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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

Verbeek, Joost (author)
Eriksson, Jonas (author)
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
Syvänen, Stina (author)
Uppsala universitet,Geriatrik,Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
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Huisman, Marc (author)
Schuit, Robert C (author)
Molthoff, Carla F M (author)
Voskuyl, Rob A (author)
de Lange, Elizabeth C (author)
Lammertsma, Adriaan A (author)
Windhorst, Albert D (author)
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 (creator_code:org_t)
2018-09-21
2018
English.
In: EJNMMI Radiopharmacy and Chemistry. - : Springer. - 2365-421X. ; 3:1
Related links:
https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Keyword

P-glycoprotein
P-gp inhibitor
Radiofluorination
[18F]-fluorisatin
[18F]4FIMPTC

Publication and Content Type

ref (subject category)
art (subject category)

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