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

Background: Actinium-225 (Ac, t = 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 Ac-radiopharmaceuticals towards the clinic. We at TRIUMF have leveraged our Isotope Separation On-Line (ISOL) facility to produce Ac and use the resulting radioactivity to screen a number of potential Ac-radiopharmaceutical compounds.

Results: MBq quantities of Ac and parent radium-225 (Ra, t = 14.8 d) were produced and separated using solid phase extraction DGA resin, resulting in a radiochemically pure 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 (Hoctapa [NO], HCHXoctapa [NO], p-NO-Bn-Hneunpa [NO], and Hphospa [NO]), all out-performed the current gold standard, DOTA for 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 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 Ac suitable for preclinical screening of radiopharmaceutical compounds; [Ac(octapa)], [Ac(CHXoctapa)], and [Ac(DOTA-CycMSH)] may be good candidates for further targeted alpha therapy studies.