Blocking of efflux transporters in rats improves translational validation of brain radioligands
Abstract 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 consid...
| Autori principali: | , , , , , , , , , , , , , , , , |
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| Natura: | Articolo |
| Lingua: | English |
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SpringerOpen
2020-10-01
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| Serie: | EJNMMI Research |
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| Accesso online: | http://link.springer.com/article/10.1186/s13550-020-00718-x |
| _version_ | 1828871118775123968 |
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| author | Vladimir Shalgunov Mengfei Xiong Elina T. L’Estrade Nakul R. Raval Ida V. Andersen Fraser G. Edgar Nikolaj R. Speth Simone L. Baerentzen Hanne D. Hansen Lene L. Donovan Arafat Nasser Siv T. Peitersen Andreas Kjaer Gitte M. Knudsen Stina Syvänen Mikael Palner Matthias M. Herth |
| author_facet | Vladimir Shalgunov Mengfei Xiong Elina T. L’Estrade Nakul R. Raval Ida V. Andersen Fraser G. Edgar Nikolaj R. Speth Simone L. Baerentzen Hanne D. Hansen Lene L. Donovan Arafat Nasser Siv T. Peitersen Andreas Kjaer Gitte M. Knudsen Stina Syvänen Mikael Palner Matthias M. Herth |
| author_sort | Vladimir Shalgunov |
| collection | DOAJ |
| description | Abstract 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-HT2A receptors ([18F]MH.MZ, [18F]Altanserin, [11C]Cimbi-36, [11C]Pimavanserin), serotonin 5-HT7 receptors ([11C]Cimbi-701, [11C]Cimbi-717 and [11C]BA-10) and dopamine D2/3 receptors ([18F]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. |
| first_indexed | 2024-12-13T06:25:10Z |
| format | Article |
| id | doaj.art-abd4cf9642dc46f89d08c15d1cabc529 |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-12-13T06:25:10Z |
| publishDate | 2020-10-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj.art-abd4cf9642dc46f89d08c15d1cabc5292022-12-21T23:56:45ZengSpringerOpenEJNMMI Research2191-219X2020-10-0110111110.1186/s13550-020-00718-xBlocking of efflux transporters in rats improves translational validation of brain radioligandsVladimir Shalgunov0Mengfei Xiong1Elina T. L’Estrade2Nakul R. Raval3Ida V. Andersen4Fraser G. Edgar5Nikolaj R. Speth6Simone L. Baerentzen7Hanne D. Hansen8Lene L. Donovan9Arafat Nasser10Siv T. Peitersen11Andreas Kjaer12Gitte M. Knudsen13Stina Syvänen14Mikael Palner15Matthias M. Herth16Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenNeurobiology Research Unit, RigshospitaletDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenNeurobiology Research Unit, RigshospitaletNeurobiology Research Unit, RigshospitaletNeurobiology Research Unit, RigshospitaletNeurobiology Research Unit, RigshospitaletNeurobiology Research Unit, RigshospitaletNeurobiology Research Unit, RigshospitaletDepartment of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, RigshospitaletNeurobiology Research Unit, RigshospitaletDepartment of Public Health and Caring Sciences/Geriatrics, Rudbeck Laboratory, Uppsala UniversityNeurobiology Research Unit, RigshospitaletDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenAbstract 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-HT2A receptors ([18F]MH.MZ, [18F]Altanserin, [11C]Cimbi-36, [11C]Pimavanserin), serotonin 5-HT7 receptors ([11C]Cimbi-701, [11C]Cimbi-717 and [11C]BA-10) and dopamine D2/3 receptors ([18F]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.http://link.springer.com/article/10.1186/s13550-020-00718-xP-gpEfflux transporterPETRodentsPigsRats |
| spellingShingle | Vladimir Shalgunov Mengfei Xiong Elina T. L’Estrade Nakul R. Raval Ida V. Andersen Fraser G. Edgar Nikolaj R. Speth Simone L. Baerentzen Hanne D. Hansen Lene L. Donovan Arafat Nasser Siv T. Peitersen Andreas Kjaer Gitte M. Knudsen Stina Syvänen Mikael Palner Matthias M. Herth Blocking of efflux transporters in rats improves translational validation of brain radioligands EJNMMI Research P-gp Efflux transporter PET Rodents Pigs Rats |
| title | Blocking of efflux transporters in rats improves translational validation of brain radioligands |
| title_full | Blocking of efflux transporters in rats improves translational validation of brain radioligands |
| title_fullStr | Blocking of efflux transporters in rats improves translational validation of brain radioligands |
| title_full_unstemmed | Blocking of efflux transporters in rats improves translational validation of brain radioligands |
| title_short | Blocking of efflux transporters in rats improves translational validation of brain radioligands |
| title_sort | blocking of efflux transporters in rats improves translational validation of brain radioligands |
| topic | P-gp Efflux transporter PET Rodents Pigs Rats |
| url | http://link.springer.com/article/10.1186/s13550-020-00718-x |
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