Interest in α-emitters for radiotherapeutic applications is on the rise. However, the number of options for α-emitters with midterm industrial availability remains limited. Currently, only 225Ac, 212Pb, and 211At have realistic chances to reach the market within the next 10 y. A review published in 2022 (1) extensively describes the history of development of 212Pb and related technologies. Because industrialization processes and realistic production costs are also important criteria, the aim of this editorial is to confirm that, as for 225Ac (2), the industry is seriously tackling the challenge of a large-scale supply of 212Pb with a short-term answer. I conducted a survey among different industrial entities claiming their involvement in such development. Surprisingly, more than 15 companies have made progress in 212Pb production, although some of them are still keeping their work confidential.
ALMOST IDEAL PROFILE
212Pb has a half-life of 10.64 h but is a β-emitter. 212Pb decays into 212Bi (half-life, 60.5 min), which is the α-emitter in the further decay sequence, but only at 36% in 208Tl; the other 64% of the decay arm produces 212Po through another β−-emission. 212Po is a pure α-emitter that decays into stable 208Pb in 0.3 μs, whereas 208Tl is both a β−-emitter and a γ-emitter (half-life, 3.06 min), which also leads to stable 208Pb. Indeed, 212Pb also does not show the expected ideal profile, as it needs to be strongly trapped in the cancer cell to keep all the benefits from the α-emission. The high-energy γ-ray emitted by the 208Tl daughter is an identified drawback that can be solved by lowering doses and shielding health care personnel from high-energy γ-rays. On the other hand, the short half-life maximizes the energy deposition in the tumor cell. Compared with 225Ac, this shorter half-life also eliminates the potential issue of storing radioactive waste, indirectly solving the question of a hospital stay and containment of patients’ biologic radioactive waste versus ambulatory treatment. For a specific clinical indication, at equal efficacy, any 212Pb-labeled molecule will have the potential to displace any 177Lu- or 225Ac-labeled analog from the market on the basis of the simple marketing advantage of a lower environmental impact from patients.
DEDICATED CHELATING AGENTS
To really benefit from the efficient secondary α-emission of the radionuclide, the first decay radionuclide, 212Bi, needs to stay trapped within the original lead-atom chelating agent. Significant improvements have been made in this area, and several groups have developed chelating agents that also strongly keep 212Bi attached to the vector (1). Since the first emission is a β-emission, the recoil effect that could eject the decay metal out of the chelating cage remains limited and is in no way comparable to the recoil effect of the emission of an α-particle, for which such trapping remains close to impossible.
AN ALTERNATIVE TO COCKTAIL THERAPIES
The evolution of radiotherapeutics is expected to follow the same trend as chemotherapeutics given as cocktails—that is, use of mixtures of radiotherapeutics instead of consecutive treatments—and has already been explored with tandem therapies (mixtures of 177Lu and 225Ac similars). Obviously, the evolution of therapies will combine molecules labeled with different energies of β-emitters and α-emitters or even Auger/conversion electron–emitting radionuclides. By maintaining both the β-emitter and the α-emitter in or next to the cancer cell, the use of 212Pb brings an additional advantage over mixtures with simultaneous efficacy in larger tumors and micrometastases. The 212Pb β-particle contribution has already been proven to be nonnegligible (3), and this effect could lead to a reduction in both the doses and their number.
IMAGING WITH LEAD
Quantitative SPECT/CT imaging of 212Pb proved feasible (4) but will probably remain used only for development purposes. 203Pb, a γ-emitter with a half-life of 51.87 h, has been presented as the ideal 212Pb surrogate for imaging. However, cyclotron production of 203Pb may not receive industry favor because it would require the creation of a large and expensive network of dedicated tools for access (5). Certainly, in the same way as for 177Lu-labeled therapeutic agents, imaging agents used for patient selection will be based on radiodiagnostics labeled with more commonly available radionuclides such as 18F, 64Cu, 68Ga, or 99mTc.
212PB PRODUCTION ROUTES
Orano Med was the first company to believe strongly in the future of 212Pb and has developed a full production process and started investing in 212Pb-labeled drugs. The company is presently building 2 industrial facilities called α-therapy laboratories (https://www.oranomed.com/en/industrial-platform) in Indianapolis and Valenciennes with a capacity of 10,000-plus doses per year by 2025 and anticipating more than 10 times this number by the end of the decade.
212Pb is most easily produced through a generator based on the decay of 228Th (1). 228Th has a 1.91-y half-life and decays successively into 224Ra (half-life, 3.66 d), 220Rn (56 s), and 216Po (0.14 s), eventually leading to 212Pb through α-emissions in each step. Generators can be based on 3 different processes.
In the first process, 212Pb can be extracted directly from the 228Th decay solution, but this process is the most cumbersome, as it involves handling of the long–half-life 228Th and can therefore be used only in an industrial environment. The first players (Orano Med [France] and TRIUMF [Canada]) originally used this technology but later gave preference to the 2-step processes. Orano Med opted to keep control of the overall process from the production and isolation of thorium to the final radiolabeling and distribution of drugs and therefore does not intend to sell generators. ATOX (Japan), Oncoinvent (Norway), and the Kurchatov Institute (Russia) are also exploring this route.
The second of the 3 processes utilizes the fact that in the decay sequence of 228Th, 224Ra can easily be extracted for loading of 224Ra/212Pb generators. Major players (Perspective Therapeutics [United States], United Well [China], and Pacific Northwest National Laboratory [United States]) use this technology now because generators containing shorter–half-life parent radionuclides will be easier to distribute from a regulatory point of view.
The third process utilizes 220Rn, a gas that can easily be separated from the 228Th/224Ra mixture as soon as it is generated and then left to decay into 212Pb in a second container (6). The companies AdvanCell (Australia), AlphaGen Therapeutics (China), ARTBIO (United States), NRG-PALLAS, FutureChemistry (The Netherlands), and Oncoinvent are developing industrial processes based on this technology. ARTBIO claims that its manufacturing approach is poised to scale comfortably to deliver 20,000-plus doses per year once its first program reaches the commercial stage.
212Pb could also be produced directly, without a generator, by using the precursor 226Ra. The conversion reaction in the same tools as those developed for the production of 225Ac or 67Cu (linear accelerator or Rhodotron [IBA Industrial Solutions]) can lead to large amounts of 212Pb, on the basis of the reaction [226Ra(γ,2n)224Ra→212Pb]. In the 225Ac production process based on photoconversion, up to 6 times more 212Pb than 225Ac is generated as a by-product and could be separated. Such a separation process would affect the yields in 225Ac and would be useful only locally. No company is presently developing such a separation process.
Investment in central industrial-scale production centers could remain low, in the range of an 18F manufacturing site investment. Because the half-life of 212Pb will allow overnight shipment to a distance of several thousand kilometers, not only could production costs remain low but individual radiopharmaceutical companies could keep control of their production.
ACCESS TO THE PRECURSORS 228TH AND 226RA
228Th is not considered of concern and is presently available from several governmental or private sources supporting access to 212Pb and recovery of parent isotopes from legacy nuclear material (Department of Energy [United States], Eckert & Ziegler [Germany], Orano [France], Rosatom [Russia], and National Nuclear Laboratory [U.K.]). The nongenerator production route needs access to 226Ra, which should not be an issue in the near future, as it is the main starting material for the production of 223Ra and 225Ac (2).
Industrial access to 212Pb is not yet ready, but an impressive number of new players have entered this field over the past 3 y, with several of them proposing new alternatives for access to 212Pb. At the same time, several 212Pb molecules are under development (>20 identified), with 7 having already reached the clinical stage (7). There is strong optimism that industrial solutions for large-scale production of 212Pb will be in place before 2028, opening an avenue for a radionuclide that could replace 225Ac over the period 2035–2045.
DISCLOSURE
No potential conflict of interest relevant to this article was reported.
ACKNOWLEDGMENTS
I thank Simon Puttick (AdvanCell), Conrad Wueller (ARTBIO), Mizuki Nagarekawa (ATOX), James Hill (FutureChemistry), Tim Tinsley (NNL), Nicolas Bozovic (Orano Med), and Bernhard Sixt and Michael Schultz (Perspective Therapeutics) for sharing information about the stage of development in their respective companies.
Footnotes
Published online Jan. 4, 2024.
- © 2024 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication November 5, 2023.
- Revision received December 19, 2023.
