Radiosynthesis and Evaluation of Talazoparib and Its Derivatives as PARP-1-Targeting Agents
Abstract
:1. Introduction
2. Method and General Information
2.1. General Information
2.2. Synthesis of Methyl 2-(4-bromophenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (2b) and Methyl 7-fluoro-2-(4-iodophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (2c)
2.3. Synthesis of 8-(4-bromophenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (3b) and 8-(4-iodophenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (3c)
2.4. Synthesis of [18F]Talazoparib (3a″)
2.5. Xenograft Model
2.6. Biodistribution
2.7. Materials and Cell Culture
2.8. Radioligand Cell Uptake Saturation Analyses
2.9. Competitive Assay
3. Results and Discussion
3.1. Organic Synthesis and Radiosynthesis
3.2. Synthesis of [3H]WC-DZ
3.3. Saturation Analyses of Radioligand Uptake in U251MG Cells
3.4. Competitive Profile of Standard and WC-DZ in U251MG Cells
3.5. Biodistribution Studies of [18F]Talazoparib
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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3a″ a | 3a | 3b | 3c | Olaparib | Raclopride | |
---|---|---|---|---|---|---|
Ki (nM) b | 0.65 ± 0.07 | 2.37 ± 0.56 | 1.92 ± 0.41 | 1.73 ± 0.43 | 1.87 ± 0.10 | >20,000 |
n′H | 0.76 ± 0.13 | 1.00 ± 0.07 | 1.24 ± 0.24 | 1.01 ± 0.20 | 1.13 ± 0.13 | None |
cLogP c | 2.58 | 2.58 | 3.25 | 3.78 | / | / |
MW | 380.36 | 380.36 | 441.26 | 488.26 | / | / |
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Zhou, D.; Chen, H.; Mpoy, C.; Afrin, S.; Rogers, B.E.; Garbow, J.R.; Katzenellenbogen, J.A.; Xu, J. Radiosynthesis and Evaluation of Talazoparib and Its Derivatives as PARP-1-Targeting Agents. Biomedicines 2021, 9, 565. https://doi.org/10.3390/biomedicines9050565
Zhou D, Chen H, Mpoy C, Afrin S, Rogers BE, Garbow JR, Katzenellenbogen JA, Xu J. Radiosynthesis and Evaluation of Talazoparib and Its Derivatives as PARP-1-Targeting Agents. Biomedicines. 2021; 9(5):565. https://doi.org/10.3390/biomedicines9050565
Chicago/Turabian StyleZhou, Dong, Huaping Chen, Cedric Mpoy, Sadia Afrin, Buck E. Rogers, Joel R. Garbow, John A. Katzenellenbogen, and Jinbin Xu. 2021. "Radiosynthesis and Evaluation of Talazoparib and Its Derivatives as PARP-1-Targeting Agents" Biomedicines 9, no. 5: 565. https://doi.org/10.3390/biomedicines9050565