Development of ²²⁵Ac Radiopharmaceuticals: TRIUMF Perspectives and Experiences

Abstract

Here we provide a review of available literature pertaining to these challenges in the 225Acradiopharmaceutical field and also provide insight into how performed and planned efforts at TRIUMF - Canada's particle accelerator centre - aim to address these issues.

Design of a Thorium Metal Target for 225Ac Production at TRIUMF

“…However, these studies do not report yields for 225 Ra production, which is known to be smaller at the reported energies of irradiation [31,38,39]. The 225 Ra produced has the potential to not only provide approximately 0.8 MBq of 225 Ac per 1 MBq of 225 Ra [14], but also to provide generator-produced 225 Ac with significantly reduced 227 Ac impurities, a long-lived (t 1/2 = 21.8 y) alpha-emitting radioisotope with low regulatory restrictions on waste disposal and accidental intake [32].…”

“…While clinical results have demonstrated the potential of 225 Ac-radiopharmaceuticals [9][10][11][12][13], the development of these drugs is slowed by the limited supply of the radionuclide. While the majority of the approximately 63 GBq global annual 225 Ac supply is derived from the decay of 229 Th (t 1/2 = 7600 y) through the 225 Ac parent isotope 225 Ra (t 1/2 = 14.9 d) [14][15][16][17][18][19], these 229 Th sources remain fixed. The resulting low annual 225 Ac availability has spurred many recent efforts to increase 225 Ac production via particle accelerators-most notably those of the US Department of Energy's Isotope Program [16,[20][21][22][23][24][25][26].…”

“…Of potential alternative accelerator-based 225 Ac-production methods, the proton-induced spallation of thorium at TRIUMF's 500 MeV Isotope Production Facility has potential to produce significant quantities of 225 Ac [14]. The co-production of 225 Ra during the spallation process is also of interest, as 225 Ra can serve as a generator of additional 225 Ac. To make 225 Ac via thorium spallation at TRIUMF, thorium targets are bombarded with 480 MeV protons at a beam current of up to 100 µA.…”

An Appendix of Radionuclides Used in Targeted Alpha Therapy

“…Currently, the lack of availability of this radioisotope in high specific activity makes studies challenging. Multiple production routes are being assessed and compared with the only current route of pure 225 Ac available nowadays (ie, decay product of 233 U) [27]. The first decay product 229 Th can be isolated from legacy material in few places worldwide, and its total production is estimated to 1.7 Ci (63 GBq)/year of 225 Ac, which is not sufficient for preclinical and clinical tests.…”

A Consensus Time for Performing Quality Control of 225Ac-Labeled Radiopharmaceuticals

“…Actinium-225 decays by emission of four alpha particles with a halflife (t½ = 9.9 d). These physical properties (12,13) and growing supply (14) contribute to an increasing interest in the use of actinium-225 for TAT. Clinical evaluations of [ 225 Ac]Ac-DOTATOC (15), [ 225 Ac]Ac-PSMA-617 (16)(17)(18), and [ 225 Ac]Ac-DOTA-Substance P (19) report significantly improved responses in patients with neuroendocrine tumors, prostate cancer, and glioma.…”