Recent Program-Supported Publications

A number of accelerator-based isotope production facilities utilize 100- to 200-MeV proton beams due to the high production rates enabled by high-intensity beam capabilities and the greater diversity of isotope production brought on by the long-range of high-energy protons. However, nuclear reaction modeling at these energies can be challenging because of the interplay between different reaction modes and a lack of existing guiding cross-section data.

Molecular imaging is a non-invasive process that enables the visualization, characterization, and quantitation of biological processes at the molecular and cellular level. With the emergence of theragnostic agents to diagnose and treat disease for personalized medicine there is a growing need for matched pairs of isotopes. Matched pairs offer the unique opportunity to obtain patient specific information from SPECT or PET diagnostic studies to quantitate in vivo function or receptor density to inform and tailor therapeutic treatment. There are several isotopes of arsenic that have emissions suitable for either or both diagnostic imaging and radiotherapy. Their half-lives are long enough to pair them with peptides and antibodies which take longer to reach maximum uptake to facilitate improved patient pharmacokinetics and dosimetry then can be obtained with shorter lived radionuclides. Arsenic-72 even offers availability from a generator that can be shipped to remote sites and thus enhances availability. Arsenic has a long history as a diagnostic agent, but until recently has suffered from limited availability, lack of suitable chelators, and concerns about toxicity have inhibited its use in nuclear medicine. However, new production methods and novel chelators are coming online and the use of radioarsenic in the pico and nanomolar scale is well below the limits associated with toxicity. This manuscript will review the production routes, separation chemistry, radiolabeling techniques and in vitro/in vivo studies of three medically relevant isotopes of arsenic (arsenic-74, arsenic-72, and arsenic-77).

Targeted alpha therapy (TAT) is an area of research with rapidly increasing importance as the emitted alpha particle has a significant effect on inducing cytotoxic effects on tumor cells while mitigating dose to normal tissues. Two significant isotopes of interest within the area of TAT are thorium-227 and actinium-225 due to their nuclear characteristics. Both isotopes have physical half-lives suitable for coordination with larger biomolecules, and additionally actinium-225 has potential to serve as an in vivo generator. In this review, the authors will discuss the production, purification, labeling reactions, and biological studies of actinium-225 and thorium-227 complexes and clinical studies.

“Isotope harvesting” is a technique that offers access to exotic radionuclides created as by-products during nuclear science research. Ongoing exploratory work at the National Superconducting Cyclotron Laboratory (NSCL) is directed towards the production and extraction of rare radionuclides from a flowing-water target and intends to pave the way for future harvesting efforts at the upcoming Facility for Rare Isotope Beams (FRIB). Here we present the collection of ⁶²Zn from an aqueous matrix irradiated with a 150 MeV per nucleon ⁷⁸Kr beam, while synergistically capturing other gaseous reaction products. In addition to the production rate for ⁶²Zn (9.08(30) × 10^{−5 62}Zn per incoming ⁷⁸Kr), the rates of formation for several other radionuclides were determined as well. The purification of ⁶²Zn from a large number of co-produced radionuclides was performed by anion exchange chromatography, allowing the isolation of 80.5(5.2)% of the generated ⁶²Zn. With the decay of ⁶²Zn the radioactive daughter ⁶²Cu is generated, and with the isolation of pure ⁶²Cu eluate, the principle of a medical radionuclide generator could be demonstrated. To illustrate the applicability of the obtained ⁶²Zn, the isolated product was used in free and DTPA-labelled form in a proof of principle plant uptake study with garden cress employing phosphor imaging for visualization.

An experiment was performed at the National Superconducting Cyclotron Laboratory using a 140 MeV/nucleon ⁴⁸Ca beam and a flowing-water target to produce ⁴⁷Ca for the first time with this production route. A production rate of 0.020 ± 0.004 ⁴⁷Ca nuclei per incoming beam particle was measured. An isotope harvesting system attached to the target was used to collect radioactive cationic products, including ⁴⁷Ca, from the water on a cation-exchange resin. The ⁴⁷Ca collected was purified using three separation methods optimized for this work: (1) DGA extraction chromatography resin with HNO₃ and HCl, (2) AG MP-50 cation-exchange resin with an increasing concentration gradient of HCl, and (3) AG MP-50 cation-exchange resin with a methanolic HCl gradient. These methods resulted in ≥99 ± 2% separation yield of ⁴⁷Ca with 100% radionuclidic purity within the limits of detection for HPGe measurements. Inductively coupled plasma-optical emission spectrometry (ICP-OES) was used to identify low levels of stable ions in the water of the isotope harvesting system during the irradiation and in the final purified solution of ⁴⁷Ca. For the first time, this experiment demonstrated the feasibility of the production, collection, and purification of ⁴⁷Ca through isotope harvesting for the generation of ⁴⁷Sc for nuclear medicine applications.

A high-intensity proton irradiation was performed with the flowing-water isotope harvesting target at the University of Wisconsin-Madison Cyclotron Laboratory to measure the rate of degradation of the target shell during irradiation conditions. The beam reached an intensity of 34 µA by the end of the irradiation and covered an area of 0.7 cm² on the target. Radiolysis products, such as H₂O₂, H₂, and O₂, were measured in the bulk water of the system and found to be present at much lower levels than predicted by literature escape yields. Radionuclides formed in the target shell were measured in the system water as a radiotracer for target degradation. Using a simple, beam intensity-dependent model, a corrosion rate of 1.5E-6 μm/(μA*s) was found to match the measured radiotracer activities at various points in the irradiation. This rate was used to extrapolate the lifetime of future isotope harvesting targets at the NSCL and FRIB, using the areal power density of different ion beams to scale the corrosion rate.

The Nuclear Medicine Global Initiative (NMGI) was formed in 2012 by 13 international organizations to promote human health by advancing the field of nuclear medicine and molecular imaging by supporting the practice and application of nuclear medicine. The first project focused on standardization of administered activities in pediatric nuclear medicine and resulted in two manuscripts. For its second project the NMGI chose to explore issues impacting on access and availability of radiopharmaceuticals around the world. Methods: Information was obtained by survey responses from 35 countries on available radioisotopes, radiopharmaceuticals and kits for diagnostic and therapeutic use. Issues impacting on access and availability of radiopharmaceuticals in individual countries were also identified. Results: Detailed information on radiopharmaceuticals utilized in each country, and sources of supply, was evaluated. Responses highlighted problems in access particularly due to the reliance on a sole provider, regulatory issues and reimbursement, as well as issues of facilities and workforce particularly in low- and middle-income countries. Conclusion: Strategies to address access and availability of radiopharmaceuticals are outlined, to enable timely and equitable patient access to nuclear medicine procedures worldwide. In the face of disruptions to global supply chains by the COVID-19 outbreak, renewed focus on ensuring reliable supply of radiopharmaceuticals is a major priority for nuclear medicine practice globally.

Harvesting isotopes from beam stops and other activated materials at accelerator facilities is a promising source of environmentally, scientifically and socially important radionuclides. At the Facility for Rare Isotope Beams (FRIB), a multitude of short- and long-lived radionuclides will be collected in a synergistic manner by dumping unused beams into a flowing-water beam stop. Ongoing exploratory research at the National Superconducting Cyclotron Laboratory (NSCL) with an analogous beam blocker aims towards obtaining the necessary radiochemical expertise for this endeavor.

Herein we present a beam blocker and an isotope harvesting system which allows collection of a wide variety of aqueous and gaseous radionuclides. The water which flows through the beam blocker functions as an isotope production target and concurrently transports the newly formed radionuclides to collection sites. The system includes analytical instruments for online measurements of conductivity, dissolved oxygen, temperature, pressure and for detection of radiolytic products. To limit the levels of radiolytically produced hydrogen peroxide, a stainless-steel based degradation system was designed and implemented. The suitability of the constructed system for the anticipated radionuclide harvesting project was demonstrated by offline tests and under irradiation with 140 MeV/u ⁴⁸Ca^20＋ ions at the NSCL Coupled Cyclotron Facility.

A flowing-water target was irradiated with a 140 MeV/u, 8 nA 40Ca20+ beam to test the feasibility of isotope harvesting at the upcoming Facility for Rare Isotope Beams. Among other radionuclides, 2.6(2)E-6 48Cr and 5.6(5)E-6 28 Mg nuclei were formed for every impingent 40Ca and were collected through ion exchange. Radiolysis-induced molecular hydrogen evolved from the target at an initial rate of 0.91(9) H2 molecules per 100 eV of beam energy deposited. No radiation-accelerated corrosion of the target material was observed.

The Isotope Production Facility (IPF) at Los Alamos National Laboratory (LANL) is used to produce an array of isotopes for medical, global security, and research applications with an intense beam of protons supplied by the linear accelerator at the Los Alamos Neutron Science Center (LANSCE). An Accelerator Improvement Project (AIP) was recently conducted at IPF to improve facility reliability and reduce programmatic risk while increasing general isotope production capacity and flexibility. This was accomplished through the installation of an improved beam window assembly, more robust beam diagnostics, an active and adjustable collimator, and a new beam rastering system. This paper will highlight the four exciting innovations and how they were designed, validated, and installed in parallel as well as the significant operational advantages they provide to IPF. Key experiments and the increased currents achieved in routine production runs demonstrating the enhanced capability from the AIP will be presented. The most notable capability enhancements include irradiations with beam currents ranging from 100 nA experimental runs up to 300 μA on routine production targets and utilization of a range of cylindrical target diameters.