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Synthesis and preli...
Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([18F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression
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Verbeek, Joost (författare)
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- Eriksson, Jonas (författare)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap,Department of Radiology & Nuclear Medicine, VU University Medical Center, P.O. box 7057, 1007, MB, Amsterdam, The Netherlands
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- Syvänen, Stina (författare)
- Uppsala universitet,Geriatrik,Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
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Huisman, Marc (författare)
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Schuit, Robert C (författare)
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Molthoff, Carla F M (författare)
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Voskuyl, Rob A (författare)
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de Lange, Elizabeth C (författare)
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Lammertsma, Adriaan A (författare)
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Windhorst, Albert D (författare)
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(creator_code:org_t)
- 2018-09-21
- 2018
- Engelska.
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Ingår i: EJNMMI Radiopharmacy and Chemistry. - : Springer. - 2365-421X. ; 3:1
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://ejnmmipharmc...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Background: Several P-glycoprotein (P-gp) substrate tracers are available to assess P-gp function in vivo, but attempts to develop a tracer for measuring expression levels of P-gp have not been successful. Recently, (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide was described as a potential selective P-gp inhibitor that is not transported by P-gp. Therefore, the purpose of this study was to radiolabel two of its analogues and to assess their potential for imaging P-gp expression using PET.Results: [18F]2-(4-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]5) and [18F]2-(6-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]6) were synthesized and both their biodistribution and metabolism were evaluated in rats. In addition, PET scans were acquired in rats before and after tariquidar (P-gp inhibitor) administration as well as in P-gp knockout (KO) mice.Both [18F]5 and [18F]6 were synthesized in 2-3% overall yield, and showed high brain uptake in ex vivo biodistribution studies. [18F]6 appeared to be metabolically unstable in vivo, while [18F]5 showed moderate stability with limited uptake of radiolabelled metabolites in the brain. PET studies showed that transport of [18F]5 across the blood-brain barrier was not altered by pre-treatment with the P-gp inhibitor tariquidar, and uptake was significantly lower in P-gp KO than in wild-type animals and indeed transported across the BBB or bound to P-gp in endothelial cells.Conclusion: In conclusion, [18F]5 and [18F]6 were successfully and reproducibly synthesized, albeit with low radiochemical yields. [18F]5 appears to be a radiotracer that binds to P-gp, as showed in P-gp knock-out animals, but is not a substrate for P-gp.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Nyckelord
- P-glycoprotein
- P-gp inhibitor
- Radiofluorination
- [18F]-fluorisatin
- [18F]4FIMPTC
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Verbeek, Joost
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Eriksson, Jonas
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Syvänen, Stina
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Huisman, Marc
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Schuit, Robert C
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Molthoff, Carla ...
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visa fler...
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Voskuyl, Rob A
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de Lange, Elizab ...
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Lammertsma, Adri ...
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Windhorst, Alber ...
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