Hua Yang1, Feng Gao1, Brooke McNeil1,2, Chengcheng Zhang3, Zheliang Yuan1, Stefan Zeisler1, Joel Kumlin1, Jutta Zeisler3, François Bénard3,4, Caterina Ramogida1,2, Paul Schaffer5,6,7. 1. Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada. 2. Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC, V5A 1S6, Canada. 3. Department of Molecular Oncology, BC Cancer Research Centre, 675 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada. 4. Department of Radiology, University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada. 5. Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada. pschaffer@triumf.ca. 6. Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC, V5A 1S6, Canada. pschaffer@triumf.ca. 7. Department of Radiology, University of British Columbia, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada. pschaffer@triumf.ca.
Abstract
BACKGROUND: 64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x = 1-4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. RESULTS: We found that the presence of pyridyl groups significantly increases 64Cu labeling conversion yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing 64Cu at room temperature within 5 min (1 × 10- 4 M). [64Cu]Cu-DOTA-xPy (x = 2-4) exhibited good stability in human serum up to 24 h. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64Cu complexes. DOTA-xPy (x = 1-3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [64Cu]Cu-DOTA-xPy-αMSH retained good serum stability (> 96% in 24 h) and showed high binding affinity (Ki = 2.1-3.7 nM) towards the melanocortin 1 receptor. CONCLUSION: DOTA-xPy (x = 1-3) are promising chelators for 64Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.
BACKGROUND:64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x = 1-4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. RESULTS: We found that the presence of pyridyl groups significantly increases 64Cu labeling conversion yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing 64Cu at room temperature within 5 min (1 × 10- 4 M). [64Cu]Cu-DOTA-xPy (x = 2-4) exhibited good stability in human serum up to 24 h. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64Cu complexes. DOTA-xPy (x = 1-3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [64Cu]Cu-DOTA-xPy-αMSH retained good serum stability (> 96% in 24 h) and showed high binding affinity (Ki = 2.1-3.7 nM) towards the melanocortin 1 receptor. CONCLUSION:DOTA-xPy (x = 1-3) are promising chelators for 64Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.
Authors: Marianna Tosato; Marco Verona; Chiara Favaretto; Marco Pometti; Giordano Zanoni; Fabrizio Scopelliti; Francesco Paolo Cammarata; Luca Morselli; Zeynep Talip; Nicholas P van der Meulen; Valerio Di Marco; Mattia Asti Journal: Molecules Date: 2022-06-28 Impact factor: 4.927
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Authors: Bayirta V Egorova; Lyubov S Zamurueva; Anastasia D Zubenko; Anna V Pashanova; Artem A Mitrofanov; Anna B Priselkova; Yuri V Fedorov; Alexander L Trigub; Olga A Fedorova; Stepan N Kalmykov Journal: Molecules Date: 2022-05-12 Impact factor: 4.927
Authors: Brooke L McNeil; Andrew K H Robertson; Winnie Fu; Hua Yang; Cornelia Hoehr; Caterina F Ramogida; Paul Schaffer Journal: EJNMMI Radiopharm Chem Date: 2021-02-01