Evaluation of Polydentate Picolinic Acid Chelating Ligands and an α-melanocyte-stimulating Hormone Derivative for Targeted Alpha Therapy Using ISOL-Produced 225Ac

Background 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. Results 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. Conclusion 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

Mercury in the Barents region – River fluxes, sources, and environmental concentrations

Arctic rivers are receiving increased attention for their contributing of mercury (Hg) to the Arctic Ocean. Despite this, the knowledge on both the terrestrial release sources and the levels of Hg in the rivers are limited. Within the Arctic, the Barents region has a high industrial development, including multiple potential Hg release sources. This study presents the first overview of potential Hg release sources on Norwegian and Russian mainland draining to the Barents Sea. Source categories cover mining and metallurgy industry; historical pulp and paper production; municipal and industrial solid waste handling; fossil fuel combustion; and past military activities. Available data on Hg in freshwater bodies near the identified potential release sources are reviewed. Levels of Hg were occasionally exceeding the national pollution control limits, thereby posing concern to the local human population and wildlife. However, the studies were sparse and often unsystematic. Finally, we present new data of Hg measured in five Barents rivers. These data reveal strong seasonality in the Hg levels, with a total annual flux constituting 2% of the panarctic total. With this new insight we aspire to contribute to the international efforts of reducing Hg pollution, such as through the effective implementation of the Minamata Convention. Future studies documenting Hg in exposed Barents freshwater bodies are warranted.publishedVersio

p-NO2-Bn-H(4)neunpa and H(4)neunpa-Trastuzumab:Bifunctional Chelator for Radiometalpharmaceuticals and In-111 Immuno-Single Photon Emission Computed Tomography Imaging

Potentially nonadentate (N5O4) bifunctional chelator p-SCN-Bn-H(4)neunpa and its immunoconjugate H(4)neunpa-trastuzumab for In-111 radiolabeling are synthesized. The ability of p-SCN-Bn H(4)neunpa and H(4)neunpa-trastuzumab to quantitatively radiolabel (InCl3)-In-111 at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In3+, Bi3+, and La3+ resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both In-111 complexes to have high stability over 5 days. Mouse biodistribution of [In-111][In(p-NO2 Bn neunpa)](-), compared to that of [In-111][In(p-NH2-Bn-CHX-A"-diethylenetriamine pentaacetic acid (DTPA))](2-), at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates In-neunpa trastuzumab and In-111-CHX-A"-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of In-111-neunpa-trastuzumab compared to that of In-111-CHX-A"-DTPA-trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN-Bn-H(4)neunpa to be a promising chelator for In-111 (and other radiometals) with high in vitro stability and also show H(4)neunpa trastuzumab to be an excellent In-111 chelator with promising biodistribution in mice

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

Background: 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. Results: 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. Conclusion: 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.Medicine, Faculty ofPharmaceutical Sciences, Faculty ofScience, Faculty ofTRIUMFNon UBCChemistry, Department ofPhysics and Astronomy, Department ofRadiology, Department ofReviewedFacult

<i>p</i>‑NO₂–Bn–H₄neunpa and H₄neunpa–Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and ¹¹¹In Immuno-Single Photon Emission Computed Tomography Imaging

Potentially nonadentate (N₅O₄) bifunctional chelator <i>p</i>-SCN–Bn–H₄neunpa and its immunoconjugate H₄neunpa–trastuzumab for ¹¹¹In radiolabeling are synthesized. The ability of <i>p</i>-SCN–Bn–H₄neunpa and H₄neunpa–trastuzumab to quantitatively radiolabel ¹¹¹InCl₃ at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In³⁺, Bi³⁺, and La³⁺ resulted in high conditional stability constant (<i>p</i>M) values. In vitro human serum stability assays have demonstrated both ¹¹¹In complexes to have high stability over 5 days. Mouse biodistribution of [¹¹¹In]­[In­(<i>p</i>-NO₂–Bn–neunpa)]⁻, compared to that of [¹¹¹In]­[In­(<i>p</i>-NH₂–Bn–CHX-A″–diethylenetriamine pentaacetic acid (DTPA))]^2–, at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates ¹¹¹In-neunpa–trastuzumab and ¹¹¹In–CHX-A″–DTPA–trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of ¹¹¹In-neunpa–trastuzumab compared to that of ¹¹¹In–CHX-A″–DTPA–trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator <i>p</i>-SCN–Bn–H₄neunpa to be a promising chelator for ¹¹¹In (and other radiometals) with high in vitro stability and also show H₄neunpa–trastuzumab to be an excellent ¹¹¹In chelator with promising biodistribution in mice