The subject matter disclosed herein relates generally to radioisotopes used in medical imaging, and more particularly to systems, methods, and an apparatus for preparing the radioisotope to be used in, e.g., a medical imaging procedure. Particularly, the present disclosed subject matter includes a radio-labeling tracer synthesizer capable of multiple configurations and fully programmable for development of novel compounds and synthesis methods for use in a variety of fields, e.g., molecular imaging.
When employed in imaging procedures, an individual dose of a premeasured radioisotope or radioisotope is administered to a subject. The individual premeasured radioisotope is prepared by a radioisotope supplier using a cyclotron to prepare the radioisotope. The radioisotope is delivered to a medical facility that administers the individual premeasured radioisotope as a radiopharmaceutical.
The process of radioisotope production in a cyclotron includes irradiating a target material, such as water, in the cyclotron with a beam of protons or deuterons to produce a desired amount of radioactivity in the target material. Typically, the cyclotron is located in a dedicated room. Examples of cyclotron produced radioisotopes include nitrogen-13, fluorine-18, carbon-11 and oxygen-15.
Often, compounds are bond to the radioactive water to produce radioisotopes such as fluorodeoxyglucose (FDG) which is produced using fluorine-18. Other radioisotopes include nitrogen-13 ammonia which is used in myocardial applications, carbon-11 tracers which are commonly used in neurologic applications; and oxygen-15 gas as well as tracers derived from it which are commonly used in blood flow applications. More specifically, the radioactive water is typically delivered to a separate room that includes a synthesizing device for bonding the compound to the radioactive water and a dispensing station for dividing the radioisotope into individual doses that are stored in individual vials or containers.
The present disclosure provides a novel system, and corresponding method, of synthesizing radioisotopes.
The purpose and advantages of the disclosed subject matter will be set forth in and apparent from the description that follows, as well as will be learned by practice of the disclosed subject matter. Additional advantages of the disclosed subject matter will be realized and attained by the methods and systems particularly pointed out in the written description and claims hereof, as well as from the appended drawings.
To achieve these and other advantages and in accordance with the purpose of the disclosed subject matter, as embodied and broadly described, the disclosed subject matter includes a radio labeling tracer synthesizer capable of multiple configurations and fully programmable, which provides development of novel compounds and synthesis methods for use in a variety of fields, including molecular imaging. The novel modular design permits new cancer radiotracers to be created in an efficient and safe manner. The software and hardware embodied in the present disclosure follow current Good Manufacturing Practice (cGMP) rules and regulations of the Food and Drug Administration (FDA).
The disclosed subject matter also includes a modular radio-labeling tracer synthesizer system comprising: a housing, the housing having at least one slot; at least one syringe actuator, the at least one syringe actuator disposed within the slot and removably attached to the housing; and at least one servo motor and at least one rotary valve, the at least one servo motor and at least one rotary valve removably attached to the housing.
In some embodiments, the at least one syringe actuator is attached via magnet(s) and the at least one rotary valve is removably attached to the at least one servo motor.
In some embodiments, the at least one syringe actuator includes a syringe driver configured to engage a syringe plunger for displacement in a loading and dispensing direction.
In some embodiments, the at least one syringe actuator includes a syringe holder, the syringe holder configured to receive a variety of syringe sizes.
In some embodiments, the syringe holder includes a door which can move from an open position to a closed position.
In some embodiments, the housing includes a stopper, the stopper limiting displacement of the syringe driver.
In some embodiments, the housing includes fourteen slots, with a syringe actuator disposed in each slot.
In some embodiments, the housing includes nine rotary valves, each rotary valve(s) has seven positions.
In some embodiments, the housing further comprises dual temperature controlled reactor vessels, a cooling element(s), a compressor, at least one radiation detector, and at least one programmable microprocessor.
In accordance with another aspect of the disclosure, a syringe actuator is provided comprising: a syringe holder, a syringe driver, and a manifold. The manifold having: a pump source, a vacuum source, a first conduit in fluid communication with the pump source, a second conduit in fluid communication with a vacuum source, and a switch valve, the switch valve configured to direct fluid flow through at least one of the conduits.
In some embodiments, a third conduit connects the switch valve and pump source in fluid communication.
In some embodiments, a forth conduit connects the switch valve and vacuum source in fluid communication.
In some embodiments, the syringe actuator includes a syringe driver configured to engage a syringe plunger for displacement in a loading and dispensing direction.
In some embodiments, the syringe actuator includes a visual indicator depicting the direction of displacement of the syringe plunger.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and are intended to provide further explanation of the disclosed subject matter claimed.
The accompanying drawings, which are incorporated in and constitute part of this specification, are included to illustrate and provide a further understanding of the method and system of the disclosed subject matter. Together with the description, the drawings serve to explain the principles of the disclosed subject matter.
A detailed description of various aspects, features, and embodiments of the subject matter described herein is provided with reference to the accompanying drawings, which are briefly described below. The drawings are illustrative and are not necessarily drawn to scale, with some components and features being exaggerated for clarity. The drawings illustrate various aspects and features of the present subject matter and may illustrate one or more embodiment(s) or example(s) of the present subject matter in whole or in part.
Reference will now be made in detail to exemplary embodiments of the disclosed subject matter, an example of which is illustrated in the accompanying drawings. The method and corresponding steps of the disclosed subject matter will be described in conjunction with the detailed description of the system.
The present disclosure is directed towards a radioisotope production system that receives the output from a cyclotron, which is a type of particle accelerator in which a beam of charged particles (e.g., H-charged particles or D-charged particles) are accelerated outwardly along a spiral orbit. The cyclotron directs the beam into a target material to generate the radioisotopes (or radionuclides). Cyclotrons are known in the art, and an exemplary cyclotron is disclosed in U.S. Pat. No. 10,123,406, the entirety, including structural components and operational controls, is hereby incorporated by reference.
The present disclosure provides rapid synthesis times and is fully configurable to suit the development of any new radioactive compound. The system uses commercially available consumables, thus reducing setup cost. Additionally, the present synthesis system can be employed with a wide range of radio metal isotopes configured as sold, liquid or gas targets.
As shown in
In accordance with an aspect of the present disclosure, a housing 100 is provided which allows for a modular synthesizer design capable of multiple configurations. In the exemplary embodiment depicted, the housing 100 includes slots or channels for incorporating fourteen linear syringe actuators and nine rotary valves, though artisans of ordinary skill will understand that additional/alternative configurations are within the scope of the disclosure, and the housing 100 can be scaled up/down as desired to accommodate the particular configuration required. For sake of clarity,
As shown in
Housing 100 also includes openings for the syringe actuator peripherals (e.g. motor, valves, tubing, etc.). As shown in the exemplary embodiment, these peripheral materials are disposed below the syringe actuators 200. The housing can accommodate a variety of configurations of the actuator peripherals, e.g. the motors and valves (220) can be located below the syringe actuator and positioned in an alternating or staggered configuration in which one motor is higher than an adjacent motor (see
The housing 100 also contains the programmable logic controller, power supply, embedded air pump(s) (140) and reservoir. Accordingly, no external gas, storage or input/supply, are required for operation of the presently disclosed synthesizer system. Instead, the synthesizer system disclosed herein is operated by self-contained pneumatic power (e.g. internal compressor tank) contained within the housing 100. Each actuator 200 can directly connect to the embedded air pump(s) within the housing; alternatively the actuators can be coupled to a manifold that serves as a gateway for directing pressurized air to select actuators. For purpose of illustration and not limitation, an exemplary synthesizer housing is approximately 30 inches (width)×15 inches (depth)×18 inches (height), though size and shape can be adjusted as desired to accommodate any desired application.
Positioned on one, or both, sides of the housing 101 are bags or pouches containing fluid for flow into and out of the syringe actuators. These bags 105 can be suspended from clips attached to the housing (integrally formed or removable) to maintain a vertical orientation to provide a gravitational supply feed. One, or both, of the bags 105 can contain sterile water for rinsing the system and permitting multiple synthesizing cycles. Additionally, one, or both, sides of the housing 100 can include a receptacle 106 for holding a container (e.g. vial) for delivery of the final solution. Additionally, the present disclosure provides a dual reactor 110, 112 (as shown in
Also included within housing 100 are two embedded radiation detectors which can report and quantify the presence of radioactivity. Each side of the synthesizer is monitored by a radiation detector that reports the final dose received in the vial product (disposed at either end 106 of the housing). These radiation detectors can trigger an alarm (visual and/or audible) and record the event when the radiation measurement exceeds a predefined threshold.
In accordance with another aspect of the disclosure, the ergonomic, and modular design allows the user to quickly troubleshoot or replace all parts of the module—without any tooling (i.e. each component can be installed/removed by hand).
Referring now to
Also, a door 203 can be included in the syringe holder 202 which can move from an open position to a closed position. For example the door can rotate downward as shown in
Syringe Actuators 200 also include a driver 204 for engaging and moving the syringe plunger. The driver 204 can include a combination of recess and slot to receive the syringe plunger, with the syringe plunger being inserted from a direction normal to the front face of the driver 204. This recess/slot design allows for a tight engagement of the driver 204 and plunger to minimize relative movement or shifting between the driver 204 and plunger. This maximizes both the efficiency of the system and the range of motion for the plunger. During operation of an upward stroke (to withdraw/load fluid into a syringe barrel), the driver 204 extends upwardly until engaging the stop 103 which precludes further upward movement. In some embodiments, the upward (and/or downward) strokes of the syringe actuators 204 are performed at differing intervals, speeds and/or to differing limits/positions. In some embodiments, all syringe actuators 204 perform uniform upward/downward strokes.
The rear side of syringe actuators 200 includes driver canister/volume 207, and a manifold 206 in direct fluid communication, via conduits 212, with a pump 208 and vacuum 209 source (as shown in
In operation, the driver canister/volume is pressurized to either push the driver 204 upwards thereby drawing fluid into the syringe, or depress the driver 204 downwards to dispense fluid out of the syringe. Also, the plurality of syringe actuators 200 can be operated simultaneously, or independently, as desired. A valve is also provided which can release overhead pressure to stop operation of the driver 204. A potentiometer is also included which can provide continuous, real time feedback of the volume remaining in the syringe and/or driver canister 207. In accordance with an aspect of the present disclosure, the syringe actuator 200 runs at maximum stroke speed for any syringe configuration. In some embodiments, the stroke speed can vary, e.g., the beginning or ending of a stroke can be performed at an alternative (faster or slower) speed than the mid portion of the stroke.
In an exemplary embodiment, nine rotary vales are included, each capable of selecting seven distinct positions (each with distinct plumbing/tubing)—for any configuration of syringe actuators employed.
Similarly to the syringe actuators 200, these rotary valves are modular in design (i.e. can be interchangeable in multiple locations in the housing 100) and can be High Performance Liquid Chromatography (HPLC) controlled valves which combine multiple fluidic paths in a single manifold, thereby reducing redundant fluid pathways. The valves, which can be servo valves which adjust fluid flow in proportion to the electrical signal that it receives, and motors are contained within modular casings 220, as shown in
Significantly, the present synthesis system does not require solenoid valves along the fluid path, nor stepper motors for operation. Accordingly, the present system is lighter, draws less power, and provides a more reliable operation than conventional synthesizers which rely on such solenoid valves to control fluid flow.
On either, or both, sides of the housing a shelf or bracket is provided for holding the target material 250 generated from the cyclotron operation. In the exemplary embodiment shown in
Graphical User Interface
In accordance with an aspect of the present disclosure, an embedded custom microprocessor printed circuit board (as shown in
A graphical user interface (GUI) is provided which allows for dynamic interaction between user and hardware units. As shown in
As shown in
The modular synthesizer and automated process disclosed herein can be employed to produce unlimited types of radio metal tracers. For purpose of illustration and not limitation, exemplary radioisotopes such as 68Ga, 64Cu and 89Zr can be radiolabeled using the system and techniques disclosed herein.
While the disclosed subject matter is described herein in terms of certain preferred embodiments, those skilled in the art will recognize that various modifications and improvements may be made to the disclosed subject matter without departing from the scope thereof. Moreover, although individual features of one embodiment of the disclosed subject matter may be discussed herein or shown in the drawings of the one embodiment and not in other embodiments, it should be apparent that individual features of one embodiment may be combined with one or more features of another embodiment or features from a plurality of embodiments. As such, the particular features presented in the dependent claims and disclosed above can be combined with each other in other manners within the scope of the disclosed subject matter such that the disclosed subject matter should be recognized as also specifically directed to other embodiments having any other possible combinations. Thus, the foregoing description of specific embodiments of the disclosed subject matter has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosed subject matter to those embodiments disclosed.
It will be apparent to those skilled in the art that various modifications and variations can be made in the method and system of the disclosed subject matter without departing from the spirit or scope of the disclosed subject matter. Thus, it is intended that the disclosed subject matter include modifications and variations that are within the scope of the appended claims and their equivalents.
This application claims the benefit of U.S. Provisional Application No. 62/723,226, filed Aug. 27, 2018, which is hereby incorporated by reference in its entirety.
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