Design and simulation of a thorium target for 225Ac production

Robertson, Andrew K. H.; Ladouceur, Keith; Nozar, M.; Moskven, Louis; Ramogida, Caterina F.; D’Auria, J.M.; Schaffer, Paul

doi:10.1063/1.4983550

Cited by 10 publications

(10 citation statements)

References 8 publications

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“…In our experience, this has made it challenging to plan more involved in vivo studies. As new sources of 225 Ac begin to emerge (11th International Symposium on Targeted Alpha Therapy (TAT11), 2019; Robertson et al 2017), medical radionuclide production at TRIUMF’s ISAC facility will transition towards less accessible radionuclides in order to harness the main advantage of ISOL facilities for medical isotope production – the flexibility to provide quick access to a diverse range of high-purity medical radionuclides without needing to establish radionuclide-specific production infrastructure or processes (Robertson et al 2018; dos Santos Augusto et al 2014; Kunz et al 2018). The limitations of ISAC-produced 225 Ac for preclinical research are highlighted by challenges associated with the 225 Ac-DOTA-CycMSH study: the relatively low levels of 225 Ac isolated by the ISOL method required the entire isolated 225 Ac fraction for one radiolabeling reaction to isolate enough purified radiotracer for one set of preclinical in vivo studies (see Additional file 1: Section S2).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced 225Ac

Ramogida

Robertson

Jermilova³

et al. 2019

EJNMMI radiopharm. chem.

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Background Actinium-225 ( 225 Ac, t 1/2 = 9.9 d) is a promising candidate radionuclide for use in targeted alpha therapy (TAT), though the currently limited global supply has hindered the development of a suitable Ac-chelating ligand and 225 Ac-radiopharmaceuticals towards the clinic. We at TRIUMF have leveraged our Isotope Separation On-Line (ISOL) facility to produce 225 Ac and use the resulting radioactivity to screen a number of potential 225 Ac-radiopharmaceutical compounds. Results MBq quantities of 225 Ac and parent radium-225 ( 225 Ra, t 1/2 = 14.8 d) were produced and separated using solid phase extraction DGA resin, resulting in a radiochemically pure 225 Ac product in > 98% yield and in an amenable form for radiolabeling of ligands and bioconjugates. Of the many polydentate picolinic acid (“pa”) containing ligands evaluated (H 4 octapa [N 4 O 4 ], H 4 CHX octapa [N 4 O 4 ], p- NO 2 -Bn-H 4 neunpa [N 5 O 4 ], and H 6 phospa [N 4 O 4 ]), all out-performed the current gold standard, DOTA for 225 Ac radiolabeling ability at ambient temperature. Moreover, a melanocortin 1 receptor-targeting peptide conjugate, DOTA-modified cyclized α-melanocyte-stimulating hormone (DOTA-CycMSH), was radiolabeled with 225 Ac and proof-of-principle biodistribution studies using B16F10 tumour-bearing mice were conducted. At 2 h post-injection, tumour-to-blood ratios of 20.4 ± 3.4 and 4.8 ± 2.4 were obtained for the non-blocking (molar activity [M.A.] > 200 kBq/nmol) and blocking (M.A. = 1.6 kBq/nmol) experiment, respectively. Conclusion TRIUMF’s ISOL facility is able to provide 225 Ac suitable for preclinical screening of radiopharmaceutical compounds; [ 225 Ac(octapa)] − , [ 225 Ac( CHX octapa)] − , and [ 225 Ac(DOTA-CycMSH)] may be good candidates for further targeted alpha therapy studies. Electronic supplementary material The online version of this article (10.1186/s41181-019-0072-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced 225Ac

Ramogida

Robertson

Jermilova³

et al. 2019

EJNMMI radiopharm. chem.

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“…Post-irradiation processing of the target also requires that the thorium be dissolved. While a previous IPF thorium target prototype used ThO 2 [32], this is not suitable for routine 225 Ac production, due to the high insolubility of ThO 2 [33]. Thorium metal was chosen as the target material as it can be readily dissolved post-irradiation.…”

Section: Design Considerationsmentioning

confidence: 99%

“…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].…”

Section: Test Irradiationsmentioning

confidence: 99%

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

et al. 2019

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With recent impressive clinical results of targeted alpha therapy using 225Ac, significant effort has been directed towards providing a reliable and sufficient supply of 225Ac to enable widespread using of 225Ac-radiopharmaceuticals. TRIUMF has begun production of 225Ac via spallation of thorium metal with 480 MeV protons. As part of this program, a new 225Ac-production target system capable of withstanding the power deposited by the proton beam was designed and its performance simulated over a range of potential operating parameters. Special attention was given to heat transfer and stresses within the target components. The target was successfully tested in two irradiations with a 72–73 µA proton beam for a duration of 36.5 h. The decay corrected activity at end of irradiation (average ± standard deviation) was (524 ± 21) MBq (14.2 mCi) and (86 ± 13) MBq (2.3 mCi) for 225Ac and 225Ra, respectively. These correspond to saturation yields of 72.5 MBq/µA for 225Ac and 17.6 MBq/µA for 225Ra. Longer irradiations and production scale-up are planned in the future.

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“…An 227 Ac to 225 Ac activity ratio of 0.1-0.2% is typically found in irradiated targets at end of bombardment. However, potential exists for current target processing methods to be modified to produce 225 Ac quantities that are free of 227 Ac by isolation of an radium-actinium generator [59]. Most methods already isolate radium from the irradiated thorium matrix, and if this is done days after EOB, only 228 Ra, 226 Ra, 225 Ra, 224 Ra, and 223 Ra will be present because of the length of their half-lives (t 1/2 = 5.7 y, 1600 y, 14.9 d, 3.6 d, and 11.4 d, respectively).…”

Section: Production Of 225acmentioning

confidence: 99%

“…Use of this mixture as a radium-actinium generator will produce 225 Ac free of 227 Ac. While 228 Ac (t 1/2 = 6.2 h) will be present after 225 Ra/ 225 Ac separation, the ratio of 228 Ac to 225 Ac activity (∼0.88% at the time of optimal 225 Ac elution [59]) will decrease with time. After sufficient 228 Ac decay, 225 Ac could then be removed from the 228 Th (t 1/2 = 1.9 y) produced by 228 Ac decay to obtain a final 225 Ac product with significantly reduced radioactive impurities when compared to the directly produced 225 Ac fraction.…”

Section: Production Of 225acmentioning

confidence: 99%