Robert E. Klinkowstein

Efficient production of high specific activity 64Cu using a biomedical cyclotron.

Copper-64 (T 1/2 = 12.7 h) is an intermediate-lived positron-emitting radionuclide that is a useful radiotracer for positron emission tomography (PET) as well as a promising radiotherapy agent for the treatment for cancer. Currently, copper-64 suitable for biomedical studies is produced in the fast neutron flux trap (irradiation of zinc with fast neutrons) at the Missouri University Research Reactor. Access to the fast neutron flux trap is only possible on a weekly basis, making the availability of this tracer very limited. In order to significantly increase the availability of this intermediate-lived radiotracer, we have investigated and developed a method for the efficient production of high specific activity Cu-64 using a small biomedical cyclotron. It has been suggested that it may be possible to produce Cu-64 on a small biomedical cyclotron utilizing the 64Ni(p,n)64Cu nuclear reaction. We have irradiated both natural nickel and enriched (95% and 98%) Ni-64 plated on gold disks. Nickel has been electroplated successfully at thicknesses of approximately 20-300 mm and bombarded with proton currents of 15-45 microA. A special water-cooled target had been designed to facilitate the irradiations on a biomedical cyclotron up to 60 microA. We have shown that it is possible to separate Cu-64 from Ni-64 and other reaction byproducts rapidly and efficiently by using ion exchange chromatography. Production runs using 19-55 mg of 95% enriched Ni-64 have yielded 150-600 mCi of Cu-64 (2.3-5.0 mCi/microAh) with specific activities of 94-310 mci/microgram Cu. The cyclotron produced Cu-64 had been used to radiolabel PTSM [pyruvaldehyde bis-(N4-methylthiosemicarbazone), used to quantify myocardial, cerebral, renal, and tumor blood flow], MAb 1A3 [monoclonal antibody MAb to colon cancer], and octreotide. A recycling technique for the costly Ni-64 target material has been developed. This technique allows the nickel eluted off the column to be recovered and reused in the electroplating of new targets with an overall efficiency of greater than 90%.

Apparatus for performing dual energy medical imaging

An energy substraction medical imaging system which is used for imaging a body part impregnated with a radio-opaque dye such as iodine is provided. The system includes an electron beam target having a target surface which, when excited by a high-energy electron beam, generates radiation having strong K.sub.α at energy levels slightly above and slightly below the K-edge energy level of the dye. The target surface is preferably formed of a compound containing lanthanum, such as lanthanum oxide. The target may also be formed of a compound containing a material having a K.sub.α line at an energy level slightly above the dye K-edge and a material with K.sub.α line slightly below the dye K-edge or with separate sections containing such materials which are alternately excited. The target is excited by a high-energy electron beam from a suitable source, the electron beam having sufficient energy to provide a high photon yield at the K.sub.α line energy levels and sufficient power to produce the required photon fluences at such energy lines for the medical imaging application. One of the K.sub.α lines in the radiation output from the excited target is selectively filtered and the output from the filter, both with the K.sub.α line filter and with the line unfiltered, are passed through the body part being imaged to an x-ray detector. The output from the detector in response to the filtered and unfiltered outputs is processed to obtain an image of the body part. Continuum radiation from the target is reduced by filtering the continuum radiation at frequencies above the below the K.sub.α line energy levels of the target compound, by viewing the radiation from the target in the backward direction to the beam, and by having the thickness of the target equal to a fraction of the electron range in the target compound material.

Production and purification of gallium-66 for preparation of tumor-targeting radiopharmaceuticals

Gallium-66 (T(1/2) = 9.49 h) is an intermediate-lived radionuclide that has potential for positron emission tomography (PET) imaging of biological processes with intermediate to slow target tissue uptake. We have produced (66)Ga by the (66)Zn(p,n) (66)Ga nuclear reaction using a small biomedical cyclotron and have investigated methods for purifying (66)Ga that could be applied to the development of an automated processing system. Measured yields of (66)Ga were very high with a production yield of nearly 14 mCi/microA-h at 14.5 MeV bombardment energy, a value in excellent agreement with theoretical predictions based on literature cross sections for the (66)Zn(p,n) (66)Ga reaction. Gallium-66 has been purified from irradiated zinc targets two ways, by cation-exchange chromatography and diisopropyl ether extraction. The concentrations of stable contaminants in (66)Ga following the two processing methods were determined, and it was found that iron and zinc were present at levels up to an order of magnitude higher after cation-exchange chromatography. The bioconjugates DOTA-Tyr(3)-octreotide and DOTA-biotin were labeled with (66)Ga purified by both methods. Following purification of (66)Ga by solvent extraction, radiochemical yields in excess of 85% were obtained for both compounds, in contrast to much lower labeling yields (less than 20%) obtained after the cation-exchange separation. Higher concentrations of stable contaminants likely contributed to the poor radiochemical yields for labeling DOTA-Tyr(3)-octreotide and DOTA-biotin with cation-exchanged (66)Ga. The lower purity and radiolabeling yields obtained using cation-exchange do not warrant the development of an automated processing system based on this method. Therefore, work is in progress to automate the diisopropyl ether extraction method for routine processing of (66)Ga.

Low-energy biomedical GC–AMS system for 14C and 3H detection

Abstract The use of accelerator mass spectrometry (AMS) in biomedical research will require the development of cost-effective, laboratory-sized AMS systems that can be used in conjunction with gas and liquid phase separation techniques. This paper describes a prototype GC–AMS system designed for the detection of 14C and 3H in organic samples. The entire AMS system including the injector, ion source, tandem accelerator, and high-energy analyzer is approximately 3.5 m wide, 1.5 m high and 1 m deep. Also described are methods for converting gas chromatograph (GC) effluent to gaseous CO2 for 14C-labeled compounds. A gas-fed cesium (Cs) sputter ion source converts the CO2 into C− for injection into the AMS accelerator, allowing on-line analysis of 14C-labeled biological samples with AMS.

Design of a compact 1 MV AMS system for biomedical research

Abstract The widespread use of accelerator mass spectrometry in biomedical research will require the development of cost-effective, laboratory-sized AMS systems which can be used in conjunction with conventional gas and liquid phase separation techniques. This paper describes the design of a low energy AMS system for the detection of 14C and 3H in labeled biological samples. The system utilizes a compact 1 MV tandem accelerator which incorporates a foil stripper. The low energy analyzer, accelerating column, and high energy analyzer are designed for efficient transport and analysis of both carbon and hydrogen beams using the minimum number of optical elements. The resulting instrument is very compact: the entire AMS system including the injector, ion source and high energy analyzer is just under 3 m wide and is approximately 1.3 m high and 1 m deep. The relatively small size of this system will allow its installation in most biomedical laboratory facilities. The system is predicted to provide a statistical precision of better than 2% for the quantitation of attomole samples.

Development of a High-Power Water-Cooled Beryllium Target for use in Accelerator-Based Boron Neutron Capture Therapy

In order for ABNCT (accelerator-based boron neutron capture therapy) to be successful, 10-16 kW or more must be dissipated from a target. Beryllium is well suited as a high-power target material. Beryllium has a thermal conductivity of 200 W/mK at 300 K which is comparable to aluminum, and it has one of the highest strength to weight ratios of any metal even at high temperatures (100 MPa at 600 degrees C). Submerged jet impingement cooling has been investigated as an effective means to remove averaged power densities on the order of 2 x 10(7) W/m2 with local power densities as high as 6 x 10(7) W/m2. Water velocities required to remove these power levels are in excess of 24 m/s with volumetric flow rates of nearly 100 GPM. Tests on a prototype target revealed that the heat transfer coefficient scaled as Re0.6. With jet-Reynolds numbers as high as 5.5 x 10(5) heat transfer coefficients of 2.6 x 10(5) W/m2K were achieved. With this type of cooling configuration 30 kW of power could be effectively removed from a beryllium target placed on the end of an accelerator. A beryllium target utilizing a proton beam of 3.7 MeV and cooled by submerged jet impingement could be used to deliver a dose of 13 RBE cGy/min mA to a tumor at a depth of 4 cm. With a beam power of 30 kW, 1500 cGy could be delivered in 14.2 min.

A Kα dual energy x-ray source for coronary angiography

The use of characteristic‐line radiation from rare‐earth targets bombarded by high‐energy (up to 1 MeV) electron beams has been evaluated as an x‐ray source for dual energy K‐edge subtraction imaging of the human coronary arteries. Two characteristic‐line x‐ray sources, one using the split K α1 and K α2 lines of lanthanum excited by a high‐energy electron beam and the other using the K α lines of barium and cerium, were studied. A Monte Carlo electron–photon simulation was used to calculate x‐ray spectra and energy deposition profiles from targets of these elements bombarded by electrons in the energy range 140 keV to 1 MeV. A general dual‐energy imaging model was developed that used these calculated source spectra to numerically investigate the dependence of the subtraction image signal‐to‐noise ratio on such factors as the ratio of K‐line to x‐ray continuum yield, continuum spectral shape, x‐ray filtering, and detector response. A signal averaging technique for enhancing the signal‐to‐noise ratio was also evaluated. The results of these calculations were used to identify an optimum electron beam, target, filter, and detector configuration. A compact electron accelerator capable of providing the required electron beam parameters was designed. Calculations indicate that under ideal conditions the optimized system would be capable of imaging 2 mg/cm2 of iodine contrast agent in 20 g/cm2 of tissue with a signal‐to‐noise ratio of 5, a detector pixel size of 0.25 mm2, and a total image acquisition time of 10 ms. These parameters are consistent with those needed to image the human coronary arteries after an intravenous injection of iodine contrast agent. These capabilities, along with the relatively modest hardware requirements of this system, make it attractive as an x‐ray source for dual energy transvenous coronary angiography.

Positron beam production with a deuteron accelerator

Abstract A graphite target was bombarded with 1.5 MeV deuterons, producing the isotope 13 N, which is a positron emitter. Using the activated material a slow positron beam with an intensity of 0.7 (0.14)×10 5 s −1 was produced. A (saturated) 13 N yield of 63 (11) MBq/μA was observed, with 1.5 MeV deuterons, which is consistent with previous calculations and experiments. Our results show that, with the method we outline, positron beams with an average intensity of up to 1×10 8 s −1 may be produced.

A windowless 13N production target for use with low energy deuteron accelerators

The recent development of low energy accelerators for positron emission tomography has necessitated the development of new targets for 13N production. 12C(d,n)13N reaction yields in graphite at low deuteron beam energies (0.8-3.2 MeV) are presented and a new technique for the in situ extraction of 13N activity from solid graphite and subsequent conversion to [13N] ammonia is described. The target is windowless and is reusable for multiple isotope production runs. This technique utilizes radio frequency induction heating to rapidly heat the graphite to combustion temperatures in an O2 gas stream. The conversion of activity induced in the target to [13N] ammonia in under 10 min with an overall decay-corrected efficiency of 45% is reported.

Production of [13N]ammonia applicable to low energy accelerators.

We have developed a technique for the rapid conversion of the nitrogen-13 induced in a graphite target into nitrogen oxides. This was accomplished by heating the graphite target in a stream of pure oxygen at 800 degrees C. Less than 20% of the radioactivity was found in the form of [13N]nitrogen. The rest of the radioactivity was efficiently trapped in a solid-phase medium that consisted of an aqueous solution of 5% NaOH dispersed in silica gel. The radioactivity from this solid-phase medium was eluted with water (94% recovery) and found to be in the form of 13NO2- (99%). This was subsequently converted to [13N]ammonia with Raney-nickel, either by a conventional liquid-phase reduction with an overall conversion efficiency to ammonia of 45%, or by an incorporation of the Raney-nickel into the solid-phase medium. The latter system resulted in an overall conversion efficiency to ammonia of 37 +/- 9%, with a radiochemical purity of nearly 100% and a synthesis time under 17 min.