Dataset Information

Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates.

ABSTRACT: The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [⁶⁸Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [⁶⁸Ga]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67?µg/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [⁶⁸Ga]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [⁶⁸Ga]Ga-DO3A-S01-GCG binding in liver. [⁶⁸Ga]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2?µg/kg. In vivo K_d for [⁶⁸Ga]Ga-DO3A-S01-GCG corresponded to 0.7?µg/kg, which indicates high potency. The test-retest reproducibility for [⁶⁸Ga]Ga-DO3A-S01-GCG binding in liver was 5.7?±?7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5?±?9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [⁶⁸Ga]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [⁶⁸Ga]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.

SUBMITTER: Eriksson O

PROVIDER: S-EPMC6800434 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates.

Eriksson Olof O Velikyan Irina I Haack Torsten T Bossart Martin M Evers Andreas A Laitinen Iina I Larsen Philip J PJ Plettenburg Oliver O Takano Akihiro A Halldin Christer C Antoni Gunnar G Johansson Lars L Pierrou Stefan S Wagner Michael M

Scientific reports 20191018 1

The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [<sup>68</sup>Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [<sup>68</sup>Ga]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose ...[more]

PMID: 31628379

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Project description:UnlabelledMicroglia play an essential role in many brain diseases. Microglia are activated by local tissue damage or inflammation, but systemic inflammation can also activate microglia. An important clinical question is whether the effects of systemic inflammation on microglia mediate the deleterious effects of systemic inflammation in diseases such as Alzheimer's dementia, multiple sclerosis, and stroke. Positron Emission Tomography (PET) imaging with ligands that bind to Translocator Protein (TSPO) can be used to detect activated microglia. The aim of this study was to evaluate whether the effect of systemic inflammation on microglia could be measured with PET imaging in nonhuman primates, using the TSPO ligand [(11)C]PBR28.MethodsSix female baboons (Papio anubis) were scanned before and at 1h and/or 4h and/or 22 h after intravenous administration of E. coli lipopolysaccharide (LPS; 0.1mg/kg), which induces systemic inflammation. Regional time-activity data from regions of interest (ROIs) were fitted to the two-tissue compartmental model, using the metabolite-corrected arterial plasma curve as input function. Total volume of distribution (V(T)) of [(11)C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in V(T) from baseline. Serum levels of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) were used to assess correlations between systemic inflammation and microglial activation. In one baboon, immunohistochemistry was used to identify cells expressing TSPO.ResultsLPS administration increased [(11)C]PBR28 binding (F(3,6)=5.1, p=.043) with a 29 ± 16% increase at 1h (n=4) and a 62 ± 34% increase at 4h (n=3) post-LPS. There was a positive correlation between serum IL-1β and IL-6 levels and the increase in [(11)C]PBR28 binding. TSPO immunoreactivity occurred almost exclusively in microglia and rarely in astrocytes.ConclusionIn the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO that is readily detected with [(11)C]PBR28 PET. The effect of LPS on [(11)C]PBR28 binding is likely mediated by inflammatory cytokines. Activation of microglia may be a mechanism through which systemic inflammatory processes influence the course of diseases such as Alzheimer's, multiple sclerosis, and possibly depression.

Dataset Information

Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates.

Publications

Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates.

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