppy disk, CD-ROM, hard drive, or any other computer readable storage medium. When computer program code is loaded into a computer and executed by the computer, the computer becomes an apparatus for carrying out embodiments of the present invention. Current systems with reprogrammable storage (eg, flash memory) can be updated to carry out embodiments of the present invention. The above may also be any transmission, for example, whether stored in a storage medium, loaded into a computer and / or executed by a computer, or through an optical fiber or by electromagnetic radiation over electrical wiring or cables, etc. It can be implemented in the form of computer program code, whether transmitted on a medium, or when the computer program code is loaded into a computer and executed by the computer, the computer implements the embodiments of the present invention. It becomes a device to execute. When executed on a general-purpose microprocessor, the computer program code segments can configure the microprocessor to create specific logic circuits in whole or in part.
Exemplary Embodiment: Chip Design FIG. 1 shows a microfluidic chip according to an exemplary embodiment of the present invention. The typical reactor 10 shown in FIG. 1 is located at the center of the chip 90 and has a cylindrical shape with dimensions of 5 mm width and 3 mm height. While this produces a reactor volume of 60 μL, it may be beneficial not to fill the reactor to maximum capacity as it may cause loss of solution into the vent and outlet. For example, using a 30-45 μL solution can provide a suitable amount for proper operation. When the reactor is partially filled, there is sufficient space above the liquid to allow a constant nitrogen flow to remove vapor from the chip.

  The reactor 10 is fixed to the center of the chip 90 and is in fluid communication with one or more inlets 20 of the reactor. As shown in FIG. 1, the tip may contain an o-ring that is in physical contact with both the top 95 and bottom 99 of the tip. Exhaust from the reactor 10 is accomplished by a vent channel 40 that is controlled by a valve plunger 50 that is in further fluid communication with a vent outlet 60. Reagent is added to reactor 10 through reagent inlet 70, which is controlled by valve plunger 55, which is in fluid communication with reagent bypass outlet 65. Below the reactor, heaters (not shown) arranged in the heater openings 80 are arranged.

  Valve: In one exemplary embodiment of the invention, the reactor is plumbed with 6 flow channels. Four of the flow channels serve to deliver reagents and two serve to elute the product. Since there is no membrane used as a seal, the valve is designed for use with this tip. Valve plungers that enter the tip through the side create a seal inside the barrel in which they travel. These seals can be created by a soft inert material such as Teflon at the tip of the plunger; other suitable materials are known to those skilled in the art. When the valve is in the closed position, the plunger is inserted to the end and pushed against the hard stop near the reactor. Reagent delivery is enabled by a vertical channel across the valve barrel. In the “valve closed” configuration, reagents are delivered through the top of the chip. The thin portion of the plunger tip allows reagent (as well as air / gas pushed by the reagent exiting the tubing during filling) to exit through the bottom of the tip. When the plunger is retracted, the inlet has a clear passage to the reactor. It is necessary to close the external valve on the outlet to prevent the reagent from continuing to leak out while filling the reactor.

  In another exemplary embodiment, the external valve is optional. This design allows the reagent inlet and outlet to be displaced along the barrel in such a way that when the plunger is pulled back into place, only the inlet gains a clear path to the reactor and the outlet is blocked. Have. Provided herein are further details about exemplary valves according to embodiments of the present invention.

  Heater: In one exemplary embodiment, heat can be transferred from a Peltier device or similar device to the reactor through an aluminum block inserted in a cylindrical opening just below the reactor. Such an arrangement allows for rapid heating and cooling of the reactor contents.

  parts. The tip includes two sections or parts that are pressure fitted in such a way that leakage at their joints can be limited or eliminated. In one exemplary embodiment, an o-ring can be placed at the interface of the two parts to eliminate the possibility of leakage. Radioactivity testing confirmed that there was little or no material in contact with the o-ring. Thus, in one exemplary embodiment of the present invention, the o-ring can be omitted. The upper part of the chip functions as a “lid” for the reactor. If the lid is designed to be excessively large, the tips can be held together by screws. FIGS. 2A to 2C show one chip so assembled from different viewing angles. It should be noted that the exemplary embodiment of the present invention shown in FIG. 1 includes a single reactor, but more than one reactor can be provided in a single chip. Such means allow for parallel operation of the reaction chambers, which can be used to carry out the same or different reactions.

Bento. The top of the reactor has two openings controlled by individual valves that function as inlets and outlets for nitrogen. When nitrogen is passed over the solution in the reactor, rapid solvent evaporation is possible even at ambient temperatures. Closing both vent channels allows the reactor to function as a “sealed tube”, generate a reaction without solvent evaporation, and superheat the reaction mixture to a temperature above the boiling point of the corresponding solvent Is possible. In another embodiment, the reaction chamber can be pressurized to facilitate the reaction.
Exemplary Embodiment: Use of Chip A to Prepare ¹⁸ F-FDG FIG. 3 is a series of illustrations involved in the synthesis of [F-18] -FDG using a reactor such as the reactor described above. The outline of a typical process is shown. The device described herein allows evaporation to occur in seconds and the total run time is determined by the reactivity of the labeling precursor. By using an exemplary device according to an embodiment of the present invention, the overall FDG growth time has proven to be less than 20 minutes after optimization.

In step 1 where valves 102 and 108 are closed and valves 104 and 106 are open, the target water is passed through ion exchange cartridge 110 to capture F-18 from the diluted solution. In step 2 where valves 104 and 106 are closed and valves 102 and 108 are opened, K ₂ CO ₃ is released into the concentrated solution entering the reactor. After the feed occurs, the valve 108 that controls the F-18 inlet is closed, and in step 3 a K222 / MeCN solution is fed from the channel 112. After the reagents are mixed, nitrogen begins to flow through the port in the reactor ceiling (not shown in FIG. 3). In step 4, the solvent evaporates rapidly, leaving behind a residue containing the [F-18] KF / K222 complex. Since evaporation is generally efficient, there is no need for a subsequent drying step using acetonitrile (MeCN), which was common in conventional systems. In step 5, the precursor (mannose triflate) is delivered through the channel 116 (at ambient temperature) into the reactor. The resulting reaction mixture is heated and boiled for several seconds to achieve mixing and redissolve the residue. Thereafter, all vents are closed and the reaction mixture is heated to 140 ° C. After cooling, the solvent is evaporated by a stream of nitrogen. In step 6, deprotection is performed by bringing ethanolic HCl into the reactor. Ethanol is one solvent that assists in dissolving the hydrophobic residue in acid. Again, the reaction mixture is heated and then the solvent is evaporated leaving behind a residue of FDG. The final product elution step (not shown in FIG. 3) occurs when water enters the reactor from one channel 118 and carries product out of the other channel 120. Optimization studies, theoretical calculations and tests using current chips show that elution is most efficient when the eluent inlet and outlet channels are arranged tangentially to the periphery of the reactor. However, other configurations are possible.

  Remote operation: To be suitable for radiosynthesis, the device must be remotely operated to avoid operator exposure to radioactivity. In one exemplary embodiment, the valve plunger can be moved manually, either during cold operation using trace levels of radioactivity or during test operation. In an exemplary embodiment, an actuator that utilizes pneumatic actuation can be built around the chip to allow manual but remote operation. FIG. 4A shows a diagram of a representative device with a manual (but remote) pneumatic actuator. FIG. 4B shows an actual representative device in which the actuator described above is used. In one configuration, a pair of pressure cylinders mounted on a rigid platform can be driven to cause the plungers to individually enter and exit the tip. This design is relatively easy to implement because it requires only a single gas source and a series of flip switches. Alternatively, a bi-directional air cylinder can be used to move the plunger back and forth.

  The chip described above has been successfully used in the preparation of [F-18] -FDG, which has demonstrated superior performance compared to the previous generation, and in some aspects conventional chemical modules. Surpasses. Table 1 shows typical performance characteristics of the chip in [F-18] FDG radiation synthesis.

  During testing, in an optimized system, using some boiling of the reagent can facilitate mixing of the components or dissolve the residue, but on the other hand it is clear that overheating is important for the reaction itself It has become.

Concentration of F-18: According to another exemplary embodiment of the present invention, in addition to the tip, a capture mechanism can be utilized to complement tip operation. In this device, [F-18] fluoride is captured from ₂ mL of dilute H ₂ ¹⁸ O solution using a small column (eg, 1.5 × 5 mm) packed with AG1-X8 resin, and concentrated K _2. It is released into a CO ₃ solution and the total packed radioactivity is transferred into as little as 5 μL of solvent. This can be achieved by incremental elution. This principle makes use of the F-18 gradient that occurs when K ₂ CO ₃ carries most concentrated F-18 solution was passed through the column at a front. Since the diffusion of F-18 by the solution is so fast, this gradient is not obvious under normal circumstances, when F-18 propagates back through the eluent and can be concentration balanced in just a few seconds. In this setup, F-18 is eluted in increments of 1 μL or less and separated by air, so the fluoride in the first fraction cannot propagate into the second fraction, and so on. is there. Since more than 90% of F-18 is contained in the first few fractions, most F-18 can be transferred into the reactor according to the technique described above. By making the column fully enclosed in PEEK (including frit), further loss of F-18 (as observed when using a stainless steel frit) is reduced or avoided. be able to.

Equipment: To build equipment around this chip, (a) automation and metering of reagent delivery, (b) automation of valve control, (c) heating using a feedback loop and (d) excessive steps Several aspects must be taken into account, such as automating a stepwise process based on process completion rather than timed. A process that addresses the above problems can be accomplished by the exemplary flow diagram of reagent delivery shown in FIG. FIG. 5 shows a series of vials containing K ₂ CO ₃ , K ¹⁸ F / H ₂ ¹⁸ O, KHCO ₃ , NaOH, MeCN, mannose triflate, Kryptofix 2.2.2, HCl and H ₂ O. . These vials are connected to syringe pumps 1-9. FIG. 5 further illustrates delivery routes for various reagents and H ₂ ¹⁸ O waste, raw FDG and municipal waste reservoirs according to an exemplary embodiment of the present invention. A more detailed description of the reagent distribution and delivery mechanism according to an exemplary embodiment of the present invention is provided herein in connection with FIG. Implementation of this scheme in the instrument allows for multiple reaction cycles to be run using intermittent priming of all reagents, reagent delivery to the reactor, product collection, and wash cycles.

  In one embodiment, the tip disclosed herein does not have a membrane that limits the capacity of the reactor, rather the tip has an open vent. Such an arrangement does not require the passage of gas across the membrane, thus allowing rapid filling of the reactor, but the uncontrolled flow of pneumatically operated liquid causes the loss of liquid into the vent. May bring about. Thus, in one exemplary embodiment, pneumatic fluid actuation, which can generate high pressure and lead to excessive reagent consumption and frequent failure, is replaced with a syringe driver based system. Syringe-based systems can accurately meter reagent volumes with minimal waste, are rapid, and do not generate high pressure. Each reagent may have a unique syringe driver that can be programmed to operate at a predetermined time in the radiosynthesis process. FIG. 5 illustrates an exemplary syringe pump that is incorporated into the flow diagram of an exemplary embodiment of the present invention.

  In one exemplary embodiment, the pneumatic valve actuator may be replaced with a solenoid to couple reagent delivery and valve actuation to a robust and compact system. Pneumatic valve actuators require two external valves to control air flow for each on-chip valve, while solenoids require only two wires for proper operation. Further, since only two positions are required for valve actuation (ie, on and off positions), the solenoid provides a suitable actuation choice. FIG. 6 shows six representative solenoids located around the chip. In another embodiment, the solenoids can be arranged in a configuration where they are not coaxial with the tip valve plunger. In one exemplary embodiment, the solenoid can be located below the chip and its heater. In this space-saving configuration, the plunger can be driven by a suitably shaped bracket connecting each solenoid-plunger pair.

  According to another exemplary embodiment of the present invention, the tip shape can be changed from rectangular to hexagonal to more efficiently utilize the space around the tip and allow a wider selection of solenoids. This can provide an equidistant spacing of valves around the tip and a wedge-shaped space for each valve actuator. In addition, such chips are easy to manufacture because they have a high degree of symmetry and allow the use of computer numerical control (CNC) technology that allows the same operation to be repeated six times over the entire surface. It is.

  One exemplary embodiment includes a hexagonal tip having a cylindrical reaction chamber. By way of example and not limitation, a reaction chamber with a diameter of 5 mm and a height of 3 mm can be implemented. The volume of this exemplary reaction chamber is 60 μL, but the maximum liquid volume can be limited to less than the total volume of the reaction chamber (eg, 50 μL) to avoid unintentional liquid loss through the vent. In one embodiment, a number of channels (eg, 6 channels) used for reagent delivery and product elution may enter the reactor horizontally along the reactor floor, but the vent inlet And the exit may enter vertically through the center of the ceiling. Placing the vent near the edge of the tip can cause liquid loss because the meniscus fills the corner between the ceiling and the wall. The vent channel in this exemplary embodiment pivots 90 degrees and connects to a fixture (eg, 10-32) that goes horizontally to the tip. The reactor floor may be curved where the walls meet the floor. In contrast to reaction chambers with sharp corners, the bends designed according to embodiments of the present invention do not have crack initiation points that can cause cracks through the reactor floor.

  The chip according to one exemplary embodiment separates into two components: a “reactor” and a “lid” that breaks off where the ceiling meets the reactor wall. Since the lid may have a circular protrusion that is slightly larger in diameter than the reactor, this can create a tight pressure fit when inserted into the top of the reactor. This configuration is advantageous because it allows the reactor to hold pressures up to several hundred psi. The reactor and the lid can be held together by a plurality of screws that are screwed directly into the reactor part, for example symmetrically arranged around the reactor. In one exemplary embodiment, three screws can be used to perform this configuration. In other embodiments, the tips can be held together by various clamps. In another embodiment, these layers can be permanently bonded together.

  In one exemplary embodiment where all the reagents enter and exit the chip from the bottom of the chip through vertical channels, metal pins cannot be used for reagent (especially [F-18] fluoride) delivery. By preparing a chip-complementary interface base, macro piping and chips can be combined in an efficient manner. Such a base further allows for easy attachment and removal of the chip from the device. FIG. 6 shows such an exemplary embodiment of a tip with a base adapter and six large solenoids around it that pushes and pulls the plunger in and out of the tip. This chip arrangement also allows for easy integration of Peltier-based heating systems, using space above the chip for easy camera access. Further details regarding exemplary embodiments of the present invention relating to lids, reactors and interfaces are disclosed herein.

  FIGS. 15A through 15D illustrate a “lid” portion 1000 of a hexagonal tip according to an exemplary embodiment of the present invention. FIG. 15A shows a bottom view of the lid 1000 with a plurality of first set holes 1002 used to attach the lid 1000 to the “reactor” portion of the chip. FIG. 15A further shows a plurality of second sets of holes 1004 that are used to attach the assembled chip to the “interface”. FIG. 15A also shows a groove 1006 that is used to place the o-ring. FIG. 15B is a cross-sectional view of the lid portion 1000 along the plane AA. FIG. 15B shows the central portion 1008 of the lid 1000 that is pressure fitted into the “reactor portion” of the microreactor. A vent port 1010 with 10-32 fixtures is also shown in FIG. FIG. 15C shows another bottom view of the lid portion 1000 and shows a groove 1006 for holding the o-ring and a central portion 1008 of the lid portion 1000. FIG. 15D shows a top view of the lid 1000 having another view of a plurality of vent ports 1010 with, for example, 10 to 32 fixtures.

  FIGS. 16A through 16D illustrate a “reactor” portion 1100 of a hexagonal tip according to an exemplary embodiment of the present invention. FIG. 16 (A) shows a top view of a reactor section 1100 with a curve 1102 (not shown) that prevents crack formation on a thin floor at the bottom of the reaction chamber. FIG. 16B is a cross-sectional view of the reactor unit 1100 along the plane AA. FIG. 16B shows a curve 1102 along the fluid inlet 1104 that runs from the barrel to the reaction chamber 1108. FIG. 16B further shows a valve plunger barrel 1106 and a reaction chamber 1108 (with a typical capacity of 60 μL). The lid 1000 is pressure fitted into the opening of the reaction chamber 1108 to form a closed cylinder. FIG. 16B further shows a counterbore 1110 for inserting the heater and a plurality of fluid inlets 1112 from the interface to the barrel. FIG. 16C is another top view of the reactor section 1100 and further shows the position of the reaction chamber 1108, the fluid inlet 1104 from the barrel to the reaction chamber 1108, and the valve plunger barrel 1106. FIG. 16D is a bottom view of the reactor unit 1100. FIG. 16D further shows a counterbore 1110 for inserting a heater and a fluid inlet 1112 from the interface to the barrel.

  FIGS. 17A through 17D illustrate an “interface” portion 1200 that complements a hexagonal tip according to an exemplary embodiment of the present invention. FIG. 17A shows a top view of the interface unit 1200 provided with a plurality of holes 1202 for mounting the interface on the device. FIG. 17A also shows a plurality of threaded holes 1204 for attaching the chip, and a through hole 1206 in the center of the interface unit 1200 used for inserting the heater into the chip. FIG. 17B is a cross-sectional view of the interface unit 1200 along the plane AA. FIG. 17C is another top view of the interface unit 1200. FIG. 17C shows a hexagonal tip and a plurality of circular depressions 1210 used to place an o-ring that forms a seal between the tip and the interface 1200 around each port. A square depression 1208 is shown. FIG. 17C further illustrates a plurality of ports 1212 that are used for reagent delivery and product outlet (eg, ¼ to 28 inches in size). FIG. 17 (D) shows a bottom view of the interface portion 1200 with a recess 1214 prepared to increase the contact area of a heat transfer block using a Peltier device.

  FIGS. 18A-C show a combined view of a chip and interface assembly 1300 according to an exemplary embodiment of the present invention. FIG. 18A shows a top view of the coupling assembly 1300. FIG. 18B is a cross-sectional view of assembly 1300 along plane AA. FIG. 18B shows an opening 1302 through which the heating block can be inserted through the interface into the reactor section 1100 and pressed against the reaction chamber floor. Liquid port 1304 and plunger port 1306 are also shown in FIG. FIG. 18C shows a coupling assembly 1300 including a lid part 1000, a reactor part 1100, and an interface part 1200.

  According to another embodiment of the invention, the reagent barrel has a flat end with a flat end that allows the plunger to seal the reactor in a closed configuration and maintain pressures up to several hundred psi. It may be like. There are two types of port arrangements around the reactor. One type has a single inlet near the end of the barrel. These ports can be used to deliver a certain amount of reagents filled into the instrument, such as Kryptofix 2.2.2 and precursors. These ports can also be implemented to allow F-18 to enter the ion exchange column and product to exit. The second type has two ports in the same barrel. Thus, when the plunger is in the closed position, the thinner the central portion of the plunger, the more fluid communication between these two ports is possible. This mechanism allows reagents such as acid and water to be primed directly into the reaction chamber without having to pass through the reaction chamber. Air may be preceded in the channel between the reagent vial and the tip before all or part of the reagent. Air is typically removed through the bypass channel in the priming process. By using a valve according to an embodiment of the present invention, if the liquid is brought all the way to the reaction chamber, the user will immediately You can be sure that it is actually a reagent, not air. The inlet may be located near the end of the barrel closest to the reaction chamber and the outlet may be located further down. When the plunger is in the open position, the first inlet is in fluid communication with the reaction chamber, but the second port is blocked by the plunger. In this state, any dispensed liquid flows into the reactor, while in the closed state, the liquid flows into the waste through the bypass mechanism.

  FIGS. 19A and 19B show an exemplary plunger scale model and method of operation thereof according to an exemplary embodiment of the present invention. A “dual port” plunger is comprised of a plurality of ridges 1402 separated by a thin portion 1404 of the plunger. FIG. 19 (A) shows a scenario where the valve is closed by inserting the plunger all the way to the rightmost position, so that it is pressed against the dead stop 1406 at the end of the barrel. The reaction chamber is sealed and the two vertical portions are now in fluid communication enabled by the combination of a ridge 1402 and a thin portion 1404 on the plunger tip. This configuration allows reagent priming (removing air from the liquid front through the bypass outlet). FIG. 19B shows that by pulling the plunger back from the rightmost position, the valve is opened just enough for the open communication between the first port 1408 and the reaction chamber, while the second port 1410 is still It shows a scenario that remains blocked. The liquid actuated against the first port 1408 can now enter the reaction chamber.

  20 (A) and 20 (B) illustrate an exemplary “dual port” plunger valve 1500 that is not to scale, according to an exemplary embodiment of the present invention. This plunger provides an exemplary configuration of a plunger that can be used in conjunction with FIG. FIG. 20A shows the operation of the plunger valve 1500 in the priming bypass mode. The plunger valve 1500 includes a plunger 1502 that can be inserted into and withdrawn from the barrel 1504. The plunger valve further includes a plurality of ridges 1506 separating the thin portions 1508 of the plunger 1502. As the plunger 1502 is inserted and retracted into the barrel 1504, the bypass outlet 1510 or liquid inlet 1512 port is blocked or exposed, allowing material to flow into and out of the barrel 1502 and the reaction chamber. FIG. 20B shows the operation of the plunger valve 1500 in the open reactor mode, where the liquid inlet 1512 is exposed to allow material to flow to the reaction chamber.

  According to another embodiment of the present invention, the vent can utilize various types of valves. Although similar in principle to a single port valve, the vent valve can utilize an o-ring mechanism to perform the seal. These valves allow large channel cross sections with minimal volume expansion. The expanded capacity is extremely important when using off-chip valves, even when small diameter piping is used. The capacity of the piping can easily double or triple the capacity of the reaction chamber. This results in significant solvent evaporation during the reaction and the disappearance of the reaction mixture into the vent piping during boiling. FIG. 21 illustrates a vent control valve according to an exemplary embodiment of the present invention. The positions of the two valves are shown in FIG. 21, namely (A) the open valve and (B) the closed valve position. These valves are controlled by moving the plunger 902 back and forth, for example by using a two-way pneumatic actuator. FIG. 21 further illustrates the use of a large o-ring 906 disposed within the PEEK plunger tip 904. A large o-ring 906 seals the gas path in the open valve position and prevents gas leakage along the barrel. FIG. 21 further illustrates the use of a small o-ring 908 that is also disposed within the plunger tip 904. A small o-ring seals the reaction chamber from all external gas connections when the valve is in the closed position. FIG. 21 also shows a fixture 910 (eg, size 10-32) used to connect the nitrogen piping and vent outlet piping to the chip.

  An on-chip vent valve according to an exemplary embodiment of the present invention eliminates these problems. They also allow the use of large diameter pipes off-chip and large cross-section channels on-chip, but this increases the gas flow rate over the liquid at low pressures and thus during the evaporation process. The solvent evaporates faster. In one exemplary embodiment, the plunger is driven by an air cylinder, allowing a pressure of several hundred psi in the reactor to be maintained at an operating pressure of less than 100 psi. In one embodiment, the vent can be extended using tubing leading to an external valve.

  In one exemplary embodiment of the invention, the transfer of heat from the heating element located below the reactor to the reactor contents is optimized by selecting an appropriate thickness of the reactor bed. Is done. In one embodiment, the floor thickness is 250 μm. Many of the materials from which chips can be made are thermal insulators (such as PEEK or poly DCPD) rather than conductors. This usually results in a significant temperature drop even when exceeding the 250 μm barrier. In the case of DCPD, the deviation at 180 degrees is about 20 degrees. The reactor section can be constructed using a wide range of materials that combine the following properties: chemical, thermal and radiation stability and manufacturability.

  Furthermore, at least a part of the lid may preferably be transparent. This feature allows visual monitoring of the reaction chamber using a camera. Machine vision techniques can also be used to track changes in the reaction chamber that indicate certain events, such as reaction completion, that can be used to trigger other events. For example, instead of waiting for the evaporation to complete completely and using extra time to ensure that the reactor is dry, a camera can be used to establish a feedback loop. According to this exemplary embodiment, the camera can send a signal to the controller at the moment when the reaction chamber is completely anhydrous, allowing the reactor to cool, stop the gas flow, and fill the precursor Causes the following steps to begin. In the absence of such a feedback mechanism, an estimate of the time required to complete a given process can be obtained by ascertaining the longest observation time required to complete the process and adding about 20% to it. It is necessary to obtain. In such a scenario, even if the process is completed in a shorter period of time, the system still needs to wait for a specified time. Furthermore, if the process takes longer than estimated, the entire synthesis process may be at risk because the next process will begin before the previous process is completed.

  According to another exemplary embodiment of the present invention, the dryness of the reaction chamber can be monitored using a capacitive sensor. Thus, a plurality of conductive probes (eg, three probes) are placed below the bottom end of the reactor that is configured to measure the change in capacitance between the dry and wet reactors. be able to. This sensing mechanism can be used in conjunction with time to assess dryness in the reactor. According to yet another exemplary embodiment, the dryness of the reaction chamber can be monitored using a flow sensor located in a vent line downstream of the chip. The flow rate increases when evaporation begins and decreases to baseline when there is no solvent left in the reactor.

  According to another exemplary embodiment of the present invention, the dryness of the reaction chamber can be monitored using a laser sensor. Therefore, the reflective laser sensor can aim at the bottom end of the reactor and measure the difference in the amount of light returning from the wet reactor and the dry reactor. Additionally or alternatively, a Thru-Beam laser sensor may be used to measure the difference in the amount of light that passes through the reactor in wet and dry reactor conditions. In this configuration, the through beam laser sensor can be arranged, for example, so that the beam of light passes through the bottom end of the reactor from the side.

  A glass lid can provide the desired transparency for incorporating a camera system, but it can be difficult and expensive to make a lid that is entirely made of glass. Thus, according to an exemplary embodiment of the invention, the lid may comprise a glass window in a frame made from a plastic material such as PEEK or DCPD. The window can be pressure fitted into a frame that retains the screw connection. The glass portion may contain, for example, only two channels that can be drilled or etched on the glass.

FIG. 22 shows a glass / PEEK combination lid according to an exemplary embodiment of the present invention. The following description provides specific numerical values and parameters associated with the exemplary lid of FIG. 22, but these numerical values and parameters are not limited to other exemplary embodiments without departing from the scope of the various embodiments of the present invention. May be modified to produce a simple lid. The various parts of the lid shown in FIG. 22 can be identified as follows.
-Two-layer glass chip, total thickness 5mm, hexagonal installation surface, approximate area 10x12mm.
O-ring groove etched into the bottom of the base glass layer (depth 300 microns x width 620 microns); small portion o-ring inserted into the etched groove.
-A channel etched into the bottom of the top layer; this gives a hemispherical horizontal channel to 10 to 32 holes.
• Two 0.6 mm diameter holes drilled through the base layer.
Chips that have been etched, drilled, fused and diced at the wafer level to reduce the cost of volume.

  The tip may be held together by three bolts that fit through holes in the top layer and screw into the bottom layer. The tip may have three more holes that pass through both layers from start to finish. These are used to bolt the chip to the interface layer. This rigid attachment creates a tight seal with the o-ring around the port, allowing liquid to enter and exit the chip through the interface. In other exemplary embodiments, other methods of securing the chip on the interface base may be implemented, including various types of latching. However, the method of bolting the tip to the interface has the advantage that it can be performed simply while saving space.

  The heater can be inserted into the counterbore in the bottom of the chip (“reactor”) through the opening in the interface layer. Tolerances in the various layers can create gaps between 0 and 300 microns anywhere between the heater and the reaction chamber floor. In order to avoid insulating voids, a heat transfer paste can be placed on top of the heater prior to chip insertion. The paste can be removed completely and replaced each time the chip is removed. In alternative embodiments, springs can be placed at various points within the chip-interface assembly. When the spring is placed below the interface layer (a spring that pulls it but does not push it up), the chip lifts the chip when the chip is bolted to the interface, so the chip is placed on top of the heater . This always minimizes the gap between the heater and the chip (guaranteed contact between the two, regardless of the tolerance addition, which may be different in various chip-interface combinations). . This configuration also eliminates the need for heat transfer compounds. To maximize heat transfer to the reaction chamber and to minimize heat transfer to the rest of the chip, significant air gaps around the cylindrical heater may remain. Therefore, any contact between the heater and the chip on the side surface can be avoided by intentionally leaving the insulating gap.

In another exemplary embodiment of the invention, the reagent container is designed to be located above the syringe driver. According to this configuration, it is possible to efficiently generate the suction of the liquid from the bottom of the container and to minimize the length of the piping between the reagent vial, the syringe driver, and the tip. The whole process can be controlled using a visual basic program by means of a PLC (programmable logic control) controller, for example. 7-10 show an exemplary embodiment of a device according to an embodiment of the present invention. Specifically, FIG. 7 shows a representative device including basic components such as a chip, solenoid and PLC controller. FIG. 8 shows an exemplary instrument capable of performing biomarker synthesis and isolation with the instrument cover closed. FIG. 9 shows an exemplary instrument with the cover removed, and FIG. 10 shows an exemplary instrument in which various components and functions associated with the device have also been identified.
Exemplary Embodiments: Synthesis of [ ¹¹ C] -labeled products Limited as an example of a process utilizing carbon 11 labeling agents (eg, methyl iodide, methyl triflate, carbon monoxide, hydrogen cyanide) Instead, the following steps can be performed in the microfluidic device.

a) Accept [ ¹¹ C] -labeling agent from cyclotron target or post-irradiation processor.

b) Generate a solution of reactive [ ¹¹ C] -labeling agent in an organic and / or polar aprotic solvent (acetonitrile, DMF, DMSO, etc.).

  c) providing a solution of the reactive precursor in an organic and / or polar aprotic solvent (acetonitrile, DMF, DMSO, etc.);

d) Using an S _N 2 nucleophilic substitution reaction or other suitable reaction to create new carbon-nitrogen, carbon-oxygen, carbon-sulfur or carbon-carbon bonds, with heat or microwave energy as required. In use, [ ¹¹ C] -labeling agent is reacted with the precursor.

e) Purify the initial [ ¹¹ C] -labeled product, eg, by solid phase extraction or chromatography.

f) The purified initial [ ¹¹ C] -labeled product is reacted with a second reagent (eg, by hydrolysis of the protecting group, if necessary) to produce the final [ ¹¹ C] -labeled product.

g) Purify the final [ ¹¹ C] -labeled product by solid phase extraction or chromatography.

h) Remove the solvent from the [ ¹¹ C] -labeled product.

i) Deliver the final [ ¹¹ C] -labeled product to the final product vial.
Exemplary Embodiment: Control System The following disclosure is a description of apparatus, processes and controls according to various embodiments of the present invention. This instrument is one embodiment of the present invention and allows for the automatic synthesis and purification of multiple types of radiolabeled compounds for use in animal and human positron emission tomography scans.

As shown in FIGS. 7-10, an exemplary instrument according to an embodiment of the present invention includes an aluminum frame; a stainless steel panel enclosure with an inspection port, and:
Programmable logic controller (PLC) for input / output (I / O) control;
High resolution CCD camera and machine vision system for viewing various events in the reactor and for drying and evaporation control;
8 or more automatic precision syringe pumps with low internal volume valves and zero dead volume syringes for precise fluid delivery;
11 high pressure liquid / gas valves for fluid control;
Low internal volume high pressure automatic control loop valve for capture and release on ion exchange columns;
Low internal volume, high pressure automatic control distribution valve for column regeneration and system washing;
Low internal volume high pressure automatic control loop valve for loading crude product into the HPLC injection loop;
A microfluidic chip containing six on-chip valves and a vented reaction chamber for the synthesis reaction;
A thermoelectric module for heating and cooling the reaction chamber;
Manual pressure regulator;
Automatic pressure regulator;
Gas manifold;
5 high pressure solenoid gas valves;
One low pressure solenoid gas valve;
Manual flow control valve;
Liquid vials and bottles;
A laptop PC that executes a visual basic control program for general control of the equipment;
It may include an apparatus consisting of two thermoelectric heaters and coolers, a purification column, on-board HPLC, and a purification system that includes a product separation valve.

  FIGS. 11-13 illustrate exemplary user interface screens for operating a device according to various embodiments of the present invention. In particular, FIG. 11 shows an exemplary input screen for automatic radiation synthesis operation according to one embodiment of the present invention. FIG. 12 is a diagram illustrating an exemplary input screen for manual radiation synthesis operation according to one embodiment of the present invention. FIG. 13 shows an exemplary screen that allows the user to select manual and automatic modes of device operation. One such device has been implemented as a visual basic control program as well as a Siemens Universal Biomarker Synthesis Instrument (Siemens general purpose biomarker synthesizer) that uses a ladder logic PLC to control the device.

This device can be used in one of three modes: (1) Full automation of the process from target water to purified product in injectable formulation with one click of the start button; (2) Pause the user after each synthesis step and which parameter to use in the next step Automating individual processes that allow the user to decide whether to skip the process or stop the process; and (3) the user can control each device in the instrument such as a valve, pressure regulator, syringe, etc. Full manual mode. All modes allow the user to monitor the processes occurring in the chip in real time by observing the output from a camera located above the chip on a separate screen. Machine vision can use the same image to drive a predetermined process sequence in an automated process or give the user an indication of process completion in manual mode.
Exemplary Embodiments: Use of the System to Prepare [ ¹⁸ F] FLT By way of example and not limitation, the following description illustrates various implementations of the invention to prepare [ ¹⁸ F] FLT A set of steps is provided that can be implemented by form. Throughout the following description, reference will be made to the various components shown in FIGS. 14 (A) and 14 (B). All terms mentioned in parentheses (eg, “LV2”) correspond to components similarly displayed in FIG. These two drawings are similar to each other in that they show detailed views of various components and fluid and gas networks according to one embodiment of the present invention. However, FIG. 14 (B) includes further details regarding the purification system disclosed herein. The following description provides specific numerical values and parameters associated with a typical use of the system according to FIG. 14B, but these numerical values and parameters do not depart from the scope of various embodiments of the present invention. It may be modified to use the system. Prior to the synthesis of [18F] FLT, the instrument goes through a wash cycle, and then the system carries the overused reagents (HCl and H ₂ O) through the dead volume bypass system to the chip. (Automatically) must be completed.

About 2.0 mL of radioactive target water containing [F-18] fluoride is placed in a suitable vial (labeled “F18 / H ₂ O (HP)”) before the capture method begins. . The “Rheodyne capture valve” is set to the “capture” position. High pressure nitrogen controlled by the air valve “AV1” is used to drive the target water through an “ion exchange column” that captures and retains [F-18] fluoride while passing strip water over the collection vial. (Labeled “H ₂ O 18 waste”). The “Rheodyne capture valve” is then switched to the “release” position. Next, 15 μL of K ₂ CO ₃ can be aspirated from the “6K ₂ CO ₃ ” vial using “Pump 6” and dispensed towards the “ion exchange column”. A precise amount of nitrogen is then aspirated from the “8-way manifold low pressure” by the “pump 4”, opens the tip valve “Solution 1 F18” and the vent valve “LV2” and then toward 15 μL of K ₂ CO _3. It is dispensed. This nitrogen is used to push K ₂ CO ₃ in the opposite direction through the “ion exchange column”, releasing the trapped [F-18] fluoride, which is then in the microfluidic “chip”. Delivered to the reaction chamber. At this point, the tip valve “Solution 1 F18” is closed and the tip valve “Solution 6 K222” is opened. An accurate amount of nitrogen is aspirated from “8-way manifold low pressure” by “Pump 7” and dispensed into a “K222” vial containing a pre-weighed amount (eg, 35 μL) of Kryptofix 2.2.2. And is used to move Kryptofix 2.2.2 into the reaction chamber. The tip valve “Solution 6 K222” is closed and the reaction chamber is then prepared for the next step which is a fluoride drying / H ₂ O evaporation step.

Fluoride drying / H ₂ O evaporation: “Automatic pressure regulator” set to 15 psig, tip thermoelectric module “TEM1” temperature set to 110 ° C., tip vent valve “LV2” opened from previous process The tip nitrogen valve “LV1” is opened, a timer is set, and the fluoride drying and H ₂ O evaporation processes are started. The 15 psig pressure starts at 1 psig and is increased by 1 psig every 3 seconds until 15 psig is reached. The pressure is controlled by an “automatic pressure regulator”. The precise degree of drying is determined by adding feedback from the machine vision system using a timer. In a machine vision system, several boxes within the viewing angle of the reactor are programmed with red, green, blue, hue, saturation, and brightness values for each box when wet and dry. These numbers plus time are used to determine the level of dryness. Then, the tip nitrogen valve “LV1” is closed.

  The machine vision system (not shown in FIG. 14) is equipped with a high resolution camera and specially designed software to monitor the reaction chamber, provide feedback, and initiate subsequent steps of the process by feedback. Enable.

  After drying, the tip vent valve “LV2” remains open. The tip valve “Solution 2 Precursor” is opened and a precise amount of nitrogen is aspirated from “Pump 8”, dispensed towards the “Precursor” vial, and used to move the precursor into the reaction chamber. . Note that the “precursor” vial contains a pre-weighed amount (40 μL) of precursor. The tip valve “Solution 2 Precursor” is closed after the entire volume has been delivered to the tip. The tip vent valve “LV2” is closed and the reaction chamber is prepared for the next step which is the fluorination step.

  Fluorination: Open “LV1”, set pressure to 15 psi with “automatic pressure regulator”, then set pressure in reaction chamber by closing “LV1”. With all the chip valves closed, the chip thermoelectric module “TEM1” is set to 140 ° C. and the timer is set to 180 seconds. At the end of the timer period, the temperature is lowered to 60 ° C. by “TEM1”. “LV1” is then opened, the pressure is reduced to 0 psi by an “automatic pressure regulator”, and then “LV1” is closed. The acetonitrile evaporation process then begins. Pressurizing the reactor at a small pressure, such as 15 psi, suppresses solvent evaporation and boiling, which causes product decomposition or loss of reactants into the vent. In another embodiment, application of high pressure further improves the reaction rate, resulting in higher yields.

  Evaporation of acetonitrile: “Automatic pressure regulator” is set to 3 psig, tip thermoelectric module “TEM1” temperature is set to 60 ° C., tip vent valve (“LV2”) is opened, tip nitrogen valve (“LV1”) Is opened, the timer is set to 17 seconds, and the acetonitrile evaporation process is started. The 3 psig pressure starts at 1 psig and is increased by 1 psig every 3 seconds until 3 psig is reached. The exact amount of dryness is determined by adding feedback from the machine vision system using a timer. In a machine vision system, several boxes within the viewing angle of the reactor are programmed with red, green, blue, hue, saturation, and brightness values for each box when wet and dry. Using these numbers plus time, the dryness is determined. The tip nitrogen valve (“LV1”) is closed while the tip vent valve (“LV2”) remains open. The evaporation of acetonitrile is designed to be only partial to clean enough space for the acid. If the evaporation is allowed to proceed completely, it is impossible to dissolve the organic residue in the acidic aqueous solution without stirring.

  Filling with HCl: The chip thermoelectric module “TEM1” is left at 60 ° C. and the “automatic pressure regulator” is set to 0 psig. 30 μL of 3N HCl is then aspirated from the “HCl” vial using “Pump 3”, the tip valve “Solution 5 HCl” is opened, and then 30 μL of HCl is dispensed into the reactor. The tip valve “Solution 5 HCl” is closed and the tip vent valve (“LV2”) is closed.

  Hydrolysis: With all tip valves closed, “TEM1” is set to 100 ° C. and the timer is set to 180 seconds. After 180 seconds, the hydrolysis process ends and the elution process begins. In the case of FLT, the pressure remains at 0 during hydrolysis, but other processes that require higher temperatures and pressures during this step are performed during hydrolysis and during fluorination. The increased pressure can be maintained in a similar manner as is done, but it must be reduced to zero before the elution step. Leaving the pressure at 0 during the hydrolysis process allows for a mild boiling of the reaction mixture, which helps to mix the components without loss of liquid into the vent channel.

Elution: “Automatic pressure regulator” remains at 0 psig, “TEM1” stays at 60 ° C., tip vent valve (“LV2”) closed, tip nitrogen valve (“LV1”) closed, and 2 0.0 mL of H ₂ O is withdrawn from the “H ₂ O” vial by “Pump 5”. The tip valve “Solution 3 H ₂ O” is opened, the tip valve “Solution 4 EXIT” is opened, and 2.0 mL of H ₂ O depends on the position selected for the “injection loop valve”. The raw product is eluted into either the “raw product vial” or the “injection loop”. The tip valve “Solution 3 H ₂ O” is closed and then the tip valve “Solution 4 EXIT” is closed. If the product is delivered to a “raw product vial”, it can now be removed from the system and analyzed.

  Purification: Once the product is eluted into the “injection loop”, the “injection loop valve” must now be switched from the “chip” to the “HPLC” position. The “HPLC pump” then begins to push the raw product into the “HPLC column”. Since the column separates various compounds in the raw product stream, they are removed from the column with various retention times (HPLC). The system is programmed to automatically detect and isolate known compounds, such as FLT, while executing a pre-programmed gradient, process or isocratic program. Radiation detectors and UV detectors with a “detection / isolation module” monitor the liquid leaving the column, and a valve directs the purified product into the “purified product” vial, Used to direct the remaining liquid to a “general waste” vial.

In another embodiment, a reaction chamber is used in place of the injection loop to minimize product transfer (and loss), and an HPLC pump is plumbed directly to one of the chip inlets, while The outlet is connected directly to the HPLC column. This arrangement eliminates the need for an injection loop. Table 2 shows representative performance characteristics associated with the chip in [F-18] FLT radiation synthesis.

  Finally, there is a cleaning step that performs ion exchange column regeneration and microfluidic chip cleaning prior to the next run.

Column regeneration: 1.0 mL of KHCO _{3 with} high pressure nitrogen valve “AV3” switched on and pre-filled into “KHCO ₃ (HP)” vials is equipped with a “Rheodyne capture valve” in the “capture” position. Driven through "ion exchange column". The “AV3” valve is switched off when the last small amount of liquid passes through the interface detector downstream from the “Rheodyne capture valve”. The “AV2” high pressure valve is now switched on and 2.0 mL of H 2 O is forced out of the “H 2 O (HP)” vial through the column. Nitrogen is then passed through the column for drying. “AV2” is then switched off.

Chip cleaning is a series of steps to prepare the system for the next run. This can be achieved without manual operation without the need to open the shield. In one exemplary embodiment, chip cleaning can be performed by the following steps. Initially the acid line is flushed with N ₂ and all the acid is removed to waste. The acid line and reaction chamber are then flushed with water and then N ₂ to remove traces of acid. The K ₂ CO ₃ line and reactor are then flushed with water and then with N ₂ . Next, Kryptofix 2.2.2 line, with acetonitrile, then flushed with N _2. Next, the precursor of the line is flushed with acetonitrile and N _2, this time, the solvent exits the tip through the crude product line to flush the HPLC injection loop. Finally, N ₂ flows through both the Kryptofix 2.2.2 and precursor vials and exits from the reactor outlet line and vent outlet while heating to ensure the reactor is dry. When all of the valves are closed and the pressure is released, the system is ready for the next run.
Exemplary Embodiment: Purification and Formulation System FIGS. 23-27 illustrate various components and processes associated with purification and formulation according to an exemplary embodiment of the invention. These systems can be integrated into the same equipment because the synthesis or the following modular design approach can be combined into individual equipment that complements the synthesis equipment. FIG. 23A shows a representative diagram for transferring the sample from the tip to the sample fill loop. The sample filling valve of FIG. 23 (A) is in the filling position. FIG. 23 (B) shows sample injection from the sample loading loop into the C18 column (or any other HPLC column). The sample filling valve of FIG. 23 (B) is in the injection position. Thus, the sample components are separated in a C18 column and continuously detected using radiation and UV detection systems. The desired sample fraction can be collected while the rest can be treated as waste. In another embodiment, several fractions can be collected individually by using additional dispensing valves in the product line beyond the UV detection module.

  FIG. 24 shows an exemplary radiation detection module based on a CsI (TI) luminescent crystal / photodiode combination shielded with a lead housing. The UV detection and sample collection module can be built on the same substrate. The UV detection system is composed of a light source, a CCD spectrometer, and an optical fiber. Fraction collection can be controlled using a three-way solenoid valve. FIG. 25 is a top view showing the internal structure of the detection / sample collection module. An exemplary radiation detection module is based on a CsI (TI) light emitting crystal / photodiode combination that is shielded with a lead housing. UV detection and sample fraction can be built on the same substrate. The UV detection system is composed of a light source, a CCD spectrometer, and an optical fiber. Fraction collection can be controlled using a three-way solenoid valve.

FIG. 26 shows a representative solvent removal module. Fraction vial heating and nitrogen flow facilitate solvent removal. As shown in FIG. 26, the removed solvent is first condensed in a cold trap and then captured in a charcoal vial. FIG. 27 illustrates another exemplary embodiment where the solvent is removed from the product using a C18 cartridge. In FIG. 27A, the fraction vial is pre-filled with excess water that dilutes the sample fraction. Using nitrogen, the diluted sample fraction is passed through a C18 cartridge that captures the desired product. More water can be delivered through the sample fraction line to wash away residual solvent from the C18 cartridge. In FIG. 27 (B), the valve is switched so that a small amount of ethanol flows through the cartridge to release the captured product, and the product is then brought to an injectable EtOH / H ₂ O ratio. Diluted with water.

  All references cited herein are incorporated by reference as if each was individually referenced and incorporated herein in its entirety. In describing embodiments of the present invention, specific terminology is used for the sake of clarity. However, it is not intended that the present invention be limited to the specific terms so selected. In this specification, no description should be taken as limiting the scope of the invention. All examples presented herein are representative and non-limiting. The embodiments described above can be modified or changed without departing from the invention, as will be appreciated by those skilled in the art in light of the above teachings. Thus, it is to be understood that within the scope of the following claims and their equivalents, the present invention may be practiced otherwise than as specifically described herein.

Claims (52)

Reaction chamber;
One or more flow channels connected to the reaction chamber;
One or more vents connected to the reaction chamber; and one or more integrated valves for performing flow control into and out of the reaction chamber;
A microfluidic chip for radiosynthesis of radiolabeled compounds.   The chip according to claim 1, wherein the reaction chamber is located inside a reactor part and a lid part of the chip fitted with pressure.   The chip according to claim 2, wherein at least a part of the lid is transparent.   The chip according to claim 2, wherein the lid includes a glass window in a frame.   The chip of claim 2, further comprising an interface configured to perform delivery of product to the reaction chamber.   The chip according to claim 5, wherein the interface is connected to the reactor section.   The chip according to claim 1, wherein the floor of the reaction chamber includes a curved portion.   The chip according to claim 1, wherein the chip has a hexagonal shape.   The chip according to claim 1, further comprising a heater for heating the reaction chamber.   The chip of claim 9, wherein the heater comprises at least one of a heating element, a resistance heater, a radiator, a microwave heater, and a laser device for remotely delivering heat to a reaction chamber.   The chip according to claim 9, wherein the heater is connected to the chip through an opening in a bottom surface of the chip.   The chip according to claim 11, wherein the heater is separated from the side wall of the opening by a gap.   The chip of claim 9, wherein the heater is separated from the reaction chamber by a portion of about 250 microns.   The chip according to claim 13, wherein the portion contains a doped DCPD material.   The chip of claim 1, wherein the valve is controlled by a pneumatic actuator or solenoid.   The tip of claim 1, wherein the valve comprises a dual port plunger with one or more narrow sections separated by one or more ridges.   The tip of claim 1, wherein the valve comprises a plunger with a thin metal portion, a tip, and one or more o-rings modified to prevent gas leakage from the reaction chamber.   The chip according to claim 1, further comprising an ion exchange column integrated with the chip.   The chip according to claim 1, further comprising an HPLC integrated with the chip.   The chip according to claim 1, further comprising an HPLC integrated in an interface part of the chip.   The chip according to claim 1, wherein the reaction chamber has a cylindrical shape and a capacity of about 60 μL.   The tip according to claim 1, wherein the tip is configured as a closed system without a pipe extension.   The chip of claim 1 further modified to communicate with a fluid and gas delivery and removal network.   24. The tip of claim 23, wherein one or more syringes are used to deliver at least one fluid or gas to the tip.   25. The tip of claim 24, wherein the syringe is placed below one or more vials with liquid contents to perform efficient delivery of liquid to the tip.   25. The tip of claim 24, wherein the syringe is used to deliver gas to the tip.   24. The chip of claim 23, wherein the network is modified to operate with at least one of prefilled individual vials and prepackaged cartridges.   28. The chip of claim 27, wherein the cartridge contains a pre-weighed amount of reagent sufficient for a single use with the chip.   24. The chip of claim 23, wherein controlled delivery of liquid is performed by a step-wise increase in pressure on the closed vent.   The chip according to claim 1, wherein solvent evaporation and vapor removal are performed by flowing a gas over the solution in the reaction chamber.   The chip according to claim 30, wherein the gas is nitrogen.   The chip according to claim 1, wherein overheating of the contents of the reaction chamber is performed by closing the vent and heating the reaction chamber with a heater.   33. The chip of claim 32, further comprising pressurizing the reaction chamber before applying the heater.   The chip according to claim 1, further comprising an integrated solvent removal module. Microfluidic chip;
A reagent source in fluid communication with the chip and containing at least one reagent;
Fluid delivery and removal network;
A controller modified to control the operation of the network; and a local radiation shield for shielding one or more radiation-critical components of the device;
Portable device for automated radiosynthesis of radiolabeled compounds.   36. The device of claim 35, further comprising a camera for monitoring a reaction chamber in the microfluidic chip.   37. The device of claim 36, further comprising a machine vision system that is modified to recognize completion of one or more steps based on information received from the camera.   38. The device of claim 37, wherein the second step is started as soon as the first step is completed.   36. The device of claim 35, wherein the device is configured to operate in a batch mode.   36. The device of claim 35, wherein the device is configured to operate in a flow through mode.   36. The device of claim 35, wherein the device is configured to operate in a batch-overflow mode.   36. The device of claim 35, wherein the local shielding is performed on at least one of an ion exchange column and an F-18 source.   36. The device of claim 35, wherein the controller comprises a programmable logic controller and a user interface.   44. The device of claim 43, wherein the user interface is configured to perform at least one of manual operation and automatic operation of the device.   36. The device of claim 35, further comprising one or more internal filters for removing exhaust.   36. The device of claim 35, wherein the local occlusion prevents exposure of the user to radiation in multiple synthetic runs performed by the user.   36. The device of claim 35, wherein all of the filled reagent is consumed by a zero waste system.   36. The device of claim 35, further modified to efficiently elute [F-18] fluoride from an ion exchange column.   36. The device of claim 35, further comprising self-metering of the reagent.   36. The device of claim 35, wherein the controller is modified for fully automatic operation of the device. Introducing one or more reagents into the microfluidic chip;
Where the chip is
A reaction chamber;
One or more flow channels connected to the reaction chamber;
One or more vents connected to the reaction chamber;
One or more integrated valves for controlling the flow into and out of the reaction chamber,
Treating said reagent to produce a radiolabeled compound; and collecting said radiolabeled compound;
A method for radiosynthesis of radiolabeled compounds. The program code comprises instructions for causing the controller to perform a method for radiosynthesising a radiolabeled compound using a microfluidic chip:
The method
Introducing one or more reagents into the reaction chamber;
Activating a synthesis system to process the reagent in response to a predetermined algorithm to produce a radiolabeled compound; and collecting the radiolabeled compound;
Program code implemented on a computer readable medium.

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