WO1995012825A1

WO1995012825A1 - Flow cell for use in a flow scintillation analyzer

Info

Publication number: WO1995012825A1
Application number: PCT/US1994/012036
Authority: WO
Inventors: Kenneth J. Borowski
Original assignee: Packard Instrument Company, Inc.
Priority date: 1993-11-03
Filing date: 1994-10-21
Publication date: 1995-05-11

Abstract

A flow cell (10) for use in a flow scintillation analyzer, the flow cell having first and second solid scintillators, a sample channeling element (18) for accepting a radioactive fluid sample containing positron emitting nuclides and directing the sample between a surface of the first solid scintillator and a surface of the second solid scintillator, and a first opaque, reflective coating (20) on the surface of the first solid scintillator.

Description

FLOW CELL FOR USE IN A FLOW SCINTILLATION ANALYZER

Background Of The Invention

1. Field of the Invention

The present invention relates generally to flow cells for monitoring the radioactivity of radioactive materials in a flowing stream. This invention particularly relates to a flow cell for use in a flow scintillation analyzer system for detecting positron emitting nuclides chemically incorporated into a radiopharmaceutical.

2. Background of the Art

Positron emission tomography (PET) is a rapidly developing form of medical imaging technology. Unlike magnetic resonance imaging (MRI) which images body tissues and organs as a function of density, PET images can map physiological functions of tissues and organs as indicated by the selective uptake of positron emitting radiopharmaceuticals.

Positron emitting nuclides are incorporated into pharmaceuticals to create the radiopharmaceuticals required for PET diagnostic imaging techniques. The radiopharmaceuticals are purified via separation techniques, such as high performance liquid chromatography (HPLC) and thin layer chromatography, to eliminate byproducts from chemical synthesis, providing a pure radiopharmaceutical for patient use. The chemical purity of the radiopharmaceutical is determined during HPLC by detecting UV absorbance and also by monitoring the intensity of radioactivity. A flow scintillation analyzer equipped with an appropriate flow cell can be used to monitor the intensity of the radioactivity. The more radioactivity present in a flowing sample stream, the greater the response from the detector.

Once the purified radiopharmaceuticals are prepared, they are injected into a patient for PET analysis. The radiopharmaceuticals are designed in such as way as to be tissue specific, that they are selectively taken up by specific active tissues, thereby enabling functions of tissues and organs to be imaged. For example, if the heart is to be imaged with a PET or gamma camera, a radiopharmaceutical is selected which will concentrate in the tissues of the heart and an image of the heart is obtained. The image indicates the physiological functionality of the heart tissue. If part of the heart muscle has died or is not functioning well, gaps will exist in the resulting image where the radiopharmaceutical was not taken up by the tissue. When another radiopharmaceutical which is site specific for tumors is selected, the tissues where the radiopharmaceutical is taken up, and subsequently an image is produced, is indicative of tumor tissue while the remaining area is normal tissue.

While it is desirable to monitor the decay of positron emitting nuclides to determine the purity of a radiopharmaceutical used in PET imaging, conventional flow scintillation analysis techniques are inefficient and inaccurate for detecting positrons. Positrons are either directly detected or the annihilation quanta of the positron emitting nuclides are detected. In direct detection of the positrons, a radiopharmaceutical is mixed with a liquid or solid scintillator and placed within a counting chamber of a scintillation spectrometer. Then as the radionuclides in the radiopharmaceutical decay, emitted positrons energize the fluor contained within the scintillator. The fluor converts the energy from the positrons into optical events which are detected by photomultiplier tubes in the scintillation spectrometer and converted into corresponding electrical pulses. Background noise and susceptibility to interference are disadvantages associated with direct positron detection. Detectors often cannot adequately distinguish between a positron and a background event. Ionizing radiation from external sources can penetrate the detector housing, shielding, or sample cell components and excite the scintillator. More important, the principal interference in any direct detection of positrons is the positron annihilation quanta that are always present along with the positrons.

Another disadvantage of direct positron detection is the differential response of most detectors to various positron emitters. Positrons emitted from C, ^N, "O, and °F all have different characteristic energy distributions which necessitates some physical or electronic discrimination means for the detector to differentiate between the various positron emitters. An additional consequence of differential response is the need to electronically tune the detector in order to optimize response for any particular positron emitting nuclide. Typical flow scintillation analyzers and conventional flow cells are incapable of identical response for all positron emitting nuclides absent such electronic adjustment.

In addition to selectivity problems, conventional flow cells using scintillation cocktails are also inefficient for detecting positron emitting nuclides. Many of the positrons are not detected because they are absorbed by the liquid sample stream and do not transfer their energy to the scintillator. The performance of the scintillator can also be reduced by the phenomenon of quenching wherein the response of the scintillator is disturbed by the chemistry of the sample stream. The problems associated with direct detection of positrons can be minimized or eliminated by detecting the annihilation quanta. When a positron encounters an electron, both particles are destroyed, and two 511 keN annihilation quanta are created. This is the source of most of the background interference which is experienced when trying to detect positrons directly. Annihilation quanta are more readily detected because all positrons annihilate by the same mechanism and yield annihilation quanta with the same energy (511 keN) regardless of the type of positron emitting nuclide. The annihilation quanta are typically detected using classic gamma detection techniques with a single crystal, sodium iodide (ΝaI[Tl]) detector, or some other inorganic scintillator. In sodium iodide detectors, radiation is deposited into a clear hermetically sealed crystal that emits light which is detected. A single sodium iodide detector, however, is not annihilation quantum specific because no coincidence counting occurs. Two sodium iodide detectors, when configured in the correct geometry with respect to the sample and with respect to each other, can be used for electronic discrimination by responding only when photons arrive at each detector simultaneously. A single detector is also subject to high background interference as discussed above, and is typically housed within a large lead container to reduce background.

Multiple sodium iodide or bismuth germanate (BGO) detectors are commonly located around the circumference of a PET camera patient opening. The detectors, which operate in coincidence to create an image, are not subject to optical crosstalk because each scintillator and photomultiplier tube assembly is optically sealed and isolated from every other detector. This arrangement where paired detectors are located a distance of several feet apart, is different from radiochromatography systems wherein photomultipliers are closely spaced, they are not optically isolated from each other and optical crosstalk is a phenomenon which can produce false coincidences. Conventional flow scintillation analyzers incorporate a flow cell between paired photomultipliers to determine the relative intensity of radiation flowing through the system. Typical flow cells use scintillation cocktails in an attempt to detect positrons directly or they incorporate scintillating windows in the flow cell body, enclosing the sample flow tubing, in an attempt to detect the annihilation quanta. Detection schemes using such flow cells, however, have a low efficiency. Also, conventional flow cells which use scintillating windows cannot perform true coincidence counting because a scintillation occurring in a window can be observed by both photomultiplier tubes, thereby triggering the coincidence circuitry. Without the ability to perform true coincidence counting, flow scintillation analyzers that incorporate such conventional flow cells are subject to high background counting rates.

There has been a need for an improved flow cell for use in purification and quality control of radiopharmaceuticals used in PET analysis which effectively detects positron emitting nuclides incorporated into the radiopharmaceuticals. The flow cell of the present invention is an improved positron emitting nuclide detector which is annihilation quantum specific and reduces background noise interference. Summary Of The Invention

It is a primary object of the present invention to provide an improved sample flow cell for flow scintillation analyzers which is primarily responsive only to coincident positron annihilation quanta created within the volume of the flow cell. In this connection, a related object of this invention is to provide such an improved flow cell which is substantially insensitive to gamma radiation originating outside the volume of the flow cell, reducing background counting interference in detecting positron emitting nuclides.

It is another object of this invention to provide such an improved flow cell having an opaque coated scintillator capable of eliminating crosstalk between photomultiplier tubes of a scintillation analyzer to minimize detection of false coincidences. It is another object of this invention to provide such an improved flow cell capable of uniform response to a variety of positron emitting nuclides without the need to electronically adjust the analyzer for each nuclide. Another important object of this invention is to provide an improved flow cell that is substantially insensitive to positrons, betas and alpha particles originating from radionuclide species within the volume of the flow cell.

Other objects and advantages of the invention will be apparent from the following detailed description and the accompanying drawings.

In accordance with the present invention the foregoing objectives are realized by providing a flow cell for use in a flow scintillation analyzer, wherein the flow cell has first and second solid scintillator components, a sample channeling element for accepting a radioactive fluid sample containing positron emitting nuclides and directing the sample between a surface of the first solid scintillator component and a surface of the second solid scintillator component, and a first opaque, reflective coating on the surface of the first solid scintillator component.

Preferably, the surface of the second scintillator component has a second opaque, reflective coating. The coating on each of the surfaces is preferably composed of silver, aluminum, titanium oxide or white teflon, and the scintillator components are preferably composed of bismuth germanate (BGO), europium activated calcium fluoride (CaF2:Eu) or cerium activated yttrium aluminum oxide with the perovskite crystal structure (YAP:Ce). Tubing is a preferred sample channeling element. The flow cell may further include a housing coupled to the first scintillator component, the second scintillator component, and the sample channeling element. Brief Description Of The Drawings

FIG. 1 is a perspective view of a flow cell embodying the present invention;

FIG. 2 is an enlarged perspective view of a scintillator window coated with an opaque, reflective material; and

FIG. 3 is a side elevational view of the flow cell taken along the line 2-2 of FIG. 1.

While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that it is not intended to limit the invention to the particular form disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims. Detailed Description Of The Preferred Embodiment

Turning now to FIG. 1, there is shown a flow cell 10 for use in a flow scintillation analyzer to determine the relative intensity of radioactivity emanating from radiolabeled materials flowing through the system. The flow cell 10 has a cell plate 12 for housing the remaining components of the flow cell. Windows 14, 16 composed of scintillating material are positioned opposed to each other and are supported by the cell plate 12. Tubing 18, which extends within an inner portion of the cell plate 12 between the windows 14, 16, carries a radiopharmaceutical sample from the HPLC outlet through an area between the windows to an outlet where the sample is collected in a receptacle. As the radiopharmaceutical sample flows past the windows, positrons emitted from the radionuclides within the sample each encounter an electron. The positron and electron are destroyed, and two 511 keN annihilation quanta emerge. The annihilation quanta energize the fluor contained within the scintillator windows. The fluor converts the energy from the annihilation quanta into optical wavelength photons in a quantity proportional to the energy deposited in the scintillator by the annihilation quanta. The optical wavelength photons are simultaneously detected by the two photomultiplier tubes in the flow scintillation analyzer (i.e., a true coincidence) and converted into corresponding electrical pulses which are recorded.

A surface of each of the scintillating windows 14, 16 is coated with a layer 20 of opaque, reflective material, as shown in FIG. 2. The opaque, reflective material greatly improves the performance of the flow cell of the present invention. The opaque coating ensures that the flow scintillation analyzer responds only to ionizing radiation (i.e., annihilation quanta) emitted from the sample within the tubing. The opaque coating also eliminates crosstalk between the photomultiplier tubes by preventing scintillations in one window from triggering the circuitry of both photomultiplier tubes which would result in inaccurate detection of decay events (a false coincidence). The reflectivity of the layer 20 enhances light collection for the photomultiplier tubes, requiring less linear amplification of a pulse from a photomultiplier tube. The reflective coating of the windows of the present invention gathers more light from each scintillation than conventional scintillating windows. The enhanced light from each scintillation causes a larger signal pulse from the photomultiplier tube. Accordingly, the pulse does not need to be amplified significantly before being processed to the rest of the circuitry. Additionally, the larger detected pulse minimizes the noise associated with amplifying the pulse.

The windows 14, 16 are positioned within recesses 22 of the cell plate 12 as illustrated in FIG. 3. The opaque, reflective layer 20 of the window 14 faces the layer 20 of window 16. Both windows must be coated with the reflective layer 20 to maintain symmetry of response of the photomultiplier tubes and to prevent distortion of the pulse height spectrum. Tubing 18 extends from the connector 24 (FIG. 1), which is attached to the HPLC outlet, between the scintillating windows 14,16 to the connector 26.

The flow cell is manufactured by first machining the cell plate 12 to its desired dimensions. The cell plate is a flat plate composed of a metal such as aluminum or stainless steel. Stainless steel is the preferred material because it is more chemically resistant and is easier to manufacture and maintain. The cell plate is preferably polished, bright nickel plated or chrome plated to give the cell plate a shiny finish. Polishing is preferred because it results in a more durable product and requires fewer manufacturing steps. The cell plate is machined to include recesses 22 for window placement, apertures 28 for securing the windows, apertures 30 for threading the tubing into the area between the windows, and a hollow indentation 32 into which the tubing can bend to prevent it from kinking within the flow cell. The cell plate is sized so that the flow cell can be substituted for conventional flow cells in a flow scintillation analyzer. A cell plate of sufficient thickness to accommodate the tubing and scintillator windows is typically about one-half inch thick. When the flow cell is installed between the photomultiplier tubes of a flow scintillation analyzer, the flat surfaces of the plate form light-tight seals between the cell plate and the photomultiplier housings.

After the cell plate is machined, the tubing 18 is inserted within the area between the recesses 22 on each side of the cell plate 12. Any hollow tubing that withstands high pressure flow without rupturing can be used, such as stainless steel, or Tefzel, a polyethylene tetrafluoroethylene tubing distributed by Upchurch Scientific of Oak Harbor, Washington. Standard stainless steel threaded fittings for HPLC instrumentation are used as the connectors 24, 26 to secure the tubing to the cell plate and provide a means for attaching external tubing to deliver and remove samples flowing through the flow cell. The scintillating windows 14, 16 are commercially available from manufacturers including Koch Crystal Finishing in Elyria, Ohio. Although the windows can be made from any solid scintillator, scintillators which are not hygroscopic and which have a high linear attenuation coefficient for gamma photons at 511 keN, high density, and a short scintillation pulse lifetime are preferred. Bismuth germanate is a preferred scintillator of the present invention. The windows need not be hermetically sealed because bismuth germanate is not hygroscopic. Bismuth germanate also has a high linear attenuation coefficient for gamma photons at 511 keN. In comparison to conventional scintillators such as sodium iodide, bismuth germanate is a dense material for stopping gamma photons, providing a window that is thinner than a sodium iodide window. Bismuth germanate also has a short scintillation pulse lifetime, responding quickly to each gamma event so that subsequent events can be detected. Cerium activated yttrium aluminum oxide (YAP:Ce) is another preferred scintillator of the present invention. Like bismuth germanate, windows made from YAP:Ce are not hygroscopic and need not be hermetically sealed. Additionally, YAP:Ce has a high linear attenuation coefficient for gamma photons at 511 keN. YAP:Ce has a scintillation pulse lifetime that is even shorter than that of bismuth germanate and has little or no after glow. The scintillating windows may also be composed of europium activated calcium fluoride (CaF₂:Eu). Once the window has been cut, polished and shaped to a size which conforms to the recesses 22 of the cell plate, the opaque, reflective coating is deposited on a surface of each window to form the layer 20. The coating may be applied by any method which provides a smooth, uniform surface, such as painting or vapor deposition. Vapor deposition, a preferred method well known in the crystal growth and semiconductor arts, involves the heating of a metal such as aluminum under high vacuum to form a vapor of the metal which rains down on the surface of the scintillator crystal and deposits there. The coating is a thin layer of any opaque, reflective material such as silver, aluminum, titanium oxide, or white teflon. The preferred coating has a thickness of about five Angstroms and is composed of aluminum.

After the scintillating windows 14, 16 are coated with the layer 20, the windows may be positioned within the cell plate. The windows are placed within the recesses 22 of the cell plate 12 and are held in place by screws which are threaded through apertures 28 (FIG.l). Preferably, the exposed surface of each window is recessed slightly below the surface of the cell plate. The tubing 18 is adjacent to the opaque, reflective layers 20 when the windows are in place. Any gaseous or liquid material carrying positron emitting nuclides can be analyzed using the flow cell. The radioactive material is formed by well known methods of labelling the material with positron emitting nuclides which are generated using a cyclotron or other nuclide generating device. The positron emitting nuclides can be purified, labelled onto pharmaceuticals, and injected into a patient while activity is high and before degradation products are formed. Cyclotrons are manufactured by Siemens of Germany and Scandatronics, a Swedish subsidiary of General Electric Corporation.

The flow cell of the present invention can be placed between two photomultiplier tubes within an existing flow scintillation analyzer, replacing a conventional flow cell. Flow scintillation analyzers which can incorporate the flow cell of the present invention are manufactured by Packard Instrument Company, Berthold (a German subsidiary of EG & G) and Raytest of Germany. Suitable Packard Instrument Company flow scintillation analyzers include the Radiomatic 500 series and the Radiomatic 100 series analyzers. In order to substitute the flow cell of the present invention for an existing flow cell in a Packard flow scintillation analyzer, the value of a single resistor should be changed to adjust the linear amplifier gain of the analyzer to correspond to the light output of the scintillator used in the flow cell. In new Packard flow scintillation analyzers containing the flow cell of the present invention, the adjustment can be made in production. With the correct linear amplifier gain, the analyzer can relate the intensity of each recorded scintillation to the energy deposited by the annihilation quanta. With this information, an energy distribution spectrum can be collected and displayed, calibrated in correct units of keV.

The flow cell can then be attached to the outlet of the HPLC instrumentation via the connectors 24, 26. Next, a radiopharmaceutical is injected into the HPLC, which performs a separation in about fifteen to twenty minutes. Spectral data and chromatograms are generated to indicate purity of the radiopharmaceutical. The baseline value of a chromatogram indicates the background counting rate, while the number and area ratio of peaks indicates the chemical purity of the radiopharmaceutical. The opaque, reflective layer on the scintillating windows of the flow cell of the present invention prevents false coincidences from being detected in most instances because scintillations occurring in one window will only be observed by the single photomultiplier associated with that scintillating window. In order for the flow scintillation analyzer coincidence circuitry to be triggered and the event recorded, scintillations must occur in both scintillators simultaneously (a true coincidence) or sequentially within the coincidence resolving time of the circuitry (a chance coincidence). Positrons annihilating within the volume of the flow cell, creating two 511 keV photons which deposit simultaneously, one in each scintillating window, will trigger the coincidence circuitry and will be recorded as a single decay event. Accordingly, charged particles such as positrons, negatrons and alphas, and photons including X-rays and gammas, depositing in either scintillator will not trigger the coincidence circuitry unless they deposit in both scintillators simultaneously or sequentially within the resolving time of the coincidence circuit. When a sample is highly radioactive or in a high background environment, chance coincidences can be detected, although it is a rare occurrence.

The following example is presented to describe preferred embodiments and utilities of the present invention and is not meant to limit the present invention unless otherwise stated in the claims appended hereto.

Example An experiment was conducted to determine whether the opaque, reflective coating on the scintillator windows of the flow cell has an effect on the amount of background radiation interfering with the detection of positron emitting nuclides. Two flow cells were assembled according to the present invention using identical components. Both flow cells were constructed from a cell plate, transparent bismuth germanate scintillators and Tefzel tubing. One of the flow cells, however, had scintillating windows with opaque, reflective layers of aluminum. The flow cells were monitored for a fifteen minute counting period without injecting any radiolabeled material into the cell so that only background radiation in the laboratory environment would be detected. Background counting rates were detected between 0 and 1024 keN.

The flow cell with transparent scintillating windows exhibited a full spectrum background counting rate of 7,350 counts per minute, while the flow cell having opaque, reflective layers on the scintillating windows exhibited a background counting rate of only 54 counts per minute. The flow cell with the opaque, reflective layer of the present invention showed a reduction in background counting rate of greater than two orders of magnitude, without the use of bulk shielding about the photomultiplier tube housings or the flow cell. The significantly lower background counting rate in comparison to the background counting rate of a flow cell with transparent scintillating windows occurs because the opaque, reflective layers on the inside surface of the scintillating flow cell windows eliminates single window scintillations from triggering the coincidence circuitry.

Claims

I CLAIM:

1. A flow cell for use in a flow scintillation analyzer, the flow cell comprising: first and second solid scintillators; sample channeling means for accepting a radioactive fluid sample containing positron emitting nuclides and directing the sample between a surface of the first solid scintillator and a surface of the second solid scintillator; and a first opaque, reflective coating on the surface of the first solid scintillator.

2. The flow cell of claim 1 wherein the first opaque, reflective coating is selected from the group consisting of silver, aluminum, titanium oxide and white teflon.

3. The flow cell of claim 1 wherein the first opaque, reflective coating is aluminum.

4. The flow cell of claim 1 wherein the first and second solid scintillators are selected from the group consisting of bismuth germanate, europium activated calcium fluoride and cerium activated yttrium aluminum oxide with the perovskite crystal structure.

5. The flow cell of claim 1 wherein the first and second solid scintillators are bismuth germanate.

6. The flow cell of claim 1 wherein the sample channeling means is tubing.

7. The flow cell of claim 1 further including a housing coupled to the first solid scintillator, the second solid scintillator, and the sample channeling means.

8. A flow cell for use in a flow scintillation analyzer, the flow cell comprising: first and second solid scintillators; sample channeling means for accepting a radioactive fluid sample containing positron emitting nuclides and directing the sample between a surface of the first solid scintillator and a surface of the second solid scintillator; a first opaque, reflective coating on the surface of the first solid scintillator; and a second opaque, reflective coating on the surface of the second solid scintillator.

9. The flow cell of claim 8 wherein the first and second opaque, reflective coatings are selected from the group consisting of silver, aluminum, titanium oxide and white teflon.

10. The flow cell of claim 8 wherein the first and second opaque, reflective coatings are aluminum.

11. The flow cell of claim 8 wherein the first and second solid scintillators are selected from the group consisting of bismuth germanate, europium activated calcium fluoride and cerium activated yttrium aluminum oxide with the perovskite crystal structure.

12. The flow cell of claim 8 wherein the first and second solid scintillators are bismuth germanate.

13. The flow cell of claim 8 wherein the sample channeling means is tubing.

14. The flow cell of claim 8 further including a housing coupled to the first solid scintillator, the second solid scintillator, and the sample channeling means.