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Synthesis of the Novel AT(1) Receptor Tracer [(18)F]Fluoropyridine–Candesartan via Click Chemistry
[Image: see text] A novel 7-((4-(3-((2-[(18)F]fluoropyridin-3-yl)oxy)propyl)-1H-1,2,3-triazol-1-yl)methyl)-1H-benzo[d]imidazole derivative of the angiotensin II type-1 receptor (AT(1)R) blocker candesartan, [(18)F]fluoropyridine–candesartan, was synthesized via the copper-catalyzed azide–alkyne cycl...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439361/ https://www.ncbi.nlm.nih.gov/pubmed/32832788 http://dx.doi.org/10.1021/acsomega.0c02310 |
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author | Abreu Diaz, Aida M. Drumeva, Gergana O. Petrenyov, Daniil R. Carrier, Jean-François DaSilva, Jean N. |
author_facet | Abreu Diaz, Aida M. Drumeva, Gergana O. Petrenyov, Daniil R. Carrier, Jean-François DaSilva, Jean N. |
author_sort | Abreu Diaz, Aida M. |
collection | PubMed |
description | [Image: see text] A novel 7-((4-(3-((2-[(18)F]fluoropyridin-3-yl)oxy)propyl)-1H-1,2,3-triazol-1-yl)methyl)-1H-benzo[d]imidazole derivative of the angiotensin II type-1 receptor (AT(1)R) blocker candesartan, [(18)F]fluoropyridine–candesartan, was synthesized via the copper-catalyzed azide–alkyne cycloaddition click reaction between 2-[(18)F]fluoro-3-(pent-4-yn-1-yloxy)pyridine ([(18)F]FPyKYNE) and the tetrazole-protected azido-candesartan derivative, followed by acid deprotection. This three-step, two-pot, and two-step purification synthesis was done within 2 h. The use of tris[(1-hydroxypropyl-1H-1,2,3-triazol-4-yl)methyl]amine (THPTA) as a Cu(I) stabilizing agent increased the overall radiochemical yield by 4-fold (10 ± 2%, n = 13) compared to the reaction without THPTA (2.4 ± 0.2%, n = 3; decay-corrected from (18)F produced at the end-of-beam). Complete separation of [(18)F]FPyKYNE from its nitro precursor and [(18)F]fluoropyridine–candesartan from the deprotected azido-candesartan allowed for high molar activities (>380 GBq/μmol) of the tracer. The use of 0.1% trifluoroacetic acid in water for reformulation and the addition of sodium ascorbate to the final formulation (1.6 ± 0.2 GBq/mL, n = 3) prevented tracer radiolysis with >97% radiochemical purity for a period of up to 10 h after the end-of-synthesis. A significant reduction in the uptake (86 ± 3%, n = 8) of the tracer was observed ex vivo in rats (at 20 min postinjection) in the AT(1)R-rich kidney cortex following pretreatment with saturating doses of the AT(1)R antagonist candesartan or losartan. This specific binding to AT(1)R was confirmed in vitro in the rat renal cortex (autoradiography) by a reduction of 26 ± 5% (n = 12) with losartan coincubation (10 μM). These favorable binding properties support further studies to assess the potential of [(18)F]fluoropyridine–candesartan as a tracer for the positron emission tomography imaging of renal AT(1)R. |
format | Online Article Text |
id | pubmed-7439361 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-74393612020-08-21 Synthesis of the Novel AT(1) Receptor Tracer [(18)F]Fluoropyridine–Candesartan via Click Chemistry Abreu Diaz, Aida M. Drumeva, Gergana O. Petrenyov, Daniil R. Carrier, Jean-François DaSilva, Jean N. ACS Omega [Image: see text] A novel 7-((4-(3-((2-[(18)F]fluoropyridin-3-yl)oxy)propyl)-1H-1,2,3-triazol-1-yl)methyl)-1H-benzo[d]imidazole derivative of the angiotensin II type-1 receptor (AT(1)R) blocker candesartan, [(18)F]fluoropyridine–candesartan, was synthesized via the copper-catalyzed azide–alkyne cycloaddition click reaction between 2-[(18)F]fluoro-3-(pent-4-yn-1-yloxy)pyridine ([(18)F]FPyKYNE) and the tetrazole-protected azido-candesartan derivative, followed by acid deprotection. This three-step, two-pot, and two-step purification synthesis was done within 2 h. The use of tris[(1-hydroxypropyl-1H-1,2,3-triazol-4-yl)methyl]amine (THPTA) as a Cu(I) stabilizing agent increased the overall radiochemical yield by 4-fold (10 ± 2%, n = 13) compared to the reaction without THPTA (2.4 ± 0.2%, n = 3; decay-corrected from (18)F produced at the end-of-beam). Complete separation of [(18)F]FPyKYNE from its nitro precursor and [(18)F]fluoropyridine–candesartan from the deprotected azido-candesartan allowed for high molar activities (>380 GBq/μmol) of the tracer. The use of 0.1% trifluoroacetic acid in water for reformulation and the addition of sodium ascorbate to the final formulation (1.6 ± 0.2 GBq/mL, n = 3) prevented tracer radiolysis with >97% radiochemical purity for a period of up to 10 h after the end-of-synthesis. A significant reduction in the uptake (86 ± 3%, n = 8) of the tracer was observed ex vivo in rats (at 20 min postinjection) in the AT(1)R-rich kidney cortex following pretreatment with saturating doses of the AT(1)R antagonist candesartan or losartan. This specific binding to AT(1)R was confirmed in vitro in the rat renal cortex (autoradiography) by a reduction of 26 ± 5% (n = 12) with losartan coincubation (10 μM). These favorable binding properties support further studies to assess the potential of [(18)F]fluoropyridine–candesartan as a tracer for the positron emission tomography imaging of renal AT(1)R. American Chemical Society 2020-08-03 /pmc/articles/PMC7439361/ /pubmed/32832788 http://dx.doi.org/10.1021/acsomega.0c02310 Text en Copyright © 2020 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Abreu Diaz, Aida M. Drumeva, Gergana O. Petrenyov, Daniil R. Carrier, Jean-François DaSilva, Jean N. Synthesis of the Novel AT(1) Receptor Tracer [(18)F]Fluoropyridine–Candesartan via Click Chemistry |
title | Synthesis of the Novel AT(1) Receptor Tracer
[(18)F]Fluoropyridine–Candesartan via Click Chemistry |
title_full | Synthesis of the Novel AT(1) Receptor Tracer
[(18)F]Fluoropyridine–Candesartan via Click Chemistry |
title_fullStr | Synthesis of the Novel AT(1) Receptor Tracer
[(18)F]Fluoropyridine–Candesartan via Click Chemistry |
title_full_unstemmed | Synthesis of the Novel AT(1) Receptor Tracer
[(18)F]Fluoropyridine–Candesartan via Click Chemistry |
title_short | Synthesis of the Novel AT(1) Receptor Tracer
[(18)F]Fluoropyridine–Candesartan via Click Chemistry |
title_sort | synthesis of the novel at(1) receptor tracer
[(18)f]fluoropyridine–candesartan via click chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439361/ https://www.ncbi.nlm.nih.gov/pubmed/32832788 http://dx.doi.org/10.1021/acsomega.0c02310 |
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