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Synthesis of DOTA-pyridine chelates for 64Cu coordination and radiolabeling of αMSH peptide Yang, Hua; Gao, Feng; McNeil, Brooke; Zhang, Chengcheng; Yuan, Zheliang; Zeisler, Stefan; Kumlin, Joel; Zeisler, Jutta; Bénard, François; Ramogida, Caterina F.; Schaffer, Paul

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.

Item Metadata

Title
Synthesis of DOTA-pyridine chelates for 64Cu coordination and radiolabeling of αMSH peptide
Creator
Yang, Hua; Gao, Feng; McNeil, Brooke; Zhang, Chengcheng; Yuan, Zheliang; Zeisler, Stefan; Kumlin, Joel; Zeisler, Jutta; Bénard, François; Ramogida, Caterina F.; Schaffer, Paul
Publisher
Springer International Publishing
Date Issued
2021-01-13
Description
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.
Subject
Copper-64; Chelating ligands; Radiolabeling; α-Melanocyte-stimulating hormone; Pyridyl; DOTA
Genre
Article
Type
Text
Language
eng
Date Available
2021-01-13
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0395588
URI
http://hdl.handle.net/2429/77083
Affiliation
Medicine, Faculty of; TRIUMF; Non UBC; Radiology, Department of
Citation
EJNMMI Radiopharmacy and Chemistry. 2021 Jan 13;6(1):3
Publisher DOI
10.1186/s41181-020-00119-4
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)