Abstract:
A compact and flexible apparatus that may be used to carry out multistep chemical or radiochemical synthesis is disclosed. Radiochemical tracers may be synthesized through a spatial temperature manipulation approach. The reaction vessel and the reagent vials can be removed after a single use, suggesting the apparatus can be used multiple times a day.

Description:
RELATED APPLICATION 
       [0001]    This application claims priority to U.S. Provisional Application No. 61/641,053 filed May 1, 2012, the contents of which is hereby incorporated in its entirety by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to a chemical synthesis apparatus in general and a radiochemical synthesis apparatus in particular. 
       BACKGROUND OF THE INVENTION 
       [0003]    Positron emission tomography (PET) is a nuclear medical imaging system that scans a body and creates a three-dimensional image of functional processes in the body. The system detects gamma rays emitted by a positron-emitting radioisotope, which is usually labeled through radiochemical synthesis on a biologically active molecule, or compound, to form a tracer. The tracer is introduced into the body. Three-dimensional images of tracer distribution within the body are then constructed by computer analysis. 
         [0004]    The most commonly used PET tracer is fludeoxyglucose (FDG), an analogue of glucose. The distribution of FDG in the body is an indication of tissue metabolic activity by virtue of glucose uptake. So the PET scan of FDG can be used for abnormal metabolic diagnosis or early cancer detection. However, based on specific needs, many new biological active compounds are investigated in research facilities worldwide. Due to the short half-life of radioisotopes (109.8 minutes for fluorine-18, for example) and the diversity of the biological active compounds, the radiochemical synthesis of these tracers needs to be fast and flexible, whether is based on macro-scale reactor or micro-fluidics. 
         [0005]    Chemical or radiochemical synthesis involves both energy transfer and mass transfer processes. Typical radiochemical synthesis systems comprises a reaction vessel  102 , which is fixed on top of a temperature manipulating element  112 , and is surrounded by a number of mass transfer lines  120  ( FIG. 1   a ). There are limitations associated with these radiochemical synthesis systems. 
         [0006]    First, the energy transfer, which is usually in the form of a series of temperature transitions, is hardly a fast and efficient process for radiochemical synthesis. Ideally, temperature transition is instantaneous and then temperature stays at a pre-determined setting ( 130 ,  FIG. 1   b ). In reality, temperature transition takes time and is followed by a period of temperature fluctuation ( 132 ,  FIG. 1   b ). Shorter transition time is achieved by higher heating power, which in turn generates more temperature fluctuation. Moreover, the temperature manipulating element is usually a big mass itself, which takes extra energy and extra time in temperature transition. New technologies, such as microwave and infrared, may improve the heating efficiency. Unfortunately, these devices are bulky, expensive and complex. 
         [0007]    Second, the immobilization of the reaction vessel and the structure of multiple mass transfer lines make the system inflexible. Meanwhile, heavy use of liquid valves and metering devices in mass transfer lines makes the system expensive, complex and unreliable. Such systems are usually designed to synthesize a few tracers, even a single tracer. It is nearly impossible for such systems to synthesize a wide range of radiochemical products without substantial system modification. 
         [0008]    For the foregoing reasons, there is a need for a fast and flexible radiochemical synthesis apparatus with improved energy and mass transfer efficiency. 
       SUMMARY OF THE INVENTION 
       [0009]    The present invention discloses an apparatus that carries out multistep chemical or radiochemical processes through a spatial temperature manipulation approach. The apparatus comprises a reaction stage and a reagent stage. The reaction stage comprises a reaction vessel, a plurality of preconditioned temperature manipulating elements and a moving means. The moving means accommodates the reaction vessel and programmatically moves the reaction vessel to reach the preconditioned temperature manipulating elements. Each movement is equivalent to a step in radiochemical process. The whole radiochemical synthesis process can be automated. The reaction vessel can be removed after a single use, suggesting the apparatus can perform multiple runs a day. These and other features and advantages of the present invention will become better understood with reference to the following drawings, description and claims. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0010]    The details of the present invention, both its structure and operation, may be gleaned in part by the accompanying drawings, in which like reference numbers refer to like parts and arrows refer to movement directions of moving components, and in which: 
           [0011]      FIG. 1  illustrates a traditional chemical or radiochemical apparatus and temperature manipulation processes; 
           [0012]      FIG. 2  illustrates an embodiment of the reaction stage of the apparatus; 
           [0013]      FIG. 3  illustrates another embodiment of the reaction stage of the apparatus; 
           [0014]      FIG. 4  illustrates yet another embodiment of the reaction stage of the apparatus; 
           [0015]      FIG. 5  shows the detail of a filling element; 
           [0016]      FIG. 6  shows the detail of an evaporation element; 
           [0017]      FIG. 7  shows the detail of a reaction element; 
           [0018]      FIG. 8  shows the detail of a retrieving element; 
           [0019]      FIG. 9  shows the detail of a vessel removing element; and 
           [0020]      FIG. 10  illustrates an embodiment of a reagent stage and the connection to a reaction vessel. 
       
    
    
     DETAILED DESCRIPTION 
       [0021]    A radiochemical synthesis needs a radioisotope and at least one reagent. A radiochemical synthesis may involve one or more reaction steps, generating a radioactive intermediate or a radiochemical product, which may be purified as a tracer. The present invention is directed to an apparatus that may be used to carry out multistep chemical or radiochemical processes. The apparatus comprises a reaction stage and a reagent stage. The reaction stage of the apparatus comprises a reaction vessel, a plurality of preconditioned temperature manipulating elements and a moving means. The moving means accommodates the reaction vessel and programmatically moves the reaction vessel to reach the preconditioned temperature manipulating elements using a step motor or similar device. Each movement is equivalent to a step in radiochemical process. The whole radiochemical process can be automated. This invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided to ensure that this disclosure is thorough and complete, and to ensure that it fully conveys the scope of the invention to those skilled in the art. 
         [0022]    The term “preconditioned” means certain condition is established before a particular operation. The term “preconditioned” also means certain material is prefilled before a particular operation. A preconditioned temperature manipulating element, for example, is an element that is preheated to a predetermined temperature before a reaction vessel reaches the element. To make temperature transition in a reaction vessel, simply move the reaction vessel to reach a preconditioned temperature manipulating element, or move the reaction vessel between two preconditioned temperature manipulating elements. Because the temperature manipulating element is preconditioned or preheated, the heating of the reaction vessel is faster than heating both the reaction vessel and the temperature manipulating element together. The heating is also more stable, considering the temperature fluctuation only occurs during the temperature transition, or at early stage of preconditioning. 
         [0023]    In instrument design, people believe “less means more”. This invention, however, shows that sometimes the opposite is true. The use of more than one temperature manipulation element simplifies the design and operation. The use of low power heaters, as required to precondition the temperature manipulating element, also reduces the size of the apparatus. 
         [0024]    With the combination of a plurality of preconditioned temperature manipulating elements and a moving means, temperature manipulation is no longer a traditional temporal process. It is rather a spatial process. The spatial temperature manipulation provides speed and stability. It should be noted that the same principle applies to fast cooling—simply move a hot reaction vessel to reach a preconditioned cooling element. Fast cooling of the reaction vessel can also be achieved by forced air after separating the preconditioned temperature manipulating element from the reaction vessel. 
         [0025]    Referring to  FIG. 2 , one embodiment of the reaction stage disclosed herein comprises a reaction vessel  102 , a plurality of preconditioned temperature manipulating elements  112 , an evaporating element  204 , and a first moving means  206 . The first moving means  206  is to accommodate the reaction vessel  102  and to move the reaction vessel  102  along a track to reach the elements  112  and  204  to perform the following: 1) to dry, evaporate or concentrate the content in the reaction vessel  102  using one of the preconditioned temperature manipulating elements  112 ; 2) to perform a radiochemical reaction in the reaction vessel  102  using another one of the preconditioned temperature manipulating elements  112 , generating a radiochemical product or a radioactive intermediate; and 3) to perform a further radiochemical reaction in the reaction vessel  102  using yet another one of the preconditioned temperature manipulating elements  112 , turning the radioactive intermediate into a radiochemical product. The elements  112  and  204  are placed along the track. The track can be straight, circular or other form. The track can be visible or invisible. The reaction vessel  102  may be sealed with a pierceable member  208 . 
         [0026]    Referring to  FIG. 3 , another embodiment of the reaction stage disclosed herein comprises a reaction vessel  102 , a plurality of preconditioned temperature manipulating elements  112 , an evaporating element  204 , one or more filling elements  302 , one or more retrieving elements  304 , and a first moving means  206 . The first moving means  206  is to accommodate the reaction vessel  102  and to move the reaction vessel  102  along a track to reach the elements  112 ,  204 ,  302  and  304  to perform the following: 1) to fill a radioisotope and at least one reagent into the reaction vessel  102 ; 2) to dry, evaporate or concentrate the content in the reaction vessel  102  using one of the preconditioned temperature manipulating elements  112 ; 3) to perform a radiochemical reaction in the reaction vessel  102  using another one of the preconditioned temperature manipulating elements  112 , generating a radiochemical product or a radioactive intermediate; 4) to perform a further radiochemical reaction in the reaction vessel  102  using yet another one of the preconditioned temperature manipulating elements  112 , turning the radioactive intermediate into a radiochemical product; and 5) to retrieve the radiochemical product or the radioactive intermediate from the reaction vessel  102 . The elements  112 ,  204 ,  302  and  304  are placed along the track. The track can be straight, circular or other form. The track can be visible or invisible. The reaction vessel  102  may be sealed with a pierceable member  208 . 
         [0027]    Referring to  FIG. 4 , yet another embodiment of the reaction stage disclosed herein comprises a reaction vessel  102 , a plurality of preconditioned temperature manipulating elements  112 , an evaporating element  204 , one or more filling elements  302 , one or more retrieving elements  304 , a vessel removing element  402 , and a first moving means  206 . The first moving means  206  is to accommodate the reaction vessel  102  and to move the reaction vessel  102  along a track to reach the elements  112 ,  204 ,  302 ,  304  and  402  to perform the following: 1) to fill a radioisotope and at least one reagent into the reaction vessel  102 ; 2) to dry, evaporate or concentrate the content in the reaction vessel  102  using one of the preconditioned temperature manipulating elements  112 ; 3) to perform a radiochemical reaction in the reaction vessel  102  using another one of the preconditioned temperature manipulating elements  112 , generating a radiochemical product or a radioactive intermediate; 4) to perform a further radiochemical reaction in the reaction vessel  102  using yet another one of the preconditioned temperature manipulating elements  112 , turning the radioactive intermediate into a radiochemical product; 5) to retrieve the radiochemical product or the radioactive intermediate from the reaction vessel  102 ; and 6) to remove the reaction vessel  102 . The elements  112 ,  204 ,  302 ,  304  and  402  are placed along the track. The track can be straight, circular or other form. The track can be visible or invisible. The reaction vessel  102  may be sealed with a pierceable member  208 . The reaction vessel  102  can be removed with the vessel removing element  402 . 
         [0028]    Referring to  FIG. 5 , the filling element  302  comprises a sealing member  202 , an inlet needle  502 , and an outlet needle  504 . To fill the reaction vessel  102  with either a radioisotope or at least one reagent, lower the sealing member  202  to seal the reaction vessel  102 , fill either the radioisotope or the at least one reagent through the inlet needle  502  and push air out through the outlet needle  504 . A mixer  506  is positioned below the reaction vessel  102  and a radiation detector  508  is positioned on the side of the reaction vessel  102 . The mixer  506  provides mixing needs while the radiation detector  508  monitors the radioactivity in the reaction vessel  102 . 
         [0029]    Referring to  FIG. 6 , the evaporating element  204  comprises a sealing member  202 , an inlet needle  602 , and an outlet needle  604 . To dry, evaporate or concentrate the content in the reaction vessel  102 , lower the sealing member  202  to seal the reaction vessel  102  and push the preconditioned temperature manipulating element  112  up to heat the reaction vessel  102 , blow nitrogen (or other inert gas) through the inlet needle  602  and vent the reaction vessel through the outlet needle  604 . Alternatively, vacuum may be applied through the outlet needle  604  to speed up the evaporating process. Charcoal may be placed in the vent line to trap the vent. 
         [0030]    Referring to  FIG. 7 , a reaction element comprises a sealing member  202 . To start a radiochemical reaction, lower the sealing member  202  to close the reaction vessel  102  and push the preconditioned temperature manipulating element  112  up to heat the reaction vessel  102 . After the radiochemical reaction, lower the preconditioned temperature manipulating element  112  and cool the reaction vessel  102  with a cooling means  702  such as air or nitrogen gas while the reaction vessel  102  remains sealed. 
         [0031]    Referring to  FIG. 8 , the retrieving element  304  comprises a sealing member  202 , an inlet needle  802  and an outlet needle  804 . To retrieve a radioactive intermediate or a radiochemical product from the reaction vessel  102 , lower the sealing member  202  to seal the reaction vessel  102 , push nitrogen or other gas in through the inlet needle  802  and push the radioactive intermediate or the radiochemical product out through the outlet needle  804 . 
         [0032]    Referring to  FIG. 9 , the vessel removing element  402  comprises a sealing member and at least one needle  402 . To remove the reaction vessel  102 , unlock the reaction vessel  102 , lower the sealing member  202  and let the at least one needle to pierce through the pierceable member  104 . As the at least one needle  402  moves up, the reaction vessel  102  is removed from the first moving means  206 . Alternatively, a gripper or similar device can be actuated to remove the reaction vessel  102 . 
         [0033]    The evaporation element  204 , the filling element  302 , the retrieving element  304 , the reaction element (which comprises a sealing member  202 ) and the vessel removing element  402  are referred to below as the functional elements. Some of the functional elements may be modified or combined; or additional functional elements may be added. 
         [0034]    Even though moving the reaction vessel  102  along a track is believed to be the best mode for present invention, the movement is relative—the preconditioned temperature manipulating elements  112  and the functional elements may be moved to reach the reaction vessel; or the reaction vessel  102 , the preconditioned temperature manipulating elements  112  and the functional elements may be moved. 
         [0035]    Additional moving means can be applied to mass transfer. Unlike the traditional multiline structure as illustrated in  FIG. 1   a,  a moving means can accommodate at least one prefilled reagent vial and programmatically move the at least one prefilled reagent vial to a loading position, where the content in the at least one vial is loaded into the reaction vessel via at least one mass transfer line. 
         [0036]    Referring to  FIG. 10 , an embodiment of the apparatus disclosed herein comprises an additional reagent stage. The reagent stage comprises a second moving means  1002 , a sealing member  1006 , an inlet needle  1008 , and an outlet needle  1010 . A mass transfer line  1012  connects the reagent stage and reaction stage. The second moving means  1002  accommodates at least one reagent vial  1004  prefilled with at least one reagent. The second moving means  1002  also moves the at least one reagent vial  1004  to a loading position, where the at least one reagent can reached by the outlet needle  1010  and transferred from the at least one reagent vial  1004  to the reaction vessel  102  through the outlet needle  1010 , the mass transfer line  1012  and the inlet needle  504 . Then the second moving means  1002 , together with the at least one reagent vial  1004 , can be removed. 
         [0037]    The at least one reagent vial  1004  may be sealed with a pierceable member  1014  to make vial movement safe and secure, to reduce reagent loss and to prevent contamination. 
         [0038]    As a result of the moving structure, the number of mass transfer lines can be reduced. The number of reagents can be increased or decreased depending on the degree of complexity of a radiochemical synthesis. Furthermore, the time-consuming and wasteful cleaning is not necessary considering both the reaction vessel and the reagent vial can be easily removed after a single use, suggesting the radiochemical apparatus can perform multiple runs a day. 
         [0039]    The moving means  206  can be designed to move more than one reaction vessel  102  for parallel processes. The moving means can be further modified for other devices such as cartridges, filters and the like, which can be sequentially or programmatically positioned for reagent, intermediate and product treatment. 
         [0040]    Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred versions contained therein.