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

  • S. EberlEmail author
  • A. Katsifis
  • M. A. Peyronneau
  • L. Wen
  • D. Henderson
  • C. Loc’h
  • I. Greguric
  • J. Verschuer
  • T. Pham
  • P. Lam
  • F. Mattner
  • A. Mohamed
  • M. J. Fulham
Original Article
First Online:

Abstract

Purpose

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.

Keywords

TSPO [18F]PBR102 [18F]PBR111 Microsomes Metabolism Non-human primate PET-CT 
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Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • S. Eberl
    • 1
    • 2
    Email author
  • A. Katsifis
    • 1
    • 3
  • M. A. Peyronneau
    • 4
  • L. Wen
    • 1
    • 2
  • D. Henderson
    • 1
  • C. Loc’h
    • 1
  • I. Greguric
    • 5
  • J. Verschuer
    • 1
  • T. Pham
    • 5
  • P. Lam
    • 1
  • F. Mattner
    • 1
  • A. Mohamed
    • 1
    • 6
  • M. J. Fulham
    • 1
    • 2
    • 6
  1. 1.Department of Molecular Imaging (PET and Nuclear Medicine)Royal Prince Alfred HospitalCamperdownAustralia
  2. 2.Faculty of Engineering and Information TechnologiesUniversity of SydneySydneyAustralia
  3. 3.Faculty of PharmacyUniversity of SydneySydneyAustralia
  4. 4.IMIV, CEA, Inserm, Univ. Paris-Sud, CNRSUniversité Paris-Saclay, CEA-SHFJOrsayFrance
  5. 5.Radiochemistry and Radiotracers PlatformANSTOLucas HeightsAustralia
  6. 6.Sydney Medical SchoolUniversity of SydneySydneyAustralia

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