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Preclinical Evaluation and Test–Retest Studies of 18F-PSS232, a Novel Radioligand for Targeting Metabotropic Glutamate Receptor 5 (mGlu5)

Milicevic Sephton, Selena, Müller, Adrienne, Mu, Lijing, Keller, Claudia, Rüdisühli, Sonja, Auberson, Yves, Schibli, Roger, Krämer, Stefanie and Ametamey, Simon (2014) Preclinical Evaluation and Test–Retest Studies of 18F-PSS232, a Novel Radioligand for Targeting Metabotropic Glutamate Receptor 5 (mGlu5). Neuroimage.


A novel, fluorine-18 labelled metabotropic glutamate receptor subtype 5 (mGlu5) derivative of [11C]-ABP688, (E)-3-(Pyridin-2-ylethynyl)cyclohex-2-enone-O-(3-(2-[18F]-fluoro-ethoxy)-propyl) oxime ([18F]-PSS232) was evaluated in vitro and in vivo for its potential as a positron emission tomography (PET) agent and used for test-retest reliability studies. Methods: The radiosynthesis of [18F]-PSS232 was accomplished via a one-step reaction using a mesylate precursor. In vitro stability was determined in PBS, plasma, and with liver microsomal enzymes. Metabolite studies were performed in vitro using rat brain homogenates, and in vivo in brain extracts, blood and urine. To confirm the selectivity of [18F]-PSS232 for mGlu5 over mGlu1, in vitro autoradiography was performed on horizontal rat brain slices using ABP688 and JNJ16259685, antagonists for mGlu5 and mGlu1, respectively. Small animal PET, biodistribution, as well as test-retest studies were performed in Wistar rats. In vivo, dose-dependent displacement studies were performed using MMPEP and blocking studies with MTEP, both specific mGlu5 antagonists. Results: [18F]-PSS232 was obtained in decay corrected radiochemical yield of 13-37% with specific activity of 80-400 GBq/μmol. [18F]-PSS232 demonstrated high stability in rat and human plasma as well as PBS. Treatment with rat and human microsomal enzymes resulted in 20% and 4% of polar radiometabolites, respectively. In vivo, 91% of intact [18F]-PSS232 was found in the brain after 20 min. In vitro autoradiography on rat brain slices showed a heterogeneous distribution consistent with the known distribution of mGlu5 with high binding to hippocampal and cortical regions and negligible radioactivity in the cerebellum. Similar distribution of radioactivity was found in PET images. Under displacement conditions with MMPEP, a reduced [18F]-PSS232-binding was found in all brain regions except the cerebellum. The fitted maximal displacement for striatum was 78.5%. Test-retest studies were reproducible with a variability ranging from 6.8 to 8.2%. An extended single dose toxicity study in Wistar rats showed no compound-related adverse effects. Conclusions: The new mGlu5 imaging probe, [18F]-PSS232, has shown specific and selective in vitro and in vivo properties and is a promising radioligand for PET imaging of mGlu5 in humans.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45


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