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Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced 225Ac Ramogida, Caterina F; Robertson, Andrew K H; Jermilova, Una; Zhang, Chengcheng; Yang, Hua; Kunz, Peter; Lassen, Jens; Bratanovic, Ivica; Brown, Victoria; Southcott, Lily; Rodríguez-Rodríguez, Cristina; Radchenko, Valery; Bénard, François; Orvig, Chris; Schaffer, Paul

Abstract

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.

Item Metadata

Title
Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced 225Ac
Creator
Ramogida, Caterina F; Robertson, Andrew K H; Jermilova, Una; Zhang, Chengcheng; Yang, Hua; Kunz, Peter; Lassen, Jens; Bratanovic, Ivica; Brown, Victoria; Southcott, Lily; Rodríguez-Rodríguez, Cristina; Radchenko, Valery; Bénard, François; Orvig, Chris; Schaffer, Paul
Publisher
Springer International Publishing
Date Issued
2019-08-06
Description
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.
Subject
Actinium-225; 225Ac; Targeted alpha therapy; Isotope separation on-line; ISAC ISOL; Radionuclide production; Chelating ligands; Radiolabeling; α-Melanocyte-stimulating hormone
Genre
Article
Type
Text
Language
eng
Date Available
2019-08-06
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0380333
URI
http://hdl.handle.net/2429/71242
Affiliation
Medicine, Faculty of; Pharmaceutical Sciences, Faculty of; Science, Faculty of; TRIUMF; Non UBC; Chemistry, Department of; Physics and Astronomy, Department of; Radiology, Department of
Citation
EJNMMI Radiopharmacy and Chemistry. 2019 Aug 06;4(1):21
Publisher DOI
10.1186/s41181-019-0072-5
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s)
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)