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

Autor: Ramogida CF; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada. cramogida@triumf.ca.; Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC, V5A 1S6, Canada. cramogida@triumf.ca., Robertson AKH; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada.; Department of Physics & Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC, V6T 1Z1, Canada., Jermilova U; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada., Zhang C; Department of Molecular Oncology, BC Cancer Research Centre, 675 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada., Yang H; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada., Kunz P; Accelerator Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada., Lassen J; Accelerator Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada., Bratanovic I; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada., Brown V; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada., Southcott L; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada., Rodríguez-Rodríguez C; Department of Physics & Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC, V6T 1Z1, Canada.; Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada., Radchenko V; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada.; Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada., Bénard F; Department of Molecular Oncology, BC Cancer Research Centre, 675 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada.; Department of Functional Imaging, BC Cancer, 600 West 10th Ave, Vancouver, BC, V5Z 4E6, Canada.; Department of Radiology, University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada., Orvig C; Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada., Schaffer P; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada. pschaffer@triumf.ca.; Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC, V5A 1S6, Canada. pschaffer@triumf.ca.; Department of Radiology, University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada. pschaffer@triumf.ca.
Jazyk: angličtina
Zdroj: EJNMMI radiopharmacy and chemistry [EJNMMI Radiopharm Chem] 2019 Aug 06; Vol. 4 (1), pp. 21. Date of Electronic Publication: 2019 Aug 06.
DOI: 10.1186/s41181-019-0072-5
Abstrakt: 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.
Databáze: MEDLINE
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