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

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)CHXoctapa [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(CHXoctapa)](−), 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.