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Methodology
John Babich
Weill Cornell Medical College
Corresponding Author
ORCiD: https://orcid.org/0000-0002-1616-3416
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: As 225Ac-labeled radiopharmaceuticals continue to show promise as targeted alpha therapeutics, there is a growing need to standardize quality control (QC) testing procedures. The determination of radiochemical purity (RCP) is an essential QC test. A significant obstacle to RCP testing is the disruption of the secular equilibrium between actinium-225 and its daughter radionuclides during labeling and analysis. In order to accelerate translation of actinium-225 targeted alpha therapy, we aimed to determine the earliest time point at which the RCP of an 225Ac-labeled radiopharmaceutical can be accurately calculated.
Results: Six ligands were conjugated to macrocyclic metal chelators and labeled with actinium-225 under conditions designed to generate diverse incorporation yields. RCP was determined by radio thin layer chromatography (radioTLC) followed by exposure of the TLC plate on a phosphor screen either 0.5, 2, 3.5, 5, 6.5, or 26 h after the plate was developed. The dataset was used to create models for predicting the true RCP using pre-equilibrium measurements at early time points. The 585 TLC measurements span RCP values of 1.8% to 99.5%. The statistical model created from these data predicted an independent data set with high accuracy. Predictions made at 0.5 h are more uncertain than predictions made at later time points. This is primarily due to the decay of bismuth-213. At 2 h the mean average error is < 3%. A measurement of RCP > 90% at this time point predicts a true RCP > 97%.
Conclusions: RCP of 225Ac-labeled radiopharmaceuticals can be quantified with acceptable accuracy at least 2 h after radioTLC. This time point best balances the need to accurately quantify RCP with the need to safely release the batch as quickly as possible.
Keywords
Target alpha therapy, Ac-225, radiopharmacy, quality control
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CURRENT STATUS: Under Review
The most recent version of this article is available here.
No community comments so far
Editorial decision: Major revision
On 07 Jun, 2021
Reviewer #4 agreed
On 30 May, 2021
Reviews received
Received 26 May, 2021
Reviewer #3 agreed
On 25 May, 2021
Review #2 received
Received 17 May, 2021
Review #1 received
Received 17 May, 2021
Reviewer #2 agreed
On 04 May, 2021
Reviewer #1 agreed
On 14 Apr, 2021
Reviewers invited
Invitations sent on 12 Apr, 2021
Editor assigned
On 11 Apr, 2021
Editor invited
On 11 Apr, 2021
Submission checks complete
On 10 Apr, 2021
First submitted
On 30 Mar, 2021
Version 1
Posted 02 Jul, 2020
Community comments: 4
Review #2 received
Received 10 Sep, 2020
Editorial decision: Reject after peer review
On 10 Sep, 2020
Reviewer #2 agreed
On 07 Sep, 2020
Review #1 received
Received 21 Jul, 2020
Reviewer #1 agreed
On 14 Jul, 2020
Editor assigned
On 10 Jul, 2020
Reviewers invited
Invitations sent on 10 Jul, 2020
Editor invited
On 09 Jul, 2020
Submission checks complete
On 01 Jul, 2020
First submitted
On 29 Jun, 2020
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This preprint is under consideration at EJNMMI Radiopharmacy and Chemistry. A preprint is 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
Methodology
John Babich
Weill Cornell Medical College
Corresponding Author
ORCiD: https://orcid.org/0000-0002-1616-3416
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: Under Review
The most recent version of this article is available here.
No community comments so far
Editorial decision: Major revision
On 07 Jun, 2021
Reviewer #4 agreed
On 30 May, 2021
Reviews received
Received 26 May, 2021
Reviewer #3 agreed
On 25 May, 2021
Review #2 received
Received 17 May, 2021
Review #1 received
Received 17 May, 2021
Reviewer #2 agreed
On 04 May, 2021
Reviewer #1 agreed
On 14 Apr, 2021
Reviewers invited
Invitations sent on 12 Apr, 2021
Editor assigned
On 11 Apr, 2021
Editor invited
On 11 Apr, 2021
Submission checks complete
On 10 Apr, 2021
First submitted
On 30 Mar, 2021
Version 1
Posted 02 Jul, 2020
Community comments: 4
Review #2 received
Received 10 Sep, 2020
Editorial decision: Reject after peer review
On 10 Sep, 2020
Reviewer #2 agreed
On 07 Sep, 2020
Review #1 received
Received 21 Jul, 2020
Reviewer #1 agreed
On 14 Jul, 2020
Editor assigned
On 10 Jul, 2020
Reviewers invited
Invitations sent on 10 Jul, 2020
Editor invited
On 09 Jul, 2020
Submission checks complete
On 01 Jul, 2020
First submitted
On 29 Jun, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
The most recent version of this article is available here.
Background: As 225Ac-labeled radiopharmaceuticals continue to show promise as targeted alpha therapeutics, there is a growing need to standardize quality control (QC) testing procedures. The determination of radiochemical purity (RCP) is an essential QC test. A significant obstacle to RCP testing is the disruption of the secular equilibrium between actinium-225 and its daughter radionuclides during labeling and analysis. In order to accelerate translation of actinium-225 targeted alpha therapy, we aimed to determine the earliest time point at which the RCP of an 225Ac-labeled radiopharmaceutical can be accurately calculated.
Results: Six ligands were conjugated to macrocyclic metal chelators and labeled with actinium-225 under conditions designed to generate diverse incorporation yields. RCP was determined by radio thin layer chromatography (radioTLC) followed by exposure of the TLC plate on a phosphor screen either 0.5, 2, 3.5, 5, 6.5, or 26 h after the plate was developed. The dataset was used to create models for predicting the true RCP using pre-equilibrium measurements at early time points. The 585 TLC measurements span RCP values of 1.8% to 99.5%. The statistical model created from these data predicted an independent data set with high accuracy. Predictions made at 0.5 h are more uncertain than predictions made at later time points. This is primarily due to the decay of bismuth-213. At 2 h the mean average error is < 3%. A measurement of RCP > 90% at this time point predicts a true RCP > 97%.
Conclusions: RCP of 225Ac-labeled radiopharmaceuticals can be quantified with acceptable accuracy at least 2 h after radioTLC. This time point best balances the need to accurately quantify RCP with the need to safely release the batch as quickly as possible.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
The full text of this article is available to read as a PDF.
This is a list of supplementary files associated with this preprint. Click to download.
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