Effective use of the 225 A c decay chain in targeted internal radioimmunotherapy requires the retention of both 225 A c and progeny isotopes at the target site. Imaging-based pharmacokinetic tests of these pharmaceuticals must therefore separately yet simultaneously image multiple isotopes that may not be colocalized despite being part of the same decay chain. This work presents feasibility studies demonstrating the ability of a microSPECT/CT scanner equipped with a high energy collimator to simultaneously image two components of the 225 A c decay chain: 221 F r (218 keV) and 213 B i (440 keV). Image quality phantoms were used to assess the performance of two collimators for simultaneous 221 F r and 213 B i imaging in terms of contrast and noise. A hotrod resolution phantom containing clusters of thin rods with diameters ranging between 0.85 and 1.70 mm was used to assess resolution. To demonstrate ability to simultaneously image dynamic 221 F r and 213 B i activity distributions, a phantom containing a 213 B i generator from 225 A c was imaged. These tests were performed with two collimators, a high-energy ultra-high resolution (HEUHR) collimator and an ultra-high sensitivity (UHS) collimator. Values consistent with activity concentrations determined independently via gamma spectroscopy were observed in high activity regions of the images. In hotrod phantom images, the HEUHR collimator resolved all rods for both 221 F r and 213 B i images. With the UHS collimator, no rods were resolvable in 213 B i images and only rods ⩾1.3 mm were resolved in 221 F r images. After eluting the 213 B i generator, images accurately visualized the reestablishment of transient equilibrium of the 225 A c decay chain. The feasibility of evaluating the pharmacokinetics of the 225 A c decay chain in vivo has been demonstrated. This presented method requires the use of a high-performance high-energy collimator.

Actinium-225 (225Ac, t1/2 = 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 225Ac-radiopharmaceuticals towards the clinic. We at TRIUMF have leveraged our Isotope Separation On-Line (ISOL) facility to produce 225Ac and use the resulting radioactivity to screen a number of potential 225Ac-radiopharmaceutical compounds. MBq quantities of 225Ac and parent radium-225 (225Ra, t1/2 = 14.8 d) were produced and separated using solid phase extraction DGA resin, resulting in a radiochemically pure 225Ac 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 (H4octapa [N4O4], H4CHXoctapa [N4O4], p-NO2-Bn-H4neunpa [N5O4], and H6phospa [N4O4]), all out-performed the current gold standard, DOTA for 225Ac 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 225Ac 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. TRIUMF’s ISOL facility is able to provide 225Ac suitable for preclinical screening of radiopharmaceutical compounds; [225Ac(octapa)]−, [225Ac(CHXoctapa)]−, and [225Ac(DOTA-CycMSH)] may be good candidates for further targeted alpha therapy studies.

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.

The development of alpha-emitting radiopharmaceuticals using ²¹¹ At requires quantitative determination of the time-dependent nature of the ²¹¹ At biodistribution. However, imaging-based methods for acquiring this information with ²¹¹ At have not found wide-spread use because of its low abundance of decay emissions suitable for external detection. In this publication we demonstrate the theranostic abilities of the ²¹¹ At/ ²⁰⁹ At isotope pair and present the first-ever ²⁰⁹ At SPECT images. The VECTor microSPECT/PET/CT scanner was used to image ²⁰⁹ At with a collimator suitable for the 511 keV annihilation photons of PET isotopes. Data from distinct photopeaks of the ²⁰⁹ At energy spectrum (195 keV (22.6%), 239 keV (12.4 %), 545 keV (91.0 %), a combined 782/790 keV peak (147 %), and ²⁰⁹ Po x-rays (139.0 %)) were independently evaluated for use in image reconstructions using Monte Carlo (GATE) simulations and phantom studies. ²⁰⁹ At-imaging in vivo was demonstrated in a healthy mouse injected with 10 MBq of free [ ²⁰⁹ At]astatide. Image-based measurements of ²⁰⁹ At uptake in organs of interest—acquired in 5 min intervals—were compared to ex vivo gamma counter measurements of the same organs. Simulated and measured data indicated that—due to the large amount of scatter from high energy (>750 keV) gammas—reconstructed images using the x-ray peak outperformed those obtained from other peaks in terms of image uniformity and spatial resolution, determined to be <0.85 mm. ²⁰⁹ At imaging using the x-ray peak revealed a biodistribution that matched the known distribution of free astatide, and in vivo image-based measurements of ²⁰⁹ At uptake in organs of interest matched ex vivo measurements within 10%. We have acquired the first ²⁰⁹ At SPECT images and demonstrated the ability of quantitative SPECT imaging with ²⁰⁹ At to accurately determine astatine biodistributions with high spatial and temporal resolution.

There is growing interest in finding new sources of ²²⁵Ac, an isotope with potential use in the treatment of metastatic disease. Proposed production alternatives include the proton irradiation of thorium above 100 MeV, however, concerns exist about the co-production of the long-lived and toxic ²²⁷Ac. This work describes the design and simulated yields for a thorium target that will be irradiated at TRIUMF, and also proposes a post-irradiation chemical isolation procedure that produces two separate ²²⁵Ac products: the first by direct production from the irradiation, and the second from the isolation of Ra isotopes that form a generator of ²²⁵Ac. FLUKA simulations combined with models of the proposed chemical isolation procedures suggest that a 1130 µA·hr irradiation at 90 µA of a target containing 1 g of thorium will directly produce 42.2 MBq of ²²⁵Ac with 0.08 MBq of ²²⁷Ac. The generator-produced ²²⁵Ac fraction will contain less activity of higher purity: 2.2 MBq of ²²⁵Ac and <1Bq of ²²⁷Ac.

Thorium targets were irradiated with 438-MeV protons, resulting in spallation and high-energy fission reactions. The measured production cross sections of 38 nuclides in the mass range 83 to 233 are reported. These cross-section data are useful for validating nuclear interaction models and are compared to simulated cross sections calculated using three different Monte Carlo packages, fluka (version 2011.2x.7), geant4 (version 10.6, with the Liege intranuclear cascade model and the abla version 3.1 evaporation code), and geant4 (version 10.6, with the binary cascade model). These data are also useful for estimating radionuclide production yields following an irradiation, in particular for the production of ${}^{225}\mathrm{Ac}$, a radionuclide of currently heightened interest in nuclear medicine for the treatment of cancer. For most nuclides reported, the measured, literature, and simulated cross-section values agree within a factor of 2.