212Pb: Production Approaches and Targeted Therapy Applications.

Over the last decade, targeted alpha therapy has demonstrated its high effectiveness in treating various oncological diseases. Lead-212, with a convenient half-life of 10.64 h, and daughter alpha-emitter short-lived 212Bi (T1/2 = 1 h), provides the possibility for the synthesis and purification of complex radiopharmaceuticals with minimum loss of radioactivity during preparation. As a benefit for clinical implementation, it can be milked from a radionuclide generator in different ways. The main approaches applied for these purposes are considered and described in this review, including chromatographic, solution, and other techniques to isolate 212Pb from its parent radionuclide. Furthermore, molecules used for lead's binding and radiochemical features of preparation and stability of compounds labeled with 212Pb are discussed. The results of preclinical studies with an estimation of therapeutic and tolerant doses as well as recently initiated clinical trials of targeted radiopharmaceuticals are presented.

Radiochemical separation of 224Ra from 232U and 228Th sources for 224Ra/212Pb/212Bi generator.

The application of diagnostic and therapeutic radionuclides in nuclear medicine has grown significantly and has translated into the increased interest in radionuclide generators and their development. 224Ra and its shorter-lived daughters, 212Pb and 212Bi, are very interesting radionuclides from Targeted Alpha Therapy point of view for treatment of small cancers or metastatic forms. The purpose of the present work was to develop a simple generator for rapid elution of carrier-free 224Ra from 232U or 228Th sources by radiochemical separation based on extraction chromatography with the utilization of a home-made material. The bis(2-ethylhexyl) hydrogen phosphate (HDEHP) extractant was immobilized on polytetrafluroethylene (PTFE) grains and its ability to selectively adsorb 232U and 228Th, with simultaneous high elution recovery of 224Ra, was checked over few years. The 224Ra was quantitatively eluted with small volume (3-5 mL) of 0.1 M HNO3 with low breakthrough (<0.005%) and was used for further milking of 212Bi and 212Pb from DOWEX 50WX12 by 0.75 M and 2.0 M HCl, respectively. The elaborated here methods allowed high recovery of 224Ra, 212Pb and 212Bi radionuclides and their application in radiolabeling of various biomolecules.

Production, purification, and radiolabeling of the 203Pb/212Pb theranostic pair.

BACKGROUND: Lead-212 (212Pb, t1/2 = 10.6 h) and lead-203 (203Pb, t1/2 = 51.9 h) are an element-equivalent, or a matched theranostic radioisotope pair that show great potential for application in targeted radionuclide therapy (TRT) and single-photon emission computed tomography (SPECT), respectively. At TRIUMF we have produced both 203Pb and 212Pb using TRIUMF's TR13 (13 MeV) and 500 MeV cyclotrons, and subsequently purified and evaluated both radioisotopes using a series of pyridine-modified DOTA analogues in comparison to the commercially available chelates DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and TCMC (1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane). RESULTS: Proton irradiation (12.8 MeV) of natural and enriched thallium-203 (203Tl) targets gave 203Pb saturation yields of 134 ± 25 and 483 ± 3 MBq/µA, respectively. Thorium-228 (228Th, t1/2 = 1.9 y), a by-product of 232Th proton spallation on TRIUMF's main 500 MeV beamline (beamline 1A, BL1A), was recovered to build a 228Th/212Pb generator with the ability to deliver up to 9-10 MBq of 212Pb daily. Both lead isotopes were purified via solid phase extraction chromatography (Pb resin), and isolated in an acetate form ([203/212Pb]Pb(OAc)2) suitable for direct radiolabeling of chelators and bioconjugates. A series of cyclen-based chelators (herein referred to as DOTA-1Py, -2Py, and -3Py) along with established chelates DOTA and TCMC were evaluated for their ability to complex both 203Pb and 212Pb. All chelates incorporated 212Pb/203Pb efficiently, with higher radiolabeling yields observed for the 212Pb-complexes. CONCLUSION: The production of 203Pb and 212Pb was established using TRIUMF 13 MeV and 500 MeV cyclotrons, respectively. Both production methods provided radiometals suitable for subsequent radiolabeling reactions using known and novel chelates. Furthermore, the novel chelate DOTA-3Py may be a good candidate for biomolecule conjugation and further theranostic 212Pb/203Pb studies.

Long-term monitoring of a water treatment technology designed for radium removal - removal efficiencies and NORM formation.

A drinking water treatment plant in Viimsi, Estonia was monitored over three years for iron, manganese, radium-226, radium-228, and their daughter nuclides in order to determine the efficiency of the treatment process, get an insight of the removal mechanisms and interactions between radium, iron, and manganese, and assess the overall longevity and performance of the technology and possible build-up of NORM from the treatment process. During the study, samples were collected from raw water, first and second stage filtrate, consumer water, backwash water, and filter materials. The results show a consistent removal efficiency for iron and manganese, as well as an average of over 85% removal for radium with a slight decline with time. Backwash process has been optimized for maximum radium removal from the filters, while keeping the radium concentrations in the backwash water below exemption levels. However, accumulation of radium and thorium occurs in the filter material, exceeding exemption levels in the top layer of the filter columns in less than a year. By the end of the observation period, activity concentrations in the top layer of the columns were above 30 000 Bq/kg for Ra-226 and Ra-228, and around 15 000 Bq/kg for Th-228. Radionuclides are not homogenously distributed in the filter columns. In order to estimate the average activity concentrations in the filter media, the height distribution of radionuclides has to be accounted for. Two years and two months after commissioning of the treatment plant average activity concentrations of Ra isotopes in the filter columns were in a range of 10 000 Bq/kg while Th-228 activity concentration was roughly 3500 Bq/kg.

Reactor production of Thorium-229.

Limited availability of (229)Th for clinical applications of (213)Bi necessitates investigation of alternative production routes. In reactor production, (229)Th is produced from neutron transmutation of (226)Ra, (228)Ra, (227)Ac and (228)Th. Irradiations of (226)Ra, (228)Ra, and (227)Ac targets at the Oak Ridge National Laboratory High Flux Isotope Reactor result in yields of (229)Th at 26 days of 74.0±7.4MBq/g, 260±10MBq/g, and 1200±50MBq/g, respectively. Intermediate radionuclide yields and cross sections are also studied.