Synthesis of DOTA-Pyridine Chelates for 64Cu Coordination and Radiolabeling of αMSH Peptide
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.
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Posted 22 Sep, 2020
On 13 Jan, 2021
Received 26 Oct, 2020
On 26 Oct, 2020
Received 12 Oct, 2020
On 05 Oct, 2020
On 02 Oct, 2020
Invitations sent on 30 Sep, 2020
On 29 Sep, 2020
On 28 Sep, 2020
On 17 Sep, 2020
On 11 Sep, 2020
Synthesis of DOTA-Pyridine Chelates for 64Cu Coordination and Radiolabeling of αMSH Peptide
Posted 22 Sep, 2020
On 13 Jan, 2021
Received 26 Oct, 2020
On 26 Oct, 2020
Received 12 Oct, 2020
On 05 Oct, 2020
On 02 Oct, 2020
Invitations sent on 30 Sep, 2020
On 29 Sep, 2020
On 28 Sep, 2020
On 17 Sep, 2020
On 11 Sep, 2020
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
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF.