Abstract
BackgroundActinium-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.ResultsMBq 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.ConclusionTRIUMF’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.
Highlights
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
Due to recent clinical results demonstrating the exceptional ability of 225Ac-radiopharmaceuticals for the treatment of late stage castration resistant prostate cancer (Sathekge et al 2018; Kratochwil et al 2016; Kratochwil et al 2018), considerable efforts within the field of nuclear medicine have been directed towards development of new radiopharmaceuticals for targeted alpha therapy (TAT) containing 225Ac or other suitable alpha-emitting radionuclides (Poty et al 2018a; Poty et al 2018b; Seidl 2014; Kim and Brechbiel 2012; 11th International Symposium on Targeted Alpha Therapy (TAT11), 2019; Elgqvist et al 2014; Morgenstern et al 2018; Baidoo et al 2013)
Etching of the radioactivity from the aluminum target post-implantation with 500 μL of 0.1 M HCl resulted in 0.2–7.5 MBq of 225Ra and 0.16–18.0 MBq of 225Ac
Summary
Due to recent clinical results demonstrating the exceptional ability of 225Ac-radiopharmaceuticals for the treatment of late stage castration resistant prostate cancer (Sathekge et al 2018; Kratochwil et al 2016; Kratochwil et al 2018), considerable efforts within the field of nuclear medicine have been directed towards development of new radiopharmaceuticals for targeted alpha therapy (TAT) containing 225Ac or other suitable alpha-emitting radionuclides (Poty et al 2018a; Poty et al 2018b; Seidl 2014; Kim and Brechbiel 2012; 11th International Symposium on Targeted Alpha Therapy (TAT11), 2019; Elgqvist et al 2014; Morgenstern et al 2018; Baidoo et al 2013) Despite these promising preliminary findings, the progression of 225Ac drugs towards the clinic has been obstructed by the limited radionuclide supply and the limited investigation of radiochemical protocols for chelating 225AcIII under mild conditions. In an effort to produce a viable alternative, an octadentate bispidine, H2bispa (Comba et al 2017), and an 18-membered macrocycle, macropa (Thiele et al 2017), have been reported that show improved properties for 225Ac radiolabeling, and to date are the only chelators that permit rapid, ambient temperature chelation (Deal et al 1999; Chappell et al 2000)
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