Preclinical evaluation and test–retest studies of [¹⁸F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu₅)

A novel, ¹⁸F-labelled metabotropic glutamate receptor subtype 5 (mGlu₅) derivative of [¹¹C]ABP688 ([¹¹C]1), [¹⁸F]PSS232 ([¹⁸F] ]5), was evaluated in vitro and in vivo for its potential as a PET agent and was used in test–retest reliability studies

The radiosynthesis of [¹⁸F]5 was accomplished via a one-step reaction using a mesylate precursor. In vitro stability was determined in PBS and plasma, and with liver microsomal enzymes. Metabolite studies were performed using rat brain extracts, blood and urine. In vitro autoradiography was performed on horizontal slices of rat brain using 1 and 8, antagonists for mGlu₅ and mGlu₁, respectively. Small-animal PET, biodistribution, and test–retest studies were performed in Wistar rats. In vivo, dose-dependent displacement studies were performed using 6 and blocking studies with 7.

[¹⁸F]5 was obtained in decay-corrected maximal radiochemical yield of 37 % with a specific activity of 80 – 400 GBq/μmol. Treatment with rat and human microsomal enzymes in vitro for 60 min resulted in 20 % and 4 % of hydrophilic radiometabolites, respectively. No hydrophilic decomposition products or radiometabolites were found in PBS or plasma. 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 6, reduced [¹⁸F]5 binding was found in all brain regions except the cerebellum. 7 reduced binding in the striatum by 84 % on average. 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.

The new mGlu₅ radiotracer, [¹⁸F]5, showed specific and selective in vitro and in vivo properties and is a promising radioligand for PET imaging of mGlu₅ in humans.