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