title: Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [18F]PBR102 and [18F]PBR111.
abstract: OBJECTIVE
  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 K1was similar for baseline and blocking studies for both radiotracers; VTwas 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.
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia. stefan.eberl@sydney.edu.au.|Faculty of Engineering and Information Technologies, University of Sydney, Sydney, NSW, 2006, Australia. stefan.eberl@sydney.edu.au.
authors.forename: S
authors.initials: S
authors.lastname: Eberl
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.|Faculty of Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Katsifis
authors.affiliation: IMIV, CEA, Inserm, Univ. Paris-Sud, CNRS, Université Paris-Saclay, CEA-SHFJ, Orsay, France.
authors.forename: M A
authors.initials: MA
authors.lastname: Peyronneau
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.|Faculty of Engineering and Information Technologies, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Henderson
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Loc'h
authors.affiliation: Radiochemistry and Radiotracers Platform, ANSTO, New Illawarra Road, Lucas Heights, NSW, 2234, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Greguric
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Verschuer
authors.affiliation: Radiochemistry and Radiotracers Platform, ANSTO, New Illawarra Road, Lucas Heights, NSW, 2234, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Lam
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Mattner
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Mohamed
authors.affiliation: Department of Molecular Imaging (PET and Nuclear Medicine), Royal Prince Alfred Hospital, Building 63, Level A7, Missenden Road, Camperdown, NSW, 2050, Australia.|Faculty of Engineering and Information Technologies, University of Sydney, Sydney, NSW, 2006, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Fulham
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008297:Male; D008657:Metabolic Clearance Rate; D057054:Molecular Imaging / Q000379:methods*; D009928:Organ Specificity; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D018079:Receptors, GABA / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: C576229:2-(6-chloro-2-(4-(2-fluoroethoxy)phenyl)imidazo(1,2-a)pyridin-3-yl)-N,N-diethylacetamide; C550561:2-(6-chloro-2-(4-(3-fluoropropoxy)phenyl)imidazo(1,2-a)pyridin-3-yl)-N,N-diethylacetamide; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: Metabolism; Microsomes; Non-human primate PET-CT; TSPO; [18F]PBR102; [18F]PBR111