Blocking of efflux transporters in rats improves translational validation of brain radioligands

EJNMMI Research

Andreas Kjaer¹  Fraser G. Edgar²  Matthias M. Herth³  Vladimir Shalgunov³  Ida V. Andersen⁴  Mengfei Xiong⁵  Elina T. L’Estrade⁶  Stina Syvänen⁷  Simone L. Baerentzen⁸  Nikolaj R. Speth⁸  Siv T. Peitersen⁸  Arafat Nasser⁸  Lene L. Donovan⁸  Nakul R. Raval⁸  Hanne D. Hansen⁹  Mikael Palner^1,10  Gitte M. Knudsen^1,11 

[1] Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;Cluster for Molecular Imaging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark;Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark;Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark;Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark;Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark;Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;Department of Public Health and Caring Sciences/Geriatrics, Rudbeck Laboratory, Uppsala University, 75185, Uppsala, Sweden;Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark;Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;Radiation Physics, Nuclear Medicine Physics Unit, Skånes University Hospital, Barngatan 3, 222 42, Lund, Sweden;Department of Public Health and Caring Sciences/Geriatrics, Rudbeck Laboratory, Uppsala University, 75185, Uppsala, Sweden;Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 149 13th Street, 02129, Charlestown, MA, USA;Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark;Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark;Institute of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark;

关键词: P-gp;    Efflux transporter;    PET;    Rodents;    Pigs;    Rats;    Translation;   

DOI  :  10.1186/s13550-020-00718-x

来源: Springer

【 摘 要 】

BackgroundPositron 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.MethodsPET 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.ResultsWithout 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.ConclusionsP-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.

【 授权许可】

CC BY