Patent Number: 060118253
Section: summary

BACKGROUND OF THE INVENTION The present invention generally relates to the production of radionuclides suitable for use in diagnostic and therapeutic radiopharmaceuticals, and specifically, to a system and method for producing radionuclides from a solid target material using a low or medium energy charged-particle accelerator. The invention particularly relates, in a preferred embodiment, to a system and method for producing .sup.64 Cu and other intermediate half-lived positron-emitting radionuclides using a biomedical cyclotron capable of generating protons at energies ranging from about 5 MeV to about 25 MeV. Low or medium energy charged-particle accelerators such as biomedical cyclotrons have been used to produce short-lived radionuclides such as .sup.15 O (t.sub.1/2 =2 minutes), .sup.13 N (t.sub.1/2 =9.96 minutes), .sup.11 C (t.sub.1/2 =20.4 minutes) and .sup.18 F (t.sub.1/2 =110 minutes) from gaseous target sources. The on-site production of these radionuclides at medical research and/or treatment centers facilitate their immediate use in diagnostic and therapeutic applications. However, other radionuclides which have become increasingly important for such applications are not currently available using an on-site accelerator in commercially significant yields and at specific activities suitable for diagnostic and therapeutic uses. For example, .sup.4 Cu is an intermediate half-lived positron-emitting radionuclide (t.sub.1/2 =12.7 hours) which is a useful radiotracer for positron emission tomography (PET) as well as a promising radiotherapy agent for the treatment of cancer. (Anderson et al., 1992; Anderson et al., 1993; Connett et al., 1993; Philpott et al., 1993; Anderson et al., 1994; Anderson et al., 1995a; Anderson, et al., 1995b). However, .sup.64 Cu is presently produced in clinically significant yields and specific activities only through fast neutron reactions using a nuclear reactor. (Herr and Botte 1950; Zinn et al., 1993) Reactor production of .sup.67 Cu at lower specific activities using a thermal neutron flux according to the reaction .sup.63 Cu(n,.gamma.).sup.64 Cu has also been reported. (Hetherington et al., 1986). As such, .sup.64 Cu is currently available for the preparation of radioimaging and radiotherapeutic agents only in limited quantities and on a limited basis via the fast neutron reaction using a nuclear reactor. Hence, improved methods are needed for producing .sup.64 Cu and other radionuclides from solid target materials using readily available in-house accelerators. The feasibility of using a hospital-sized proton cyclotron for producing a broad range of radionuclides, including .sup.64 Cu, has been investigated. (Nickles et al. 1991). Cylclotron production of .sup.64 Cu has been reported from pressed powder pellets of elemental .sup.64 Ni according to the reaction .sup.64 Ni(d,2n).sup.64 Cu (Zweit et al., 1991), and from a stack of enriched .sup.64 Ni plated foils according to the reaction .sup.64 Ni(p,n).sup.64 Cu (Szelecsenyi et al., 1993). Co-production of .sup.55 Co and .sup.64 Cu from a nickel foil soldered onto a copper or stainless steel support has also been reported. (Maziere et al., 1983). These approaches, while confirming the feasibility of producing .sup.64 Cu, did not produce clinically significant amounts of .sup.64 Cu and did not produce .sup.64 Cu at a specific activity which was suitable for use in clinical radiopharmaceutical diagnostic and/or therapeutic compositions. Moreover, these approaches did not address the practical difficulties encountered in scaling up to the high power irradiation required for such commercially useful production. The use of a cyclotron accelerator for producing other radionuclides is reported in U.S. Pat. No. 4,487,738 to O'Brien et al. (.sup.67 Cu), Mirzadeh et al., 1986 (.sup.67 Cu), Piel et al., 1991 (.sup.62 Cu), Sharma et al., 1986 (.sup.55 Co), Mushtaq and Qaim, 1989 (.sup.73 Se), Michael et al., 1981 (123I), Guillaume et al., 1988 (.sup.38 K), Vaalburg et al., 1985 (.sup.75 Br), Rosch and Qaim, 1993 (.sup.94m Tc) and Ferrier et al., 1983 (.sup.13 N from solid .sup.13 C). While these references disclose various reactions, targets, target holders, conveyance systems and separation systems, the references do not provide a comprehensive system or method for the automated, in-house production of radionuclides from solid targets in significant yields and at specific activities suitable for diagnostic or therapeutic use. SUMMARY OF THE INVENTION It is therefore an object of the present invention to produce .sup.64 Cu or other radionuclides from a solid target material using a low or medium energy charged-particle accelerator such as a cyclotron commonly found on-site at major medical treatment and/or research facilities. It is also an object to produce radionuclides in commercially significant yields and at specific activities which are suitable for use in diagnostic and therapeutic applications. It is a further object to provide a system in which such production is effected remotely, with minimal human intervention and therefore, without significant human exposure to ionizing radiation. An additional object of the invention is to minimize the expense of preparing such radionuclides. Briefly, therefore, the present invention is directed to a method for producing a radionuclide from a target nuclide using an accelerator capable of generating a beam of charged particles at energies of at least about 5 MeV. A solid target which includes the target nuclide is loaded in a target holder suitable for use with the accelerator, and irradiated with the charged-particle beam at energies of at least about 5 MeV to form the radionuclide. After irradiation, the irradiated target is remotely and automatically transferred, without direct human contact and without human exposure to measurable ionizing radiation, from the target holder to an automated separation system. The irradiated target is transferred alone, in its own free form, without transferring any subassembly of the target holder. The radionuclide is then separated from unreacted target nuclide using the automatic and remotely operable separation system. In a variation of this method, the irradiated target is transferred from the target holder to a pneumatic or hydraulic conveyance system which includes a transfer fluid moving through a transfer line, the fluid movement being effected by a motive force means. The irradiated target is conveyed using the pneumatic or hydraulic conveyance system, either in direct contact with the transfer and being entrained therein, or alternatively, in a transfer capsule which houses the target. The invention is also directed to a method for producing a radionuclide from a target nuclide using an accelerator capable of generating a beam of charged particles at energies ranging from about 5 MeV to about 25 MeV. A solid target comprising the target nuclide is loaded in a target holder adapted for use with the accelerator. The target comprises a substrate and a target layer electroplated on a surface of the substrate. The substrate consists essentially of a material which is chemically inert relative to the target layer and which, preferably, has a thermal conductivity and a melting point which is at least about equal to the thermal conductivity and the melting point, respectively, of the target layer. The target layer consists essentially of a target nuclide capable of reacting with charged particles generated by the accelerator at energies ranging from about 5 MeV to about 25 MeV to form the radionuclide. The target layer has a projected thickness that will produce at least about 50% of the thick target yield for the energy at which the reaction takes place. This target is irradiated with a beam of charged particles generated by the accelerator for at least about one hour to form the radionuclide. The charged-particle beam has an energy ranging from about 5 MeV to about 25 MeV and a current sufficient to produce a clinically significant yield of the radionuclide. In a preferred application, the present invention is directed to a method for producing clinical grade .sup.64 Cu suitable for use in preparing radiodiagnostic agents such as a PET imaging agent or for use in preparing radiotherapeutic agents suitable for use in clinical applications. A target comprising isotopically enriched .sup.64 Ni is irradiated with a proton beam to produce .sup.64 Cu according to the reaction .sup.64 Ni(p,n).sup.64 Cu. The amount of .sup.64 Cu produced is at least sufficient for preparing a radiodiagnostic agent or, alternatively, at least sufficient for preparing a radiotherapeutic agent. The proton beam has an energy of at least about 5 MeV and a current at least sufficient to produce an amount of .sup.64 Cu sufficient for preparing a radiodiagnostic agent or, alternatively, at least sufficient for preparing a radiotherapeutic agent during the period of irradiation. The .sup.64 Cu is separated from unreacted .sup.64 Ni, and the separated .sup.64 Cu has a specific activity which is at least sufficient for clinical use in a radioimaging or radiotherapeutic agents. The invention is further directed to a method for preparing a solid target which is suitable for use in producing a radionuclide using an accelerator capable of generating a beam of charged particles at energies ranging from about 5 MeV to about 25 MeV. A target material is electroplated onto a surface of a substrate consisting essentially of an inert material to form a target layer thereon. The target material consists essentially of a target nuclide capable of reacting with charged particles generated in the accelerator at energies ranging from about 5 MeV to about 25 MeV to form the radionuclide. The target layer has a projected thickness that will produce at least about 50% of the thick target yield for the reaction. The invention is directed, as well, to a target holder for use with an accelerator to irradiate a solid target with a charged-particle beam generated by the accelerator at an energy greater than about 5 MeV for production of a radionuclide. The target holder comprises an elongated body having a first end and a second end and a passage therethrough extending from the first end to second end. The first end of the body is adapted to sealingly engage an accelerator capable of generating a beam of charged particles at an energy of at least about 5 MeV for the production of a radionuclide. The body also has an irradiation chamber which is defined in the body by the passage through the body. The second end of the body has a seat adapted to sealingly receive a solid target such that the target is in direct alignment with the charged-particle beam during irradiation of the target. The seat has an aperture for allowing fluid communication between the irradiation chamber and the target, thereby allowing the charged-particles generated by the accelerator during irradiation to travel unimpeded from the accelerator to the target. The body has at least one port in fluid communication with the irradiation chamber for drawing and sustaining a vacuum in the chamber or for pressurizing the chamber. A vacuum drawn in the chamber is effective to hold the target in the seat prior to or after irradiation. Pressure in the chamber is effective to act through the aperture in the seat to separate the target from the seat and eject the target for further processing after irradiation. In another embodiment, the target holder comprises an elongated body having a first end and a second end and a passage therethrough extending from the first end to second end with the first end of the body being adapted to sealingly engage an accelerator, the passage through the body defining an irradiation chamber, and the second end of the body having a seat adapted to sealingly receive a solid target with the target in direct alignment with the charged-particle beam during irradiation of the target. The seat can include an aperture as described above, or alternatively, can include a window or a foil which separates the irradiation chamber from the target during irradiation. The irradiation chamber is generally adapted to sustain a vacuum during irradiation of the target. The target holder further comprises a cooling head adapted to simultaneously hold a plurality of targets. The cooling head includes a plurality of cavities and seats adapted to sealingly receive a target. Each seat has an aperture for allowing fluid communication between the respective cavity and the target. The head is retractable from the body and engageable with the body to successively hold each of the targets against the seat of the body during irradiation. The invention is directed, moreover, to a system for use in producing a radionuclide from a target nuclide by irradiating the target nuclide with charged particles generated in an accelerator, the resulting radionuclide being useful for diagnostic or therapeutic radiopharmaceutical applications. The system comprises a solid target which includes a target nuclide capable of reacting with charged particles having an energy of at least about 5 MeV to form the radionuclide, an accelerator capable of generating a beam of the charged particles at an energy of at least about 5 MeV to irradiate the target, a target holder adapted for use with the accelerator for positioning the target in the charged particle beam during irradiation, the target holder including means for remotely unloading the irradiated target from the target holder after irradiation, and a pneumatic or hydraulic conveyance system to which the irradiated target is remotely transferred from the target holder. Other features and objects of the present invention will be in part apparent to those skilled in the art and in part pointed out hereinafter.