Ruth E. Shefer

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%.

Accelerator‐based epithermal neutron beam design for neutron capture therapy

Recent interest in the production of epithermal neutrons for use in boron neutron capture therapy (BNCT) has promoted an investigation into the feasibility of generating such neutrons with a high current proton accelerator. Energetic protons (2.5 MeV) on a 7Li target produce a spectrum of neutrons with maximum energy of roughly 800 keV. A number of combinations of D2O moderator, lead reflector, 6Li thermal neutron filtration, and D2O/6Li shielding will result in a useful epithermal flux of 1.6 x 10(8) n/s at the patient position. The neutron beam is capable of delivering 3000 RBE-cGy to a tumor at a depth of 7.5 cm in a total treatment time of 60-93 min (depending on RBE values used and based on a 24-cm diameter x 19-cm length D2O moderator). Treatment of deeper tumors with therapeutic advantage would also be possible. Maximum advantage depths (RBE weighted) of 8.2-9.2 (again depending on RBE values and precise moderator configuration) are obtained in a right-circular cylindrical phantom composed of brain-equivalent material with an advantage ratio of 4.7-6.3. A tandem cascade accelerator (TCA), designed and constructed at Science Research Laboratory (SRL) in Somerville MA, can provide the required proton beam parameters for BNCT of deep-seated tumors. An optimized configuration of materials required to shift the accelerator neutron spectrum down to therapeutically useful energies has been designed using Monte Carlo simulation in the Whitaker College Biomedical Imaging and Computation Laboratory at MIT. Actual construction of the moderator/reflector assembly is currently underway.

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.

Boron neutron capture synovectomy: Treatment of rheumatoid arthritis based on the 10B(n,α)7Li nuclear reaction

A novel application of the 10 B (n,α) 7 Li nuclear reaction for the treatment of rheumatoid arthritis is under investigation. Rheumatoid arthritis is characterized by a painful inflammation of the membrane (synovium) lining articular joints. Since the tissue targeted for treatment is the diseased synovial membrane and the goal is synovial ablation (“synovectomy”), the proposed treatment is called Boron Neutron Capture Synovectomy. Development of this therapeutic modality has been carried out in a number of areas, including the ex vivo and in vivo evaluation of 10 B in arthritic synovium, and the design and construction of a dedicated neutron beam assembly for joint irradiation. Ex vivo evaluation of boron uptake in human arthritic synovium using K 2 B 12 H 12 has demonstrated that 10 B concentrations of 550–2400 ppm are repeatedly obtained. Preliminary in vivo experiments in an arthritic rabbit model have shown that synovial boron concentrations of approximately 265–950 ppm are obtained at 15 min post intra-articular injection. With these uptake levels experimental evaluation of the efficacy of BNCS in the treatment of rheumatoid arthritis in an animal model can be carried out. Optimal neutron beams suitable for joint irradiation are shown to be lower in energy than those used for BNCT. An assembly comprising a graphite reflector surrounding a D 2 O moderator has been designed, constructed, and installed on the 4.1 MeV tandem electrostatic accelerator at MIT’s Laboratory for Accelerator Beam Applications. Monte Carlo calculations predict a total therapy time of between 8.4 and 31 min for the human knee, depending on the charged particle reaction used; a particle beam current of 1 mA is assumed. Therapy times to treat a human finger joint range from 4 to 14 min for a 1 mA accelerator current. These treatment times are based on average 10 B in vivo uptake levels (observed experimentally in the rabbit knee) of 950 ppm and a 10 000 RBE-cGy treatment dose. It is concluded that Boron Neutron Capture Synovectomy, consisting of intra-articular injection of a 10 B -labeled compound followed by neutron irradiation of the joint, has considerable potential as a means of treating rheumatoid arthritis.

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.

An investigation of the feasibility of gadolinium for neutron capture synovectomy.

Neutron capture synovectomy (NCS) has been proposed as a possible treatment modality for rheumatoid arthritis. Neutron capture synovectomy is a two-part modality, in which a compound containing an isotope with an appreciable thermal neutron capture cross section is injected directly into the joint, followed by irradiation with a neutron beam. Investigations to date for NCS have focused on boron neutron capture synovectomy (BNCS), which utilizes the 10B(n,alpha)7Li nuclear reaction to deliver a highly localized dose to the synovium. This paper examines the feasibility of gadolinium, specifically 157Gd, as an alternative to boron as a neutron capture agent for NCS. This alternative modality is termed Gadolinium Neutron Capture Synovectomy, or GNCS. Monte Carlo simulations have been used to compare 10B and 157Gd as isotopes for accelerator-based NCS. The neutron source used in these calculations was a moderated spectrum from the 9Be(p,n) reaction at a proton energy of 4 MeV. The therapy time to deliver the NCS therapeutic dose of 10000 RBE-cGy, is 27 times longer when 157Gd is used instead of 10B. The skin dose to the treated joint is 33 times larger when 157Gd is used instead of 10B. Furthermore, the impact of using 157Gd instead of 10B was examined in terms of shielded whole-body dose to the patient. The effective dose is 202 mSv for GNCS, compared to 7.6 mSv for BNCS. This is shown to be a result of the longer treatment times required for GNCS; the contribution of the high-energy photons emitted from neutron capture in gadolinium is minimal. Possible explanations as to the relative performance of 157Gd and 10B are discussed, including differences in the RBE and range of boron and gadolinium neutron capture reaction products, and the relative values of the 10B and 157Gd thermal neutron capture cross section as a function of neutron energy.

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.

Development and construction of a neutron beam line for accelerator-based boron neutron capture synovectomy

A potential application of the 10B(n, alpha)7Li nuclear reaction for the treatment of rheumatoid arthritis, termed Boron Neutron Capture Synovectomy (BNCS), is under investigation. In an arthritic joint, the synovial lining becomes inflamed and is a source of great pain and discomfort for the afflicted patient. The goal of BNCS is to ablate the synovium, thereby eliminating the symptoms of the arthritis. A BNCS treatment would consist of an intra-articular injection of boron followed by neutron irradiation of the joint. Monte Carlo radiation transport calculations have been used to develop an accelerator-based epithermal neutron beam line for BNCS treatments. The model includes a moderator/reflector assembly, neutron producing target, target cooling system, and arthritic joint phantom. Single and parallel opposed beam irradiations have been modeled for the human knee, human finger, and rabbit knee joints. Additional reflectors, placed to the side and back of the joint, have been added to the model and have been shown to improve treatment times and skin doses by about a factor of 2. Several neutron-producing charged particle reactions have been examined for BNCS, including the 9Be(p,n) reaction at proton energies of 4 and 3.7 MeV, the 9Be(d,n) reaction at deuteron energies of 1.5 and 2.6 MeV, and the 7Li(p,n) reaction at a proton energy of 2.5 MeV. For an accelerator beam current of 1 mA and synovial boron uptake of 1000 ppm, the time to deliver a therapy dose of 10,000 RBEcGy ranges from 3 to 48 min, depending on the treated joint and the neutron producing charged particle reaction. The whole-body effective dose that a human would incur during a knee treatment has been estimated to be 3.6 rem or 0.75 rem, for 1000 ppm or 19,000 ppm synovial boron uptake, respectively, although the shielding configuration has not yet been optimized. The Monte Carlo design process culminated in the construction, installation, and testing of a dedicated BNCS beam line on the high-current tandem electrostatic accelerator at the Laboratory for Accelerator Beam Applications at the Massachusetts Institute of Technology.