Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in viv...

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Autores principales:	Daria D. Vaulina, Kira I. Stosman, Konstantin V. Sivak, Andrey G. Aleksandrov, Nikolai B. Viktorov, Nikolay N. Kuzmich, Mariia M. Kiseleva, Olga F. Kuznetsova, Natalia A. Gomzina
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	structural analogs of honokiol fluorine-18 neuroinflammation radioligand anti-inflammatory activity cyclooxygenase-2 (COX-2) Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/dc280d6893ef40ce9b8093ad7de45e15
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spelling	oai:doaj.org-article:dc280d6893ef40ce9b8093ad7de45e152021-11-11T18:36:03ZPreliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-<i>O</i>-(2-Fluoroethyl) Moiety and the Potential of Their <sup>18</sup>F-Labeled Derivatives for Neuroinflammation Imaging10.3390/molecules262166301420-3049https://doaj.org/article/dc280d6893ef40ce9b8093ad7de45e152021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6630https://doaj.org/toc/1420-3049Neolignans honokiol and 4′-<i>O</i>-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [<sup>11</sup>C]MPbP (<i>4′-[<sup>11</sup>C]methoxy-5-propyl-1,1′-biphenyl-2-ol</i>) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which <i>4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl</i> (<b>F-IV</b>) was selected for labeling with fluorine-18 (T<sub>1/2</sub> = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of <b>F-IV</b> to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand <b>[<sup>18</sup>F]F-IV</b> in a rodent model of neuroinflammation. <b>[<sup>18</sup>F]F-IV</b> was prepared with good radiochemical yield and high molar activity and radiochemical purity by <sup>18</sup>F-fluoroethylation of the precursor with Boc-protecting group (<b>15</b>) with [<sup>18</sup>F]2-fluoro-1-bromoethane ([<sup>18</sup>F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that <b>[<sup>18</sup>F]F-IV</b> is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [<sup>11</sup>C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of <b>[<sup>18</sup>F]F-IV</b> can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.Daria D. VaulinaKira I. StosmanKonstantin V. SivakAndrey G. AleksandrovNikolai B. ViktorovNikolay N. KuzmichMariia M. KiselevaOlga F. KuznetsovaNatalia A. GomzinaMDPI AGarticlestructural analogs of honokiolfluorine-18neuroinflammationradioligandanti-inflammatory activitycyclooxygenase-2 (COX-2)Organic chemistryQD241-441ENMolecules, Vol 26, Iss 6630, p 6630 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	structural analogs of honokiol fluorine-18 neuroinflammation radioligand anti-inflammatory activity cyclooxygenase-2 (COX-2) Organic chemistry QD241-441
spellingShingle	structural analogs of honokiol fluorine-18 neuroinflammation radioligand anti-inflammatory activity cyclooxygenase-2 (COX-2) Organic chemistry QD241-441 Daria D. Vaulina Kira I. Stosman Konstantin V. Sivak Andrey G. Aleksandrov Nikolai B. Viktorov Nikolay N. Kuzmich Mariia M. Kiseleva Olga F. Kuznetsova Natalia A. Gomzina Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-<i>O</i>-(2-Fluoroethyl) Moiety and the Potential of Their <sup>18</sup>F-Labeled Derivatives for Neuroinflammation Imaging
description	Neolignans honokiol and 4′-<i>O</i>-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [<sup>11</sup>C]MPbP (<i>4′-[<sup>11</sup>C]methoxy-5-propyl-1,1′-biphenyl-2-ol</i>) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which <i>4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl</i> (<b>F-IV</b>) was selected for labeling with fluorine-18 (T<sub>1/2</sub> = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of <b>F-IV</b> to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand <b>[<sup>18</sup>F]F-IV</b> in a rodent model of neuroinflammation. <b>[<sup>18</sup>F]F-IV</b> was prepared with good radiochemical yield and high molar activity and radiochemical purity by <sup>18</sup>F-fluoroethylation of the precursor with Boc-protecting group (<b>15</b>) with [<sup>18</sup>F]2-fluoro-1-bromoethane ([<sup>18</sup>F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that <b>[<sup>18</sup>F]F-IV</b> is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [<sup>11</sup>C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of <b>[<sup>18</sup>F]F-IV</b> can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.
format	article
author	Daria D. Vaulina Kira I. Stosman Konstantin V. Sivak Andrey G. Aleksandrov Nikolai B. Viktorov Nikolay N. Kuzmich Mariia M. Kiseleva Olga F. Kuznetsova Natalia A. Gomzina
author_facet	Daria D. Vaulina Kira I. Stosman Konstantin V. Sivak Andrey G. Aleksandrov Nikolai B. Viktorov Nikolay N. Kuzmich Mariia M. Kiseleva Olga F. Kuznetsova Natalia A. Gomzina
author_sort	Daria D. Vaulina
title	Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-<i>O</i>-(2-Fluoroethyl) Moiety and the Potential of Their <sup>18</sup>F-Labeled Derivatives for Neuroinflammation Imaging
title_short	Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-<i>O</i>-(2-Fluoroethyl) Moiety and the Potential of Their <sup>18</sup>F-Labeled Derivatives for Neuroinflammation Imaging
title_full	Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-<i>O</i>-(2-Fluoroethyl) Moiety and the Potential of Their <sup>18</sup>F-Labeled Derivatives for Neuroinflammation Imaging
title_fullStr	Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-<i>O</i>-(2-Fluoroethyl) Moiety and the Potential of Their <sup>18</sup>F-Labeled Derivatives for Neuroinflammation Imaging
title_full_unstemmed	Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-<i>O</i>-(2-Fluoroethyl) Moiety and the Potential of Their <sup>18</sup>F-Labeled Derivatives for Neuroinflammation Imaging
title_sort	preliminary assessment of the anti-inflammatory activity of new structural honokiol analogs with a 4′-<i>o</i>-(2-fluoroethyl) moiety and the potential of their <sup>18</sup>f-labeled derivatives for neuroinflammation imaging
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/dc280d6893ef40ce9b8093ad7de45e15
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Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-<i>O</i>-(2-Fluoroethyl) Moiety and the Potential of Their <sup>18</sup>F-Labeled Derivatives for Neuroinflammation Imaging

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