Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [18F]PBR102 and [18F]PBR111

Simple item page
dc.contributor.authorEberl, Sen_AU
dc.contributor.authorKatsifis, Aen_AU
dc.contributor.authorPeyronneau, MAen_AU
dc.contributor.authorWen, LFen_AU
dc.contributor.authorHenderson, Den_AU
dc.contributor.authorLoc’h, Cen_AU
dc.contributor.authorGreguric, Ien_AU
dc.contributor.authorVerschuer, Jen_AU
dc.contributor.authorPham, TQen_AU
dc.contributor.authorLam, Pen_AU
dc.contributor.authorMattner, Fen_AU
dc.contributor.authorMohamed, Aen_AU
dc.contributor.authorFulham, MJen_AU
dc.date.accessioned2020-03-12T06:04:06Zen_AU
dc.date.available2020-03-12T06:04:06Zen_AU
dc.date.issued2016-10-04en_AU
dc.date.statistics2020-03-11en_AU
dc.description.abstractPurpose To determine the metabolic profiles of the translocator protein ligands PBR102 and PBR111 in rat and human microsomes and compare their in vivo binding and metabolite uptake in the brain of non-human primates (Papio hamadryas) using PET-CT. Methods In vitro metabolic profiles of PBR102 and PBR111 in rat and human liver microsomes were assessed by liquid chromatography–tandem mass spectrometry. [18F]PBR102 and [18F]PBR111 were prepared by nucleophilic substitution of their corresponding p-toluenesulfonyl precursors with [18F]fluoride. List mode PET-CT brain imaging with arterial blood sampling was performed in non-human primates. Blood plasma measurements and metabolite analysis, using solid-phase extraction, provided the metabolite profile and metabolite-corrected input functions for kinetic model fitting. Blocking and displacement PET-CT scans, using PK11195, were performed. Results Microsomal analyses identified the O-de-alkylated, hydroxylated and N-de-ethyl derivatives of PBR102 and PBR111 as the main metabolites. The O-de-alkylated compounds were the major metabolites in both species; human liver microsomes were less active than those from rat. Metabolic profiles in vivo in non-human primates and previously published rat experiments were consistent with the microsomal results. PET-CT studies showed that K1 was similar for baseline and blocking studies for both radiotracers; VT was reduced during the blocking study, suggesting low non-specific binding and lack of appreciable metabolite uptake in the brain. Conclusions [18F]PBR102 and [18F]PBR111 have distinct metabolic profiles in rat and non-human primates. Radiometabolites contributed to non-specific binding and confounded in vivo brain analysis of [18F]PBR102 in rodents; the impact in primates was less pronounced. Both [18F]PBR102 and [18F]PBR111 are suitable for PET imaging of TSPO in vivo. In vitro metabolite studies can be used to predict in vivo radioligand metabolism and can assist in the design and development of better radioligands. © 2016 Springer-Verlagen_AU
dc.identifier.citationEberl, S., Katsifis, A., Peyronneau, M. A., Wen, L., Henderson, D., Loc’h, C., Greguric, I., Pham, T., Lam, P., Mattner, F., Mohamed, A., & Mattner, F. (2017). Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [18F] PBR102 and [18F] PBR111. European Journal of Nuclear Medicine and Molecular Imaging, 44(2), 296-307. doi:10.1007/s00259-016-3517-zen_AU
dc.identifier.govdoc8747en_AU
dc.identifier.issn1619-7089en_AU
dc.identifier.issue2en_AU
dc.identifier.journaltitleEuropean Journal of Nuclear Medicine and Molecular Imagingen_AU
dc.identifier.pagination293-307en_AU
dc.identifier.urihttps://doi.org/10.1007/s00259-016-3517-zen_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/9151en_AU
dc.identifier.volume44en_AU
dc.language.isoenen_AU
dc.publisherSpringer Linken_AU
dc.subjectProteinsen_AU
dc.subjectRatsen_AU
dc.subjectMetabolitesen_AU
dc.subjectBrainen_AU
dc.subjectIn vitroen_AU
dc.subjectPositron computed tomographyen_AU
dc.subjectPrimatesen_AU
dc.subjectMetabolitesen_AU
dc.subjectBlood plasmaen_AU
dc.subjectMetabolismen_AU
dc.titlePreclinical in vivo and in vitro comparison of the translocator protein PET ligands [18F]PBR102 and [18F]PBR111en_AU
dc.typeJournal Articleen_AU
Files
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Journal Articles