DESCRIPTION MULTI-PURPOSE AUTOMATED RADIOTRACER SYNTHESIZER
This patent application claims priority to, and incorporates by reference in its entirety, U.S. Provisional Patent Application Serial No. 60/517,439 filed on November 5, 2003.
BACKGROUND OF THE INVENTION
1. Field of the Invention The invention relates generally to the field of radiotracer synthesizers. More particularly, the invention relates to a multipurpose automated radiotracer synthesizer.
2. Discussion of the Related Art Positron emission tomography (PET) and Single Positron Emitting Computed Tomography (SPECT) are examples of in vivo imaging methods which use gamma radiotracers to track the biochemical, molecular, and or pathophysiological processes in humans and animals. In PET and SPECT systems, positron-emitting isotopes serve as beacons for identifying the exact location of diseases and pathological processes under study without surgical exploration of the human body. With these non-invasive imaging methods, the diagnosis of may be more comfortable for patients, as opposed to the more traditional and invasive approaches, such as exploratory surgeries. Some of the available gamma radiotracers are produced from a cyclotron (F-18) process. A cyclotron system accelerates charged particles to high speeds and cause these charged particles to collide with a target to produce a nuclear reaction and subsequently create a radioisotope. However, the cyclotron-based tracers are constrained by the availability of local cyclotron and the cost of production. Another method for producing radiotracers is from a generator process. The generator process uses a parent-daughter (P/D) nuclidic pair where the parent (P) isotope decays to a shortlived daughter (D) isotope used for imaging. However, the current generator-based radiotracers are limited by the half-life of radioisotopes and the limited choices of imaging agents. For example, the copper-62 generator produces a Cu-62 based radioisotope has a half life of less than 10 minutes. As known in the art, radiosynthesis of radiotracers must be rapid because the usable
amount of the radioisotope will decay with lengthy chemical synthesis and can cause a higher risk of radiation exposure during the production process. h the past few years, several PET and SPECT radiotracer synthesizing apparatuses (black boxes) have been made commercially available that reduce radiation exposure and health hazards. However, at present, hardware and software for commercially available black boxes cannot be modified for different chemistries and/or processes, hi addition, these black boxes are not designed for both diagnostic and therapeutic radiopharmaceutical agents' production. The referenced shortcomings are not intended to be exhaustive, but rather are among many that tend to impair the effectiveness of previously known techniques concerning image reconstruction; however, those mentioned here are sufficient to demonstrate that the methodologies appearing in the art have not been satisfactory and that a significant need exists for the techniques described and claimed in this disclosure.
SUMMARY OF THE INVENTION
There is a need for the following embodiments. Of course, the invention is not limited to these embodiments. In one respect, the invention includes a system for producing radiotracers. The system may include an isotope preparation unit which may produce an isotope from a cyclotron isotope unit, a single dose isotope unit, or an isotope generator. The isotope may be transferred via a flow unit to a synthesizer unit. The synthesizer may synthesize radiotracers using the isotope, where the synthesizer unit is configured to process both water soluble agents and oil soluble agents. In another respect, the invention includes a method for producing radiotracers. The method includes providing an isotope, h one embodiment, the isotope may be provided from a cyclotron. In another embodiment, the isotope may be provided from an isotope generator. Alternatively, the isotope may be a single-dose isotope. The isotope may be transferred to a synthesizer, where the synthesizer is capable of synthesizing both water soluble and oil soluble agents. A regent may be added to the isotope to create an agent and the agent may be synthesized to produce a radiotracer. In other respects, a method is provided where the method includes providing a configurable system. The configurable system may include a plurality of configurable components for producing both water soluble and oil soluble agents. The method includes
operating the configurable system to produce an isotope, such as a cyclotron-based isotope, a generator based isotope, or a single dose isotope. Next, the method operates the configurable system to add at least one reagent to the isotope to produce an agent. The method may also include operating the configurable system to perform a hydrolysis process on the agent to produce a radiotracer. These, and other, embodiments of the invention will be better appreciated and understood when considered in conjunction with the following description and the accompanying drawings. It should be understood, however, that the following description, while indicating various embodiments of the invention and numerous specific details thereof, is given by way of illustration and not of limitation. Many substitutions, modifications, additions and or rearrangements may be made within the scope of the invention without departing from the spirit thereof, and the invention includes all such substitutions, modifications, additions and/or rearrangements.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawings accompanying and forming part of this specification are included to depict certain aspects of the invention. A clearer conception of the invention, and of the components and operation of systems provided with the invention, will become more readily apparent by referring to the exemplary, and therefore nonlimiting, embodiments illustrated in the drawings, wherein like reference numerals (if they occur in more than one view) designate the same or similar elements. The invention may be better understood by reference to one or more of these drawings in combination with the description presented herein. It should be noted that the features illustrated in the drawings are not necessarily drawn to scale.
FIG. 1 is a block diagram of a multipurpose automated radiotracer synthesizer system, according to an embodiment of the invention.
FIG. 2 is a block diagram of a synthesizer unit of the system in FIG. 1, according to an embodiment of the invention.
FIG. 3 is an exploded view of the synthesizer unit, according to an embodiment of the invention.
FIGS. 4-31 are graphical user interfaces showing program steps for a [18F]FDG synthetic protocol with [18O]H2O recovery system, according to an embodiment of the invention.
FIGS. 32-53 are graphical user interfaces showing program steps for a [123I]Iodomisonidazole synthetic protocol, according to an embodiment of the invention.
FIGS. 54-61 are graphical user interfaces showing program steps for a [64Cu]EC-Guanine synthetic protocol, according to an embodiment of the invention.
DETAILED DESCRIPTION
The invention and the various features and advantageous details thereof are explained more fully with reference to the nonlimiting embodiments that are illustrated in the accompanying drawings and detailed in the following description. It should be understood that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only and not by way of limitation. Various substitutions, modifications, additions and/or rearrangements within the spirit and/or scope of the underlying inventive concept will become apparent to those of ordinary skill in the art from this disclosure. The invention may include a method and system for a multipurpose automated radiotracer synthesizer (MARS). The MARS may utilized multiple radioisotopes from gas, water, or solid targets, hi one configuration, the multipurpose automated radiotracer synthesizer may synthesize a water-soluble radiotracer. In another configuration, the multipurpose automated radiotracer synthesizer may synthesize an oil-soluble radiotracer. In yet another configuration, the multipurpose automated radiotracer synthesizer may synthesize both water-soluble and oil- soluble radiotracers. As one of ordinary skill in the art will recognize in light of this disclosure, the water-soluble and/or oil-soluble radio tracers synthesized by the multipurpose automated radiotracer synthesizer of the present invention may have diagnostic and/or therapeutic utility, hi addition, although the present disclosure presents several specific configurations that are capable of synthesizing different respective radio tracers, it will be appreciated that these specific configurations are given as nonlimiting examples, and that other configurations capable of producing other radio tracers are also contemplated by the present invention.
Referring to FIG. 1, a block diagram of a multipurpose automated radiotracer synthesizer system 100 is shown. System 100 may include isotope preparation unit 10, flow unit 20, and synthesizer unit 30. The isotope preparation unit 10 may include cyclotron unit 11 for cyclotron- produced isotopes unit including, but not limited to 18F, nC, and 6 Cu. Cyclotron unit 11 may include cyclotron target 14, which may provide various isotopic forms (e.g., solid, gas or liquid). Coupled to cyclotron target 14 may be extraction unit, ion exchange column 12, and cold trap 15. Extraction unit 12 may extract solid metallic substances such as nickel-61 for copper-61 from solid targets. Ion-exchange column unit 13 may include anion exchange column to recover oxygen- 18 water and trap fluoride ion. Cold trap unit 15 may include trap of carbon- 11 methyliodide or carbon dioxide. Isotope preparation unit 10 may also include single-dose isotope unit 16 for single-injection based isotopes which may provide isotopes including, but not limited to I, Ga, and In. Isotopes from single-dose isotope unit 16 may include isotopes without further purification or extraction such as indium-I ll chloride, gallium-67 chloride and may be ready for radiopharmaceutical synthesis. Additionally, isotope preparation unit 10 may include generator 18 coupled to saline elution unit 19 for producing saline-based isotopes such as, but not limited to Re and Tc. Elution unit 19 may include an aluminum column or ion exchange column to improve isotope purity. It is noted that isotope preparation unit 10 may include any combination of cyclotron unit 11, single-dose isotope unit 16, and generator 18. For example, isotope preparation unit 10 may include only a cyclotron unit. Similarly, isotope preparation unit 10 may include only a single- dose isotope unit or only a generator coupled to an elution unit. Alternatively, isotope preparation unit 10 may include a cyclotron unit and a single-dose isotope unit or a cyclotron unit and a generator coupled to an elution unit or a single-dose isotope unit and a generator coupled to an elution unit. System 100 of FIG. 1 may also include flow unit 20. It is noted that several flow units may be coupled in series for selected synthesis pathways and/or depending on the complexity of the chemical reaction. The isotope from isotope preparation unit 10 (e.g., a cyclotron produced isotope, a generator produced isotope, or a unit dose isotope) may be provided to valve assembly 21. Coupled to the valve assembly 21 may be vacuum 25 and charcoal trap 22 which may trap, collect, and vent waste (e.g., hazardous waste) from the flow unit. Nitrogen (N2) gas, which may be stored in a gas chamber 24, may be provided to valve assembly 21 which may aid in the transfer, mixing, or evaporating of the chemical compounds or solvents, drugs, and/or other
products through the system 100. Additionally, a plurality of reagents, which may be housed in a reagent unit 23, may also be provided to valve assembly 21, the reagents may include chemical compounds, drugs, and/or other components needed to produce a radiopharmaceutical agent. System 100 may also include synthesizer unit 30 for synthesizing radiotracers and configured to process both water-soluble and oil-soluble agents during the synthesis process. In one embodiment, for an oil-soluble agent, the isotope, provided from flow unit 20 may be provided to a displacement unit 31 which may add a reagent, such as a pro-drug, to the isotope. The resulting oil-soluble agent may be provided to an extraction unit 32 for extracting the organic solvent from the oil-soluble agent. Next the oil-soluble agent may be provided to hydrolysis unit 33 which may perform a hydrolysis or de-protection function, yielding a radiotracer. Alternatively, synthesizer unit 30 may synthesize water-soluble agents, hi one embodiment, displacement unit 31 may receive an isotope from the first valve assembly 120 and may add a reagent, such as pro-drug to the isotope. The resulting water-soluble agent may be provided to hydrolysis unit 33 which may perform a hydrolysis or de-protection function, yielding a radiotracer. Any unreacted tosylated, mesylated or triflated precursors and/or certain protected functional groups such as amine, carboxylic acid or hydroxy groups may be removed during hydrolysis and column purification steps. Coupled to system 100 may be computing device 105 and controller 115. The computing device 105 may executes a program of instructions stored in the program storage device (shown in FIG. 2) and sends commands to the controller 115. As such, system 100 may be configurable, reconfigurable, and controllable via a software graphical user interface (GUI) depending on the configuration (e.g., producing a water-soluble or a lipid-soluble agent). It is noted that system 100 may also include a plurality of configurable valve assemblies, radiotracer mixing vials, fluid conduit unit, a heater, and other radiotracer synthesizer components. Referring to FIG. 2, a block diagram of a multipurpose automated radiotracer synthesizer unit 300 is depicted according to an embodiment of the invention. A computing device 105 may be coupled to a program storage device 110 and to a controller 115. The controller 115 may be coupled to a first valve assembly 120, a second valve assembly 125, a third valve assembly 130, a heater 135, a vacuum pump 140, and a turntable 145. The first valve assembly 120 may also be coupled to the second valve assembly 125 through 2-way valve 121, and the second valve assembly 125 may be coupled to the second valve assembly 130 through 2-way valve 122. The
vacuum pump 140 may be coupled to valve assemblies 120, 125, and 130. The controller 115 may be coupled to the valve assemblies (120, 125, and 130), the 2-way valve elements (121 and 122), the heater (135), the vacuum pump (140) and the turntable (145) through a set of electrical relays. Additionally, the valve elements (120, 125, and 130), the 2-way valve elements (121 and 122), the heater element (135), the vacuum pump (140) and the turntable (145) each may be coupled to a power supply (not shown). It will be understood that other configurable components may also be included in synthesizer unit 300. The computing device 105 may execute a program of instructions stored in the program storage device 110 and sends commands to the controller 115. The controller 115 may, for example, open, close or change the state of one or more valves in one of the valve assemblies 120, 125, and 130, control the heater 135, the vacuum pump 140, and/or the turntable 145, as a function of the program instruction. The computing device 105 may present a user with a graphical user interface (GUI) for controlling each element of synthesizer unit 300. For example, programs including the steps for synthesizing l^F- Fluorodeoxyglucose (l^F-FDG, a tumor metabolism tracer), l^j.jo o^gofljda^oie (a tumor hypoxia tracer) or 61Cu-guanosine (a tumor proliferation tracer) are detailed in FIGS. 4-31, 32-53, and 54-61, respectively. One of ordinary skill in the art will recognize in light of this disclosure that other programs may be used to synthesize other radiotracer agents, including, but not limited to, the radiotracers listed in Table 1.
The vacuum pump 140 may be used for waste collection and/or venting. A power supply may supply current drive to the valve assemblies 120, 125, 130 and turntable 145. The controller 115 may include, for example, two 24-channel parallel I/O cards for operating relays by software. The computing device 105 may be, for example, a personal computer or a laptop computer. The computing device 105 may also be a programmable circuit, such as, for example, a microprocessor or digital signal processor-based circuit, that operates in accordance with instructions stored in the program storage media 110. The program storage media 110 may be any type of readable memory including, for example, a magnetic or optical media such as a card, tape or disk, or a semiconductor memory such as a PROM or FLASH memory. The controller 115 may be, for example, a programmable logic controller. The valve assemblies 120-130 may each include, for example, a plurality of valves, rotary valves, and the like. The heater 135 may be, for example, an infrared spot heater. The turntable 145 may be. for example, a turning motor for rotating a reaction tube carousel.
In one embodiment, the multipurpose automated radiotracer synthesizer unit 300 may be used for synthesizing a lipid-soluble agent. In this case, the first valve assembly 120 may perform, for example, a displacement function for adding isotopes, the second valve assembly 125 may perform, for example, an organic solvent extraction function, and the third valve assembly 130 may perform, for example, a hydrolysis or de-protection function. In another embodiment, the multipurpose automated radiotracer synthesizer unit 300 may be used for synthesizing a water-soluble agent. In this case, the first valve assembly 120 may perform, for example, a displacement function for adding isotopes, the second valve assembly 125 may perform, for example, a hydrolysis or de-protection function, and the third valve assembly 130 may unused. Referring to FIG. 3, an exploded view of the multipurpose automated radiotracer synthesizer unit 300 detailed in FIG. 2 is depicted according to an exemplary embodiment of the invention. A top unit 201, a bottom unit 202, a back unit (not shown), and front unit 205 form an enclosure, which may be a lead-shielded chassis. Each of the valve assemblies (120, 125 and 130) may be mounted on cards that slide in and out of the chassis. A printed circuit board (PCB) backplane may be used to connect solenoid valves on each valve assembly (120, 125, and 130) to the relay circuits. Two-way valves 121, 122 couple the valve assemblies 120, 125, and 130 for transferring products among each other. The computing device 105 is coupled to a control module 116 of controller 115, which may also include a direct logic module 117 and a set of output modules 118, each output module being coupled to a valve assembly 120, 125, and 130. The valve assemblies 120, 125, and 130 may be coupled through tubes and/or fittings to a set of bottles and/or vials 215 in the front unit 205 and to the vacuum pump 140. A shade unit 210 may be used to reflect or to absorb heat from heater 135. The turntable 145 may be coupled to a reaction tube carousel 206.
EXAMPLES
The following examples are included to demonstrate specific embodiments of this disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute specific modes for its practice.
However, those of skill in the art should, in light of the present disclosure, appreciate that many
changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Referring to FIGS. 4-61, screen captures of graphical user interfaces (GUIs) shows program steps for synthesizer unit 30, 300 of FIGS. 1 and 2, respectively, and the synthesis protocol for specific radiotracers. In each of FIGS. 4-61, the valve state for each of the valves is shown, and the states of the heater, vacuum pump, and turn table are indicated. For example, in FIG. 4, valves 1 A0 and 1 A2 are "on", and valves 1 Al and 1 A3 are "off.
Example 1 - Water Soluble Agent: [ FJFDG Synthesis Referring to FIGS. 4-31, graphical user interface figures showing program steps for a [18F]FDG synthetic protocol with [18O]H2O recovery system are depicted illustrating an aspect of the invention, i a first step shown in FIG. 4, 18F from target/18O recovery is added into bottle 1. In the next step shown in FIG. 5, K CO3/collect 18F is added in vial #1. In the next step shown in FIG. 6, K2CO3 is evaporated under N2 and vacuum, hi the next step shown in FIG. 7, CH CN is added into vial #1. hi the next step shown in FIG. 8, CH CN is evaporated under N and vacuum. In the next step shown in FIG. 9, CH3CN is added into vial #1. In the next step shown in FIG. 10, CH3CN is evaporated under N2 and vacuum. In the next step shown in FIG. 11, triflate/CH3CN is added into vial #1. In the next step shown in FIG. 12, vial #1 is heated, performing an 18F-exchange. In the next step shown in FIG. 13, CH3CN is evaporated under N2 and vacuum, h the next step shown in FIG. 14, 0.25ml CH3CN and 5ml H2O are added into vial 1. In the next step shown in FIG. 15, a solution is transferred from vial #1 to bottle #5 (waste). In the next step shown in FIG. 16, 3ml H O are added into vial #1. hi the next step shown in FIG. 17, the solution is transferred from vial #1 to bottle #5 (waste), hi the next step shown in FIG. 18, 3ml HCl (0.1N) are added into vial #1. In the next step shown in FIG. 19, a solution is transferred from vial #1 to bottle #5 (waste). In the next step shown in FIG. 20, 3ml THF are added into vial #1. h the next step shown in FIG. 21, the solution is transferred from vial #1 to vial #2. hi the next step shown in FIG. 22, THF is evaporated under N2 and vacuum, hα the next step shown in FIG. 23, 2ml HCl (2N) are added into vial #2. In the next step shown in FIG. 24, vial #2 is heated for 3 min, hydrolyzing [18F]triflate. In the next step shown in FIG. 25, vial #2 is cooled under N for 10 sec. In the next step shown in FIG. 26, 1.8ml NaOH (2N) is added into vial #2, adjusting the pH. In the next step shown in FIG. 27, vial #2 is cooled under N2 for 10 sec. In the next step shown in FIG. 28, 4ml NaHCO3 (IN) are added into vial #2. the next
step shown in FIG. 29, [18F]FDG is transfened from vial #2 to bottle #6. In the next step shown in FIG. 30, 3ml H2O are added to vial #2. In the next step shown in FIG. 31, H2O is transferred from vial #2 to bottle #6. The final product ([18F]FDG) is in bottle #6.
Example 2 - Oil Soluble Agent: [ I] Iodomisonidazole Synthesis Referring to FIGS. 32-53, graphical user interface figures showing program steps for a [123I]Iodomisonidazole synthetic protocol are depicted illustrating an aspect of the invention. In a first step shown in FIG. 32, Na 123I is added to vial #1 through the K2CO3 port line. In the next step shown in FIG. 33, tosyl-MISO/CH3CN is added into vial #1. In the next step shown in FIG.
34, vial #1 is heated for 5 min, and 123I-exchange is performed. In the next step shown in FIG.
35, CH3CN is evaporated under N2 and vacuum is applied. In the next step shown in FIG. 36, 0.25ml CH3CN and 5ml H2O are added into vial 1. hi the next step shown in FIG. 37, a solution is transferred from vial #1 to bottle #5 (waste). In the next step shown in FIG. 38, 3ml H2O is added into vial #1. In the next step shown in FIG. 39, the solution is transferred from vial #1 to bottle #5 (waste). In the next step shown in FIG. 40, 3ml H20 (0.1N) are added into vial #1. In the next step shown in FIG. 41, the solution is transferred from vial #1 to vial #2. hi the next step shown in FIG. 42, 3ml CH2C12 are added into vial #2. hi the next step shown in FIG. 43, the solution is transferred from vial #2 to vial #3. the next step shown in FIG. 44, CH2C12 is evaporated under N2 and vacuum is applied. In the next step shown in FIG. 45, 2ml HCl (IN) are added into vial #3. In the next step shown in FIG. 46, vial #3 is heated for 3 min, hydrolyzing [123I]iodo-2'-acetyl MISO and tosyl MISO. In the next step shown in FIG. 47, vial #3 is cooled under N2 for 10 sec. In the next step shown in FIG. 48, 1.8ml NaOH (IN) are added into vial #3, adjusting the pH. In the next step shown in FIG. 49, cool vial #3 is cooled under N2 for 10 sec. In the next step shown in FIG. 50, 4ml NaHCO3 (IN) are added into vial #3. In the next step shown in FIG. 51, [123I]IMISO is transferred from vial #3. to bottle #7. In the next step shown in FIG. 52, 3ml H2O (0.1 ethanol) are added to vial #3. hi the next step shown in FIG. 53, H2O is transferred from vial #3 to bottle #7. The final product ([123I]Iodomisonidazole) is in bottle #7. It is noted that other oil-soluble pharmaceuticals suitable for the program steps of FIGS. 32-53 include, but is not limited to iodo-alpha-methyltyrosine (precursor tosyl-alpha- methyltyrosine), iodotyrosine (amino acid, precursor tosyl-tyrosine), iododeoxyuridine (RNA, precursor mercuric uridine), Iodoadenosine (DNA marker, precursor tosyladenosine),
iodotamoxifen (receptor, precursor tosyl tamoxifen), iodopenciclovir (gene expression, precursor tosylpenciclovir).
Example 3 - Water Soluble Agent: i Cu] EC-Guanine Synthesis Referring to FIGS. 54-61, graphical user interface figures showing program steps for a [64Cu]EC-Guanine synthetic protocol are depicted illustrating an aspect of the invention. In a first step shown in FIG. 54, 64Cu-acetate is added to vial #1 through K2CO3 port line. In the next step shown in FIG. 55, EC-guanin/water is added to vial #1. In the next step shown in FIG. 56, vial #1 is heated for 5 min, performing a 64Cu-exchange. In the next step shown in FIG. 57, the solution is transferred from vial #1 to vial #2. In the next step shown in FIG. 58, 2ml EC/saline (0.9%) is added into vial #2. hi the next step shown in FIG. 59, vial #2 is heated for 1 min, removing excess 64Cu-acetate. In the next step shown in FIG. 60, vial #2 is cooled under N2 for 100 sec. In the next step shown in FIG. 61, [64Cu]EC-Guanine is transferred from vial #2 to bottle #6. The final product ([64Cu]EC-Guanine) is in bottle #6. It is noted that other oil-soluble pharmaceuticals suitable for the program steps of FIGS. 54-61 include, but not limited to copper-alpha-methyltyrosine (precursor Tosyl-alpha- methyltyrosine), Copper-tyrosine (amino acid; precursor Tosyl-tyrosine), copper-deoxyuridine (RNA; precursor mercuric uridine), copper-adenosine (DNA marker; precursor tosyladenosine), copper-tamoxifen (receptor; precursor tosyl tamoxifen), and copper-penciclovir (gene expression; precursor tosylpenciclovir). It will be manifest that various substitutions, modifications, additions and/or rearrangements of the features of the invention may be made without deviating from the spirit and/or scope of the underlying inventive concept. It is deemed that the spirit and/or scope of the underlying inventive concept as defined by the appended claims and their equivalents cover all such substitutions, modifications, additions and/or rearrangements. The terms a or an, as used herein, are defined as one or more than one. The term plurality, as used herein, is defined as two or more than two. The term another, as used herein, is defined as at least a second or more. The terms including and/or having, as used herein, are defined as comprising (i.e., open language). The term coupled, as used herein, is defined as connected, although not necessarily directly, and not necessarily mechanically. The term program, computing device program, and/or software, as used herein, is defined as a sequence of instructions designed for execution on a computer system. A program may include, for example,
a subroutine, a function, a procedure, an object method, an object implementation, and an executable application and/or other sequence of instructions designed for execution on a computer system.