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 CHX octapa [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( CHX octapa)] − , and [ 225 Ac(DOTA-CycMSH)] may be good candidates for further targeted alpha therapy studies.