[18F]AZD2461, an insight on difference in PARP binding profiles for DNA damage response PET imaging
Purpose Poly(ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1-3 affinity. Herein, we propose to study AZD2461, a P...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Verlag
2020
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| _version_ | 1797081664616136704 |
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| author | Guibbal, F Hopkins, S Pacelli, A Isenegger, PG Mosley, M Torres, J Dias, GM Mahaut, D Hueting, R Gouverneur, V Cornelissen, B |
| author_facet | Guibbal, F Hopkins, S Pacelli, A Isenegger, PG Mosley, M Torres, J Dias, GM Mahaut, D Hueting, R Gouverneur, V Cornelissen, B |
| author_sort | Guibbal, F |
| collection | OXFORD |
| description | Purpose
Poly(ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as
anti-cancer drugs, as single agents or in combination with other therapies. Most
radiotracers developed to date have been chosen on the basis of strong PARP1-3
affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity
towards PARP3 and to investigate its potential for PARP targeting in vivo .
Procedures
Using the Cu-mediated 18 F-fluorodeboronation of a carefully designed radiolabelling
precursor, we accessed the 18 F-labeled isotopologue of the PARP inhibitor
AZD2461. Cell uptake of [ 18 F]AZD2461 in vitro was assessed in a range of
pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP
expression, and in vivo in xenograft-bearing mice. Blocking experiments were
performed with both olaparib and AZD2461.
Results
[ 18 F]AZD2461 was efficiently radiolabelled via both manual and automated
procedures (9% ± 3% and 3% ± 1% Activity yields non-decay corrected). [ 18
F]AZD2461 was taken up in vivo in PARP1-expressing tumours and the highest
uptake was observed for PSN-1 cells (7.34 ± 1.16%ID/g). In vitro blocking
experiments showed a lesser ability of olaparib to reduce [ 18 F]AZD2461 binding,
indicating a difference in selectivity between olaparib and AZD2461.
Conclusion
Taken together, we show the importance of screening the PARP selectivity profile of
radiolabelled PARP inhibitors for use as PET imaging agents. |
| first_indexed | 2024-03-07T01:17:17Z |
| format | Journal article |
| id | oxford-uuid:8f201508-7cae-4816-8599-3838ce7aeb4c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:17:17Z |
| publishDate | 2020 |
| publisher | Springer Verlag |
| record_format | dspace |
| spelling | oxford-uuid:8f201508-7cae-4816-8599-3838ce7aeb4c2022-03-26T23:02:20Z[18F]AZD2461, an insight on difference in PARP binding profiles for DNA damage response PET imagingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8f201508-7cae-4816-8599-3838ce7aeb4cEnglishSymplectic ElementsSpringer Verlag2020Guibbal, FHopkins, SPacelli, AIsenegger, PGMosley, MTorres, JDias, GMMahaut, DHueting, RGouverneur, VCornelissen, BPurpose Poly(ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1-3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3 and to investigate its potential for PARP targeting in vivo . Procedures Using the Cu-mediated 18 F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18 F-labeled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [ 18 F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression, and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. Results [ 18 F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9% ± 3% and 3% ± 1% Activity yields non-decay corrected). [ 18 F]AZD2461 was taken up in vivo in PARP1-expressing tumours and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16%ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [ 18 F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. Conclusion Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents. |
| spellingShingle | Guibbal, F Hopkins, S Pacelli, A Isenegger, PG Mosley, M Torres, J Dias, GM Mahaut, D Hueting, R Gouverneur, V Cornelissen, B [18F]AZD2461, an insight on difference in PARP binding profiles for DNA damage response PET imaging |
| title | [18F]AZD2461, an insight on difference in PARP binding profiles for DNA damage response PET imaging |
| title_full | [18F]AZD2461, an insight on difference in PARP binding profiles for DNA damage response PET imaging |
| title_fullStr | [18F]AZD2461, an insight on difference in PARP binding profiles for DNA damage response PET imaging |
| title_full_unstemmed | [18F]AZD2461, an insight on difference in PARP binding profiles for DNA damage response PET imaging |
| title_short | [18F]AZD2461, an insight on difference in PARP binding profiles for DNA damage response PET imaging |
| title_sort | 18f azd2461 an insight on difference in parp binding profiles for dna damage response pet imaging |
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