Production, isolation, and shipment of clinically relevant quantities of astatine-211: A simple and efficient approach to increasing supply.

The alpha emitter astatine-211 (211At) is a promising candidate for cancer treatment based on Targeted Alpha (α) Therapy (TAT). A small number of facilities, distributed across the United States, are capable of accelerating α-particle beams to produce 211At. However, challenges remain regarding strategic methods for shipping 211At in a form adaptable to advanced radiochemistry reactions and other uses of the radioisotope. PURPOSE: Our method allows shipment of 211At in various quantities in a form convenient for further radiochemistry. PROCEDURES: For this study, a 3-octanone impregnated Amberchrom CG300M resin bed in a column cartridge was used to separate 211At from the bismuth matrix on site at the production accelerator (Texas A&M) in preparation for shipping. Aliquots of 6 M HNO3 containing up to ≈2.22 GBq of 211At from the dissolved target were successfully loaded and retained on columns. Exempt packages (<370 MBq) were shipped to a destination radiochemistry facility, University of Texas MD Anderson Cancer Center, in the form of a convenient air-dried column. Type A packages have been shipped overnight to University of Alabama at Birmingham. MAIN FINDINGS: Air-dried column hold times of various lengths did not inhibit simple and efficient recovery of 211At. Solution eluted from the column was sufficiently high in specific activity to successfully radiolabel a model compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1), with 211At. The method to prepare and ship 211At described in this manuscript has also been used to ship larger quantities of 211At a greater distance to University of Alabama at Birmingham. PRINCIPAL CONCLUSIONS: The successful proof of this method paves the way for the distribution of 211At from Texas A&M University to research institutions and clinical oncology centers in Texas and elsewhere. Use of this simple method at other facilities has the potential increase the overall availability of 211At for preclinical and clinical studies.

Complexation of Astatine(III) with Ketones: Roles of NO3- Counterion and Exploration of Possible Binding Modes.

Ketones have been proven effective in extracting astatine(III) from aqueous solvents. Previous theoretical studies suggested a mechanism where the "sp2" lone pair on the carbonyl oxygen donates electron density into the π system of the AtO+ molecular cation to form a dative-type bond. In this study, co-extraction of NO3- as AtO(NO3)·(O═CR1R2) species into the organic phase appears to be a key factor. Adjusting the electronic properties of the ketone, by having an aryl group instead of an alkyl group in the alpha position of the ketone, increased the electron density on C═O, increased the bond strength between the ketone and AtO+, and in turn increased the extraction of 211At into the organic phase. Extraction with diketones shows dependence on the bridging distance between the two carbonyl moieties, where a C3 or longer bridge results in a 10-fold increase in extraction into the organic phase. DFT calculations show the longer bridge allows for the chelation of AtO(NO3) by either the second carbonyl or the phenyl ring.

Astatine partitioning between nitric acid and conventional solvents: indication of covalency in ketone complexation of AtO.

Astatine-211 has been produced at Texas A&M University on the K150 cyclotron, with a yield of 890 ± 80 MBq through the 209Bi(α,2n)211At reaction via an 8 h bombardment with a beam current of 4-8 µA and an α-particle beam energy of 28.8 MeV. The target was then dissolved in HNO3 and the extraction of 211At was investigated into a variety of organic solvents in 1-3 M HNO3. Extraction of 211At with distribution ratios as high as 11.3 ± 0.6, 12.3 ± 0.8, 42.2 ± 2.2, 69 ± 4, and 95 ± 6 were observed for diisopropyl ether, 1-decanol, 1-octanol, 3-octanone, and methyl isobutyl ketone, respectively, while the distribution ratios for 207Bi were ≤0.05 in all cases. The extraction of 211At into both methyl isobutyl ketone and 3-octanone showed a strong, linear dependence on the HNO3 initial aqueous concentration and better extraction than other solvents. DFT calculations show stronger binding between the carbonyl oxygen of the ketone and the At metal center.

Preliminary production of 211At at the Texas A&M University Cyclotron Institute.

A feasibility study for the production of the alpha particle-emitting radionuclide At was performed at the Texas A&M University Cyclotron Institute as part of the Interdisciplinary Radioisotope Production and Radiochemistry Program. The mission of this program centers upon the production of radionuclides for use in diagnostic and therapeutic nuclear medicine with the primary focus on development of novel therapeutic strategies. As a first step in establishing this program, two goals were outlined: (i) verify production of At and compare results to published data, and (ii) evaluate shielding and radiological safety issues for large-scale implementation using an external target. The radionuclide At was produced via the Bi (α, 2n) At reaction using the K500 cyclotron. Two experiments were conducted, using beam energies of 27.8 MeV and 25.3 MeV, respectively. The resulting yields for At were found to be 36.0 MBq µA h and 12.4 MBq µA h, respectively, which fall within the range of published yield data. Strategies for increasing absolute yield and production efficiency were also evaluated, which focused chiefly on using a new target designed for use with the K150 cyclotron, which will enable the use of a higher beam current. Finally, neutron and gamma dose rates during production were evaluated by using the Monte Carlo code MCNPX. It was determined that a simple structure consisting of 4-in thick borated polyethylene will reduce the neutron dose rate within the cyclotron production vault by approximately a factor of 2, thereby decreasing activation of equipment.