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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 64 Cu labeling yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing 64 Cu at room temperature within 5 min (10 -4 M). [ 64 Cu]Cu-DOTA-xPy (x=2-4) exhibited good stability in human serum up to 24 hours. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64 Cu 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. [ 64 Cu]Cu-DOTA-xPy-αMSH retained good serum stability (>96% in 24 hours) 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 64 Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.
Keywords
Copper-64, Chelating ligands, Radiolabeling, α-Melanocyte-stimulating hormone, Pyridyl, DOTA
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CURRENT STATUS: Published
View the published article at EJNMMI Radiopharmacy and Chemistry.
Version 1
Posted 22 Sep, 2020
No community comments so far
Review #2 received
Received 26 Oct, 2020
Editorial decision: Major revision
On 26 Oct, 2020
Review #1 received
Received 12 Oct, 2020
Reviewer #2 agreed
On 05 Oct, 2020
Reviewer #1 agreed
On 02 Oct, 2020
Reviewers invited
Invitations sent on 30 Sep, 2020
Editor assigned
On 29 Sep, 2020
Editor invited
On 28 Sep, 2020
Submission checks complete
On 17 Sep, 2020
First submitted
On 11 Sep, 2020
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Subject Areas
Nuclear Chemistry
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See the published version of this preprint at EJNMMI Radiopharmacy and Chemistry.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at EJNMMI Radiopharmacy and Chemistry.
Version 1
Posted 22 Sep, 2020
No community comments so far
Review #2 received
Received 26 Oct, 2020
Editorial decision: Major revision
On 26 Oct, 2020
Review #1 received
Received 12 Oct, 2020
Reviewer #2 agreed
On 05 Oct, 2020
Reviewer #1 agreed
On 02 Oct, 2020
Reviewers invited
Invitations sent on 30 Sep, 2020
Editor assigned
On 29 Sep, 2020
Editor invited
On 28 Sep, 2020
Submission checks complete
On 17 Sep, 2020
First submitted
On 11 Sep, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Nuclear Chemistry
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at EJNMMI Radiopharmacy and Chemistry.
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 64 Cu labeling yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing 64 Cu at room temperature within 5 min (10 -4 M). [ 64 Cu]Cu-DOTA-xPy (x=2-4) exhibited good stability in human serum up to 24 hours. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64 Cu 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. [ 64 Cu]Cu-DOTA-xPy-αMSH retained good serum stability (>96% in 24 hours) 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 64 Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
This preprint is available for download as a PDF.
This is a list of supplementary files associated with this preprint. Click to download.
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