Patent Application
20080067413
The above-mentioned features of the invention will become more clearly understood from the following detailed description of the invention read together with the drawings in which:
The present invention, i.e., the biomarker generator system, is described more fully hereinafter. This invention may, however, 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.
Definitions
The terms “patient” and “subject” refer to any human or animal subject, particularly including all mammals.
The term “radiochemical” is intended to encompass any organic or inorganic compound comprising a covalently-attached radioisotope (e.g., 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG)), any inorganic radioactive ionic solution (e.g., Na[18F]F ionic solution), or any radioactive gas (e.g., [11C]CO2), particularly including radioactive molecular imaging probes intended for administration to a patient or subject (e.g., by inhalation, ingestion, or intravenous injection) for human imaging purposes, such probes are referred to also in the art as radiopharmaceuticals, radiotracers, or radioligands. These same probes are also useful in other animal imaging.
The term “reactive precursor” refers to an organic or inorganic non-radioactive molecule that, in synthesizing a biomarker or other radiochemical, is reacted with a radioactive isotope (radioisotope), typically by nucleophilic substitution, electrophilic substitution, or ion exchange. The chemical nature of the reactive precursor varies and depends on the physiological process that has been selected for imaging. Exemplary organic reactive precursors include sugars, amino acids, proteins, nucleosides, nucleotides, small molecule pharmaceuticals, and derivatives thereof.
The term “unit dose” refers to the quantity of radioactivity, expressed in millicuries (mCi), that is administered for PET to a particular class of patient or subject. For example, a human adult generally requires a unit dose of biomarker in the range of approximately ten (10) mCi to approximately fifteen (15) mCi. In another example, a unit dose for a small animal such as a mouse may be only a few microcuries (μCi). A unit dose of biomarker necessarily comprises a unit dose of a radioisotope.
Other terms are defined as necessary in the detailed description that follows.
Biomarker Generator System and Method
The biomarker generator system includes (1) a small, low-power particle accelerator for generating a unit dose of a positron-emitting radioisotope and (2) a radiochemical synthesis subsystem having at least one microreactor and/or microfluidic chip. The radiochemical synthesis subsystem is for receiving the unit dose of the radioisotope, for receiving at least one reagent, and for synthesizing the unit dose of a biomarker using the unit dose of the positron-emitting radioisotope and the reagent(s). Although the following description of the biomarker generator system may emphasize somewhat the production of biomarkers that are labeled with either fluorine-18 (18F) or carbon-11 (11C), one skilled in the art will recognize that the biomarker generator system is provided for producing unit doses of biomarkers that are labeled with other positron-emitting radioisotopes as well, including nitrogen-13 (13N) and oxygen-15 (15O). One skilled in the art will recognize that the biomarker generator system is provided also for producing unit doses of biomarkers that are labeled with radioisotopes that do not emit positrons or for producing small doses of radiochemicals other than biomarkers. A description of the small, low-power particle accelerator is followed by a description of the radiochemical synthesis subsystem.
As stated previously, most clinically-important positron-emitting radioisotopes have half-lives that are very short. Consequently, the particle accelerators used in generating these radioisotopes are for producing a large amount of radioisotope, typically on the order of curies (Ci), in recognition of the significant radioactive decay that occurs during the relatively long time that the radioisotope undergoes processing and distribution. Regarding the present invention, the small, low-power particle accelerator (hereinafter, “micro-accelerator”) departs significantly from this established practice in that it is engineered to produce per run a maximum amount of radioisotope on the order of millicuries (mCi), which is three orders of magnitude less than a conventional particle accelerator. In most embodiments, the micro-accelerator produces per run a maximum of less than, or equal to, approximately sixty (60) mCi of the desired radioisotope. In one such embodiment, the micro-accelerator produces per run a maximum of approximately eighteen (18) mCi of fluorine-18. In another such embodiment, the micro-accelerator produces per run a maximum of approximately five (5) mCi of fluorine-18. In another such embodiment, the micro-accelerator produces per run a maximum of approximately thirty (30) mCi of carbon-11. In still another such embodiment, the micro-accelerator produces per run a maximum of approximately forty (40) mCi of nitrogen-13. In still another such embodiment, the micro-accelerator produces per run a maximum of approximately sixty (60) mCi of oxygen-15. Such embodiments of the micro-accelerator are flexible in that they can provide a quantity of radioisotope adequate, or slightly more than adequate, for the each of various classes of patients and subjects that undergo PET, including, for example, human adults and children, which generally require between approximately five (5) and approximately fifteen (15) mCi of radioactivity per unit dose of biomarker, and small laboratory animals, which generally require approximately one (1) mCi of radioactivity per unit dose of biomarker.
A particle accelerator for producing per run a maximum of less than, or equal to, approximately sixty (60) mCi of radioisotope requires significantly less beam power than a conventional particle accelerator, which typically generates a beam having a power of between 1,400 and 2,160 watts (between 1.40 and 2.16 kW) and typically having a current of approximately 120 microamperes (μA) and typically consisting essentially of charged particles having an energy of approximately 11 to approximately 18 MeV (million electron volts). Specifically, all embodiments of the micro-accelerator generate a beam having a maximum power of only less than, or equal to, approximately fifty (50) watts. In one such embodiment, the micro-accelerator generates an approximately one (1) μA beam consisting essentially of protons having an energy of approximately seven (7) MeV, the beam having beam power of approximately seven (7) watts and being collimated to a diameter of approximately one (1) millimeter. As a direct result of the dramatic reduction in maximum beam power, the micro-accelerator is significantly smaller and lighter than a conventional particle accelerator and requires less electricity. Many of the components of the micro-accelerator are less costly and less sophisticated, such as the magnet, magnet coil, vacuum pumps, and power supply, including the RF oscillator. In some embodiments, the micro-accelerator has an electromagnet that has a mass of only approximately three (3) tons, as opposed to between ten (10) and twenty (20) tons, which represents the mass of an electromagnet typical of a conventional particle accelerator used in PET. In other embodiments, a permanent magnet is used instead of the customary electromagnet, eliminating the need for the magnet coil, further reducing the size, mass, and complexity of the micro-accelerator. The overall architecture of the micro-accelerator may vary, also. In some embodiments, the micro-accelerator is a two-pole cyclotron. In other embodiments, it is a four-pole cyclotron. One skilled in the art will recognize that it may be advantageous to use a four-pole cyclotron for certain applications, partly because a four-pole cyclotron accelerates charged particles more quickly than a two-pole cyclotron using an equivalent accelerating voltage. One skilled in the art will recognize also that other types of particle accelerators may function as a micro-accelerator. Such particle accelerators include linear accelerators, radiofrequency quadrupole accelerators, and tandem accelerators. Subtler variations in the micro-accelerator are described in the next few paragraphs.
One skilled in the art will acknowledge that, in an accelerating field, beams of positively-charged particles generally are more stable than beams of negatively-charged particles. Specifically, at the high velocities that charged particles experience in a particle accelerator, positively-charged particles are more stable, as they either have no electrons to lose (e.g., H+) or, because of their electron deficit, are less likely to lose electrons than are negatively-charged particles. When an electron is lost, it usually causes the charged particle to strike an interior surface of the particle accelerator, generating additional radiation, hence increasing the shielding necessary to reduce radiation outside the particle accelerator to acceptable levels. Therefore, in some embodiments, the micro-accelerator has an ion source system optimized for proton (H+) production. In other embodiments, the micro-accelerator has an ion source system optimized for deuteron (2H+) production. In still other embodiments, the micro-accelerator has an ion source system optimized for alpha particle (He2+) production. One skilled in the art will recognize that particle accelerators that accelerate only positively-charged particles require significantly less vacuum pumping equipment, thus further reducing the particle accelerator's size, mass, and complexity. One skilled in the art will recognize also, however, that the acceleration of negatively-charged particles is necessary for certain applications and requires a micro-accelerator having an ion source system appropriate for that purpose.
As stated previously, and as depicted in
In this embodiment of the micro-accelerator, the target substance 180 is a solution comprising [18O]water. The target substance 180 is conducted by a stainless steel tube 192. The stainless steel tube 192 is secured such that a section of it (hereinafter, “target section” 194) is centered in the path 190 that the beam 184 travels following the final increment of acceleration. Additionally, the longitudinal axis of the target section 194 is approximately parallel to the magnetic field 182 generated by the magnet subsystem and approximately perpendicular to the electric field generated by the RF subsystem. The remainder of the stainless steel tube is selectively shaped and positioned such that it does not otherwise obstruct the path followed by the beam during or following its acceleration. The target section 194 defines, on the side proximate to the beam, an opening 196 that is adapted to receive the beam 184. The opening is sealed with a very thin layer of foil comprised of aluminum, and the foil, which functions as the target window 198, also assists in preventing the target substance from escaping. Also, valves 200, 202 in the stainless steel tube secure a selected volume of the target solution in place for bombardment by the beam 184.
The diameter of the stainless steel tube varies depending on the configuration of the micro-accelerator, or more specifically, the micro-cyclotron. Generally, it is less than, or equal to, approximately the increase per orbit in the orbital radius of the beam, which in this embodiment is approximately four (4) millimeters. In this embodiment of the micro-cyclotron, the diameter of the stainless steel tube is approximately four (4) millimeters. Recall that with every orbit, the beam gains a predetermined fixed quantity of energy that is manifested by an incremental fixed increase in the orbital radius of the beam. When a tube having that diameter or less is centered in the path that the beam travels following its final increment of acceleration, an undesirable situation is avoided in which part of the beam, during its previous orbit, bombards the edge of the tube proximate to the center of the orbit, reducing the efficiency of the beam.
As the beam 184 of protons bombards the target substance 180, which in this embodiment has an unusually small volume of approximately one (1) milliliter, the beam 184 interacts with the oxygen-18 atoms in the [180]water molecules. That nuclear interaction produces no-carrier-added fluorine-18 via an 18O(p,n)18F reaction. Such an unusually small volume of the target substance 180 is sufficient because a unit dose of biomarker for PET requires a very limited quantity of the radioisotope, i.e., a mass of radioisotope on the order of nanograms or less. Because the concentration of fluorine-18 obtained from a proton bombardment of [18O]water usually is below one (1) ppm, this dilute solution of fluorine-18 needs to be concentrated to approximately 100 ppm to optimize the kinetics of the biomarker synthesis reactions. This occurs upon transfer of the target substance 180 from the micro-accelerator to the radiochemical synthesis subsystem. Before proceeding further, it is also appropriate to note that one skilled in the art will recognize that the internal target subsystem may be modified to enable the production of other radioisotopes (or radiolabeled precursors), including [11C]CO2 and [11C]CH4, both of which are widely used in research. One skilled in the art will recognize also that certain methods of producing a radioisotope (or radiolabeled precursor) require an internal target subsystem that can manipulate a gaseous target substance. Still other methods require an internal target subsystem that can manipulate a solid target substance.
As indicated previously, the target substance is transferred to the radiochemical synthesis subsystem having at least one microreactor and/or microfluidic chip. Additionally, in order to synthesize the biomarker, at least one reagent other than the radioisotope must be transferred to the radiochemical synthesis subsystem. Reagent, in this context, is defined as a substance used in synthesizing the biomarker because of the chemical or biological activity of the substance. Examples of a reagent include a solvent, a catalyst, an inhibitor, a biomolecule, and a reactive precursor. Synthesis, in this context, includes the production of the biomarker by the union of chemical elements, groups, or simpler compounds, or by the degradation of a complex compound, or both. It, therefore, includes any tagging or labeling reactions involving the radioisotope. Synthesis includes also any processes (e.g., concentration, evaporation, distillation, enrichment, neutralization, and purification) used in producing the biomarker or in processing the target substance for use in synthesizing the biomarker. The latter is especially important in instances when, upon completion of the bombardment of the target substance, (1) the volume of the target substance is too great to be manipulated efficiently within some of the internal structures of the microreaction subsystem (or microfluidic subsystem) and (2) the concentration of the radioisotope in the target substance is lower than is necessary to optimize the synthesis reaction(s) that yield the biomarker. In such instances, the radiochemical synthesis subsystem incorporates the ability to concentrate the radioisotope, which may be performed using integrated separation components, such as ion-exchange resins, semi-permeable membranes, or nanofibers. Such separations via semi-permeable membranes usually are driven by a chemical gradient or electrochemical gradient. Another example of processing the target substance includes solvent exchange.
The radiochemical synthesis subsystem, after receiving the unit dose of the radioisotope and after receiving one or more reagents, synthesizes a unit dose of a biomarker. Overall, the micro-accelerator and the radiochemical synthesis subsystem, together in the same system, enable the generation of a unit dose of the radioisotope in combination with the synthesis of a unit dose of the biomarker. Microreactors and microfluidic chips typically perform their respective functions in less than fifteen (15) minutes, some in less than two (2) minutes. One skilled in the art will recognize that a radiochemical synthesis subsystem having at least one microreactor and/or microfluidic chip is flexible and may be used to synthesize a biomarker other than [18F]FDG, including a biomarker that is labeled with a radioisotope other than fluorine-18, such as carbon-11, nitrogen-13, or oxygen-15. One skilled in the art will recognize also that such a subsystem may comprise parallel circuits, enabling simultaneous production of unit doses of a variety of biomarkers. Finally, one skilled in the art will recognize that the biomarker generator system, including the micro-accelerator, may be engineered to produce unit doses of biomarker on a frequent basis.
In still another embodiment of the biomarker generator system, the micro-accelerator is engineered to produce a “precursory unit dose of the radioisotope” for transfer to the radiochemical synthesis subsystem, instead of a unit dose. Unit dose, as stated previously, refers to the quantity of radioactivity, expressed in millicuries (mCi), that is administered for PET to a particular class of patient or subject. For example, a human adult generally requires a unit dose of biomarker in the range of approximately ten (10) mCi to approximately fifteen (15) mCi. Because clinically-important positron-emitting radioisotopes have half-lives that are short, e.g., carbon-11 has a half-life of only approximately twenty (20) minutes, it sometimes is insufficient to produce merely a unit dose of the radioisotope, primarily due to the time required to synthesize the biomarker. Instead, a precursory unit dose of the radioisotope is required, i.e., a dose of radioisotope that, after decaying for a length of time approximately equal to the time required to synthesize the biomarker, yields a quantity of biomarker having a quantity of radioactivity approximately equal to the unit dose appropriate for the particular class of patient or subject undergoing PET. For example, if the radiochemical synthesis subsystem requires twenty (20) minutes to synthesize a unit dose of a biomarker comprising carbon-11 (t½=20 min), the precursory unit dose of the radioisotope (carbon-11) is approximately equal to 200% of the unit dose of the biomarker, thereby compensating for the radioactive decay. Such a system therefore requires an embodiment of the micro-accelerator that can produce per run at least approximately thirty (30) mCi of carbon-11. Accordingly, such a system requires an embodiment of the radiochemical synthesis subsystem that can receive and process per run at least approximately thirty (30) mCi of carbon-11, which generally is in the form of one of the following two radiolabeled precursors: [11C]CO2 and [11C]CH4.
Another clinically-important positron-emitting radioisotope has a half-life that is even shorter: oxygen-15 has a half-life of only approximately two (2) minutes. Thus, if a microreaction system (or microfluidic system) requires four (4) minutes to synthesize a unit dose of a biomarker comprising oxygen-15, the precursory unit dose of the radioisotope (oxygen-15) is approximately equal to 400% of the unit dose of the biomarker, thereby compensating for the radioactive decay. Such a system therefore requires an embodiment of the micro-accelerator that can produce per run approximately sixty (60) mCi of oxygen-15. Accordingly, such a system requires an embodiment of the radiochemical synthesis subsystem that can receive and process per run approximately sixty (60) mCi of oxygen-15.
One skilled in the art will recognize that, in some instances, the precursory unit dose may need to compensate also for a radiochemical synthesis subsystem that has a percent yield that is significantly less than 100%. One skilled in the art will recognize also that, in some instances, the precursory unit dose may need compensate also for radioactive decay during the time required in administering the biomarker to the patient or subject. Finally, one skilled in the art will recognize that, due to the significant increase in inefficiency that would otherwise result, the synthesis of a biomarker comprising a positron-emitting radioisotope should be completed within approximately the two half-lives immediately following the production of the unit dose (or precursory unit dose) of the positron-emitting radioisotope. The operative half-life is, of course, the half-life of the positron-emitting radioisotope that has been selected to serve as the radioactive tag or label. Accordingly, none of the various embodiments of the micro-accelerator can produce per run more than approximately seventy (70) mCi of radioisotope, and none of the various embodiments of the radiochemical synthesis subsystem can receive and process per run more than approximately seventy (70) mCi of radioisotope.
In sum, the biomarker generator system allows for the nearly on-demand production of approximately one (1) unit dose of biomarker via the schematic illustration depicted in
