Evaluation of the new radioligand [18F]AQ-28A by small animal PET/MR demonstrates increase of PDE10A expression in striatum and brown adipose tissue (BAT) of obese mice


Evaluation of the new radioligand [18F]AQ-28A by small animal PET/MR demonstrates increase of PDE10A expression in striatum and brown adipose tissue (BAT) of obese mice

Wagner, S.; Kranz, M.; Hankir, M.; Deuther-Conrad, W.; Scheunemann, M.; Teodoro, R.; Wenzel, B.; Fischer, S.; Egerland, U.; Fenske, W. K.; Hesse, S.; Höfgen, N.; Steinbach, J.; Brust, P.

Objectives: Phosphodiesterase 10A (PDE10A) hydrolyses cAMP and cGMP. It is abundantly expressed in striatum, where it modulates intracellular dopamine signaling. There is evidence that PDE10A is involved in the regulation of whole body energy balance [1], but changes in its expression associated with obesity have not been described so far. To investigate this issue, we developed the new PDE10A radioligand [18F]AQ-28A and performed preliminary PET/MR studies in various animal models of obesity.
Methods: [18F]AQ-28A was synthesized by nucleophilic aromatic substitution from a nitro precursor. Ex vivo and in vitro autoradiography of [18F]AQ-28A was performed on mice and pig brain, respectively. Mice brain and plasma samples (30 min p.i) were investigated by radio-HPLC. Uptake of [18F]AQ-28A in striatum and brown adipose tissue (BAT) of adult female CD-1 mice (n=5) was studied by dynamic animal PET/MR before (control) and after a high fat diet for 12 weeks as well as in genetically obese leptin deficient (ob/ob) mice (n=5).
Results: [18F]AQ-28A was synthesized fully automated with a radiochemical yield of 31.0±7.0% (n=3), a specific activity of 65.9±19.9 GBq/μmol (n=3) and a radiochemical purity of >98%. Ex vivo and in vitro, distribution patterns of [18F]AQ-28A in mouse and pig brain corresponded to the expression of PDE10A. In vivo, 89% and 64% of intact tracer accounted for total radioactivity in brain and plasma of mice at 30 min p.i. Dynamic PET/MR studies revealed a target specific accumulation in striatum (max. SUVmean=2.04). Follow-up studies after high fat diet showed a 130% higher SUV in BAT and a 30% higher SUV in striatum of obese mice in comparison to controls. Similar radioligand accumulation was observed in genetically obese mice with 86% parent fraction in BAT at 30 min p.i.
Conclusions: We have successfully used the new radioligand [18F]AQ-28A for PET imaging of PDE10A in various animal models of obesity. Small animal PET/MR studies demonstrated for the first time that an increase of the PDE10A expression in the striatum of obese mice is accompanied by an even stronger increase in BAT suggesting that PDE10A is a potential therapeutic target.
References: [1] Nawrocki AR, et al. (2014) Diabetes, 63: 300.

  • Lecture (Conference)
    21st International Symposium on Radiopharmaceutical Sciences - ISRS2015, 26.-31.05.2015, Columbia, Missouri, USA
  • Open Access Logo Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 58(2015)1, 52
    DOI: 10.1002/jlcr.3302_1
    ISSN: 1099-1344

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Publ.-Id: 21343