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

Autor: Hua Yang, Lily Southcott, Paul Schaffer, Peter Kunz, Ivica Bratanovic, Francois Benard, Valery Radchenko, Una Jermilova, Victoria Brown, Andrew K. H. Robertson, Chengcheng Zhang, Caterina F. Ramogida, Cristina Rodríguez-Rodríguez, Chris Orvig, Jens Lassen
Rok vydání: 2019
Předmět:
Zdroj: EJNMMI Radiopharmacy and Chemistry, Vol 4, Iss 1, Pp 1-20 (2019)
EJNMMI Radiopharmacy and Chemistry
ISSN: 2365-421X
DOI: 10.1186/s41181-019-0072-5
Popis: 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. Electronic supplementary material The online version of this article (10.1186/s41181-019-0072-5) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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