Search: id:"swepub:oai:DiVA.org:uu-425491" >
Blocking of efflux ...
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Shalgunov, VladimirUniv Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Jagtvej 160, DK-2100 Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Clin Physiol Nucl Med & PET, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
(author)
Blocking of efflux transporters in rats improves translational validation of brain radioligands
- Article/chapterEnglish2020
Publisher, publication year, extent ...
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2020-10-19
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SPRINGER,2020
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-425491
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-425491URI
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https://doi.org/10.1186/s13550-020-00718-xDOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Background Positron emission tomography (PET) is a molecular imaging technique that can be used to investigate the in vivo pharmacology of drugs. Initial preclinical evaluation of PET tracers is often conducted in rodents due to the accessibility of disease models as well as economic considerations. Compared to larger species, rodents display a higher expression and/or activity of efflux transporters such as the P-glycoprotein (P-gp). Low brain uptake could, therefore, be species-specific and uptake in rodents not be predictive for that in humans. We hypothesized that a better prediction from rodent data could be achieved when a tracer is evaluated under P-gp inhibition. Consequently, we compared the performance of eight neuroreceptor tracers in rats with and without P-gp inhibition including a specific binding blockade. This data set was then used to predict the binding of these eight tracers in pigs. Methods PET tracers targeting serotonin 5-HT(2A)receptors ([F-18]MH.MZ, [F-18]Altanserin, [C-11]Cimbi-36, [C-11]Pimavanserin), serotonin 5-HT(7)receptors ([C-11]Cimbi-701, [C-11]Cimbi-717 and [C-11]BA-10) and dopamine D(2/3)receptors ([F-18]Fallypride) were used in the study. The brain uptake and target-specific binding of these PET radiotracers were evaluated in rats with and without inhibition of P-gp. Rat data were subsequently compared to the results obtained in pigs. Results Without P-gp inhibition, the amount of target-specific binding in the rat brain was sufficient to justify further translation for three out of eight evaluated tracers. With P-gp inhibition, results for five out of eight tracers justified further translation. The performance in pigs could correctly be predicted for six out of eight tracers when rat data obtained under P-gp inhibition were used, compared to four out of eight tracers without P-gp inhibition. Conclusions P-gp strongly affects the uptake of PET tracers in rodents, but false prediction outcomes can be reduced by evaluating a tracer under P-gp inhibition.
Subject headings and genre
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Xiong, MengfeiUppsala universitet,Geriatrik,Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Jagtvej 160, DK-2100 Copenhagen, Denmark.;Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.(Swepub:uu)menxi814
(author)
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L'Estrade, Elina T.Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Jagtvej 160, DK-2100 Copenhagen, Denmark.;Skanes Univ Hosp, Nucl Med Phys Unit, Radiat Phys, Barngatan 3, S-22242 Lund, Sweden.
(author)
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Raval, Nakul R.Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
(author)
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Andersen, Ida V.Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Jagtvej 160, DK-2100 Copenhagen, Denmark.;Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Edgar, Fraser G.Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Jagtvej 160, DK-2100 Copenhagen, Denmark.
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Speth, Nikolaj R.Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Baerentzen, Simone L.Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Hansen, Hanne D.Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.;Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA.
(author)
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Donovan, Lene L.Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Nasser, ArafatRigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Peitersen, Siv T.Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Kjaer, AndreasCopenhagen Univ Hosp, Rigshosp, Dept Clin Physiol Nucl Med & PET, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Biomed Sci, Cluster Mol Imaging, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
(author)
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Knudsen, Gitte M.Rigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Inst Clin Med, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
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Syvänen, StinaUppsala universitet,Geriatrik(Swepub:uu)stsyv838
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Palner, MikaelRigshosp, Neurobiol Res Unit, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Ctr Translat Neuromed, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
(author)
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Herth, Matthias M.Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Jagtvej 160, DK-2100 Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Clin Physiol Nucl Med & PET, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
(author)
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Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Jagtvej 160, DK-2100 Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Clin Physiol Nucl Med & PET, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.Geriatrik
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