Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Radiochemistry
2.3. In Vitro Binding Assays
2.4. In Vivo Assays
3. Discussion
4. Materials and Methods
4.1. General Methods
4.2. Chemistry
4.2.1. Synthesis of 2-Butyl-4-chloro-5-(2-fluoroethoxy)methyl-1-[(2′-(1H-(1-(triphenylmethyl)) tetrazol-5-yl) biphenyl-4-yl)methyl]-1H-imidazole (5)
4.2.2. Synthesis of 2-Butyl-4-chloro-5-(2-fluoroethoxy)methyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-imidazole (FEtLos)
4.2.3. Synthesis of 2-Butyl-4-chloro-5-(azidomethyl)-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-imidazole (7)
4.2.4. Synthesis of 2-Butyl-4-chloro-5-[((1H-1,2,3-triazol-4-yl)-(N,N-dimethyl-ammoniomethyl-trifluoroborate)methyl)methyl]-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-imidazole (AMBF3Los)
4.3. Radiochemistry
4.3.1. Concentration and [18F]F− Drying
4.3.2. Radiosynthesis of 2-[18F]Fluoroethyl Tosylate (2*)
4.3.3. Radiosynthesis of [18F]FEtLos
4.3.4. Radiosynthesis of [18F]AMBF3Los
Radiosynthesis Using Low Activities (0.7 ± 0.2 GBq) of [18F]F−
Radiosynthesis Using High Activities (61 ± 23 GBq) of [18F]F−
4.3.5. Quality Control
Log D7.4 Measurements
4.4. In Vitro Assays
4.4.1. Competition Binding Assays in Membranes Containing Human AT1R
4.4.2. Cell Culture
4.4.3. Real-Time Polymerase Chain Reaction (RT-PCR)
4.4.4. Cell Binding Assays
4.5. In Vivo Assays
4.5.1. Animals
4.5.2. Imaging and Biodistribution Studies
4.5.3. Autoradiography
4.5.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds FEtLos and AMBF3Los are available from the authors. |
Tissues | Baseline | AT1R Blocking |
---|---|---|
Blood | 0.05 ± 0.03 | 0.08 ± 0.08 |
Fat | 0.011 ± 0.004 | 0.008 ± 0.002 |
Testis | 0.03 ± 0.01 | 0.029 ± 0.008 |
Intestines | 63 ± 9 | 62 ± 3 |
Stomach | 0.06 ± 0.05 | 2 ± 2 |
Spleen | 0.2 ± 0.1 | 0.08 ± 0.03 |
Liver | 0.5 ± 0.5 | 0.6 ± 0.3 |
Pancreas | 0.05 ± 0.03 | 0.07 ± 0.06 |
Adrenal glands | 0.1 ± 0.1 | 0.11 ± 0.06 |
Kidneys | 3.5 ± 1.2 | 1.9 ± 1.3 |
Lungs | 0.06 ± 0.03 | 0.08 ± 0.04 |
Heart | 0.03 ± 0.01 | 0.04 ± 0.03 |
Muscle | 0.02 ± 0.01 | 0.05 ± 0.04 |
Bone | 0.11 ± 0.06 | 0.11 ± 0.03 |
Brain | 0.006 ± 0.005 | 0.005 ± 0.004 |
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Sahylí Ortega Pijeira, M.; Sérgio Gonçalves Nunes, P.; Nascimento dos Santos, S.; Zhang, Z.; Pérez Nario, A.; Araujo Perini, E.; Miguel Turato, W.; Rodríguez Riera, Z.; Chammas, R.; H. Elsinga, P.; et al. Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors. Molecules 2020, 25, 1872. https://doi.org/10.3390/molecules25081872
Sahylí Ortega Pijeira M, Sérgio Gonçalves Nunes P, Nascimento dos Santos S, Zhang Z, Pérez Nario A, Araujo Perini E, Miguel Turato W, Rodríguez Riera Z, Chammas R, H. Elsinga P, et al. Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors. Molecules. 2020; 25(8):1872. https://doi.org/10.3390/molecules25081872
Chicago/Turabian StyleSahylí Ortega Pijeira, Martha, Paulo Sérgio Gonçalves Nunes, Sofia Nascimento dos Santos, Zhengxing Zhang, Arian Pérez Nario, Efrain Araujo Perini, Walter Miguel Turato, Zalua Rodríguez Riera, Roger Chammas, Philip H. Elsinga, and et al. 2020. "Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors" Molecules 25, no. 8: 1872. https://doi.org/10.3390/molecules25081872