Patent Description:
In the synthesis of radiolabelled compounds, as compared with manual techniques, automated techniques allow reduced operator exposure to radiation, shorter reaction times, better control of reaction conditions and reduced reagent consumption.

Positron emission tomography (PET) is a nuclear medical imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of photons emitted indirectly by a PET tracer comprising a biologically active molecule and at least one positron-emitting radionuclide. Given the short half-life of the positron-emitting radionuclides used in PET tracers, the advantages presented by automated synthesis techniques are clear. Typically, the automated synthesis of a PET tracer is carried out on a disposable device such as a cassette or microchip with the synthesis process being driven by associated hardware and software.

Radioactivity in the synthesis of radiolabelled compounds is typically present in low concentration relative to the overall volume of the substance that comes together with the radioactivity. Taking <NUM>F produced from [<NUM>O]H<NUM>O as an example, a variation in <NUM>F concentration of <NUM> orders of magnitude is easily possible without increasing the volume of [<NUM>O]H<NUM>O, meaning that in an <NUM>F-labelled PET tracer preparation the same volume of water could contain activity for <NUM> or <NUM> PET scans. Therefore, a disposable device supplied to a producer of a radiopharmaceutical, such as a kit for [<NUM>F]-fluorodeoxyglucose ([<NUM>F]FDG), could be used to synthesise one or many doses depending on the concentration of activity used in the synthesis.

Another distinctive feature of radiosynthesis processes is that the radioactivity is constantly decaying with time. Therefore, for the same patient dose of a PET tracer, a different quantity of the radioactive product is required at the end-of-synthesis time as compared with a time later in the day after the end of synthesis.

Because disposable devices for the production of PET tracers are sold at a fixed price,.

There is therefore a need for a reliable method that would allow for measurement of the number of doses of a PET tracer actually synthesised.

<CIT> describes disposable components for a separation and purification system including a flow cell, an end cap for a chromatography column and a chromatography column useful for medium-pressure liquid chromatography. The flow cell may include an aperture for positioning a cable terminating at a radiation sensor which can detect the radiation signature of the product flowing through the flow cell. Alternatively, the radiation sensor may be separately housed on a cassette to analyze the eluate flowing from the flow cell.

<CIT> describes a system, apparatus and method for transferring chemical solutions and synthesizing a tracer. The system may comprise a computer and various sensors, including radioactivity sensors, can be integrated into the chemical system and be in electronic communication with the computer for process control and monitoring purposes.

<CIT> describes a method and apparatus for preparation of radiochemicals wherein the reaction that couples the radioactive isotope to the reactive precursor to form a positron-emitting molecular imaging probe is performed in a microfluidic environment. Radiation sensors may be integrated into the microfluidic apparatus for the purpose of monitoring the reactants and products.

<CIT> describes a radioisotope transportation container comprising a plurality of separable shields and means for measuring the dose inside each layer from the outside. A dosimeter such as a TLD may be inserted between each layer to directly measure the dose.

<CIT> describes a pellet-type LiF element for a thermoluminscent dosimetry (TLD) and its preparation. It describes the use of TLD as a radiation detector to measure the personal exposed dose. <NPL> describes a prototype miniature dosimeter probe employing a small, radiation sensitive metal oxide semiconductor field effect transistor (MOSFET) chip to measure, in vivo, the total accumulated dose and dose rate as a function of time after internal administration of long range beta particle radiolabelled antibodies and in external high energy photon and electron beams.

<CIT> describes a multi-sensor radiation dosimeter system with a self-indicating, instant radiation sensor and a convention radiation sensor for monitoring high energy radiations, such as X-ray, electrons and neurons, for indicating exposure instantly in the event of a dirty bomb, nuclear detonation or a radiological accident.

The present invention uses the concept that radiation-sensitive material embedded in a disposable radiochemistry device gives the device the additional capability of recording radiation dose, for readout at a later time. The present invention allows for the measurement of the actual amount of radiolabelled compound produced by a disposable radiochemistry device, with the advantage that charging can be related to compound produced rather than number of devices. The presently claimed invention is set out in the independent claim.

Described herein is a device comprising:.

A "device" in the context of the present invention is suitably a disposable device designed to be suitable for radiopharmaceutical manufacture and therefore manufactured from materials, generally polymers, which are of pharmaceutical grade and ideally also resistant to radiolysis. A suitable such device may be a microfabricated device or a cassette for use with automated synthesisers.

A "microfabricated device", also commonly referred to as a "microsynthsiser card" or "microsynthsiser chip" (and herein may simply be referred to as a "card" or a "chip") is a device in which predetermined networks of microchannels or capillaries, typically <NUM>-<NUM>, more typically <NUM>-<NUM> in diameter, are etched or otherwise machined or formed in or on the surface of a substrate, suitably made of ceramic or glass or silicon or polymer. Alternatively, the microchannels may be created using polydimethylsiloxane, which may be poured over a master (usually glass), allowed to cure and then peeled off, or are fabricated by injection moulding, hot embossing, casting, lithography, or machining. These channels may be sealed through bonding of a cover plate, suitably made from a metal (for example, gold, platinum or silver) or, more commonly, glass, to create a contained network capable of manipulating picolitre to microlitre volumes of liquid or gas. The sealing method used depends on the materials selected and may be selected from thermal bonding (for glass chips), anodic bonding (for silicon-glass chips), and for polymer chips the sealing method may be selected from clamping, gluing, application of heat and pressure, and natural adhesion. Nanolitre and picolitre volumes may be used for analytical aspects but the devices can handle flows of up to hundreds of microlitres per minute. This could be increased further, for example, by stacking multiple devices. These devices are designed to be used either with syringe pumps (available from Kloehen Limited, Las Vegas, USA) or under electroosmotic flow or pressure driven flow or capillary force driven flow or electrowetting. Fused silica capillaries or steel appropriately sized metal or polymer tubing or a custom manifold can be used for interfacing with reagents or reagent sources and analytical systems (such as ultraviolet (UV), capillary electrophoresis (CE), capillary electrochromatography (CEC), electrochemical, refractive index, and radioactivity detectors). The reader is referred for more detail to "<NPL>) and to "<NPL>). <FIG> illustrates the layout of a typical microfabricated device suitable for radiosynthesis, with all apart from features <NUM> and <NUM> being features of a known device.

A "cassette" as referred to herein is a piece of apparatus designed to fit removably and interchangeably onto an automated synthesis apparatus, in such a way that mechanical movement of moving parts of the synthesizer controls the operation of the cassette from outside the cassette, i.e. externally. A typical cassette comprises a linear array or other arrangement of valves, each linked to a port where reagents or vials can be attached, by either needle puncture of an inverted septum-sealed vial, or by gas-tight, marrying joints. Each valve has a male-female joint which interfaces with a corresponding moving arm of the automated synthesis apparatus. External rotation of the arm thus controls the opening or closing of the valve when the cassette is attached to the automated synthesis apparatus. Additional moving parts of the automated synthesis apparatus are designed to clip onto syringe plunger tips, and thus raise or depress syringe barrels. The cassette is versatile, typically having several positions where reagents can be attached, and several suitable for attachment of syringe vials of reagents or chromatography cartridges (e.g. for solid phase extraction). The cassette always comprises a reaction vessel, typically having a volume of <NUM> to <NUM>. Tubing links the components together to allow passage of reagents and reaction mixture sequentially through the cassette. Automated synthesiser apparatus are commercially available from a range of suppliers including: GE Healthcare; CTI Inc; Ion Beam Applications S. (Chemin du Cyclotron <NUM>, B-<NUM> Louvain-La-Neuve, Belgium); Raytest (Germany) and Bioscan (USA), Trasis (Liege, Belgium), Ora (B-<NUM> Philippeville, Belgium). <FIG> illustrates the layout of a typical cassette for use with an automated synthesis apparatus.

The term "means for introduction of" refers for example to the microchannels or capillaries of a microfabricated device, or to the tubing of a cassette, which lead to a vessel (loop in the microfabricated device or vial on the cassette) into which the relevant reactant is stored or reacted. Alternatively such means may be a vial that can be attached to or is attached to a cassette. In one embodiment, said precursor compound is comprised in said device.

A "precursor compound" comprises a derivative of a radiolabelled compound, designed so that a chemical reaction with a convenient chemical form of a radionuclide occurs site-specifically; can be conducted in the minimum number of steps (ideally a single step); and without the need for significant purification (ideally no further purification), to give the desired radiolabelled compound. Such precursor compounds are synthetic and can conveniently be obtained in good chemical purity. The precursor compound may optionally comprise a protecting group for certain functional groups of the precursor compound. Protecting groups are described in '<NPL>). There are many examples of known precursor compounds, as described in <NPL>.

A "radionuclide" (also referred to as "radioactive isotopes" or "radioisotopes") is an atom with an unstable nucleus, characterised by excess energy available to be imparted either to a newly created radiation particle within the nucleus or via internal conversion. During this process, the radionuclide undergoes radioactive decay, resulting in the emission of gamma ray(s) and/or subatomic particles such as alpha or beta particles. These emissions constitute ionizing radiation. Radionuclides with suitable half-lives play an important part in a number of technologies, e.g. in nuclear medicine. Preferred radionuclides in the context of the present invention are those suitable for in vivo imaging, i.e. capable of being detected externally following administration to a subject being imaged. Examples of radionuclides suitable for in vivo imaging include radioactive metal ions (e.g. positron emitters such as <NUM>Cu, <NUM>V, <NUM>Fe, <NUM>Co, <NUM>Tc <NUM>Zr or <NUM>Ga; or gamma-emitters such as <NUM>Tc, <NUM>In, <NUM>In, or <NUM>Ga), gamma-emitting radioactive halogens (e.g. <NUM>I, <NUM>I or <NUM>Br) and positron-emitting radioactive non-metals (e.g. <NUM>C, <NUM>N, <NUM>O, <NUM>F, <NUM>F, <NUM>Br, <NUM>Br or <NUM>I). For the present invention a preferred radionuclide is a positron-emitter. A preferred positron-emitter is <NUM>Zr, <NUM>Ga, <NUM>C or <NUM>F, most preferably <NUM>Ga,<NUM>C or <NUM>F and especially preferably <NUM>Ga or <NUM>F.

A suitable "radiation-sensitive material" in the context of the present invention is one that can record radiation dose for read out at a later time. Furthermore, it must be possible to embed the radiation-sensitive material into a device as defined herein above. The term "embedded" refers to the secure incorporation of one or more pieces of radiation-sensitive material into the structure of the device of the invention so that it forms part of said device but does not interfere with the normal functioning of said device. The one or more pieces of radiation-sensitive material must be located to permit exposure to radiation from the radiolabelled compound being synthesised, but to as little an extent as possible radiation from the radionuclide prior to formation of the radiolabelled compound.

In the presently claimed invention, said one or more pieces of radiation-sensitive material comprises a thermoluminescence (TL) material. TL is an established method for personal dosimetry, as described by <NPL>) along with other such methods. "TL materials" are low-cost, inorganic polycrystalline materials that can easily be embedded into polymer material typically used in suitable devices of the invention as described hereinabove. Luminescence occurs when the card is heated, which makes readings easy to carry out but also means that care needs to be taken not to inadvertently expose the material to heat prior to read-out. The device of the invention can be engineered to have various trap depths. These traps can release charge at a variety of temperatures from <NUM>-<NUM> (or alternatively the charge can be released by exposure to light), resulting in luminescence. The radiation dose, that the material has been exposed to can be measured by heating the material and counting the photons that are emitted during thermally induced decay of exited metastable electronic states in the material. Commercially available read-out devices for TL dosimeters could be used for this purpose. Examples of known TL materials include those comprising aluminium oxide (A1<NUM>O<NUM>), beryllium oxide (BeO), calcium fluoride (CaF<NUM>), lithium fluoride (LiF), calcium sulfate (CaSO<NUM>), lithium borate (Li<NUM>B<NUM>O<NUM>), calcium borate (Ca<NUM>(BO<NUM>)<NUM>), magnesium borate (MgB<NUM>O<NUM>), potassium bromide (KBr) or feldspar (KAlSi<NUM>O<NUM> - NaAlSl<NUM>O<NUM>- CaAl<NUM>Si<NUM>O<NUM>). A preferred TL material for the present invention comprises CaF<NUM>, Li<NUM>B<NUM>O<NUM>, Al<NUM>O<NUM>, CaSO<NUM> or LiF, preferably LiF, e.g. LiF:Mg,Ti or LiF:Mg,Cu,P.

In another example useful for understanding the presently claimed invention, said one or more pieces of radiation-sensitive material comprises a direct ion-storage (DIS) dosimeter measures radiation by absorbing charges into a miniature (MOSFET) ion chamber. The dosimeter can be instantaneously processed and read by an internal USB based reader. The process only take a few moments to read and record the results. Exposure to gamma, X-ray and beta radiation can be measured using this technology and instant and unlimited readouts are possible. Accumulated dose is not affected by the readout process. The dosimeter is small, durable and water resistant, as well as moderately priced.

In a further example useful for understanding the presently claimed invention, said one or more pieces of radiation-sensitive material comprises an optically-stimulated lumine (OSL) sensor. OSL sensors only require an optical path whereby a stimulating beam of light can illuminate the OSL sensor(s) and the resultant radiation induced luminescence can be routed back through the same or alternate optical path to a light detector such as a photomultiplier tube that quantifies the amount of luminescent light. In one example, the invention employs an optical path whereby an external beam of light can enter the interior of the holder, illuminate each OSL sensor and enable the luminescent light to exit the holder along the same optical path without need to remove the sensors from their normal position with respect to any filters or converting materials. The optical path may be either an optical fibre or an uninterrupted air channel through which light can travel. Dose is read from measuring return optical signal under laser illumination.

The radiation dose of each used device can be either read by the user or sent to another party to read out the radiation dose. Where the radiation dose is read someone other than the user of the device it is preferred that the device is set up to ensure that the measurement accurately reflects radiation dose due to radiolabelled compound synthesised by the device. The radiation-sensitive material is a TL material and exposing the material to an elevated temperature (sometimes referred to as "fading") can result in an erroneous reading. Alternatively, an erroneous reading that is too low could result if the path between the radioactivity emitted by the radiolabelled compound is somehow blocked. The device of the invention is therefore preferably configured to ensure an accurate reading.

The radiation-sensitive material is a TL material and the following configurations are possible:.

Claim 1:
A device comprising:
(i) means for the introduction of a precursor compound;
(ii) means for the introduction of a radionuclide;
(iii) a reaction vessel for reacting said precursor compound and said suitable source of a radionuclide to obtain a radiolabelled compound; and
(iv) one or more pieces of radiation-sensitive material (<NUM>) embedded into said device wherein at least one of said pieces is positioned to be exposed to radioactivity associated with said radiolabelled compound, wherein said one or more pieces of radiation-sensitive material (<NUM>) comprises a thermoluminescence (TL) material.