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

• Published in: European journal of nuclear medicine and molecular imaging Vol. 42; no. 1; pp. 128 - 137
• Main Authors: Sephton, Selena Milicevic, Herde, Adrienne Müller, Mu, Linjing, Keller, Claudia, Rüdisühli, Sonja, Auberson, Yves, Schibli, Roger, Krämer, Stefanie D., Ametamey, Simon M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2015; Springer Nature B.V
• Subjects: Animals; Cardiology; Chemical synthesis; Clinical trials; Drug Evaluation, Preclinical; Imaging; Male; Medical imaging; Medicine; Medicine & Public Health; Neurons; Nuclear Medicine; Oncology; Original Article; Orthopedics; Oximes - chemical synthesis; Oximes - pharmacokinetics; Positron-Emission Tomography; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Radiology; Radiopharmaceuticals - adverse effects; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors; Reproducibility of Results; Tissue Distribution; mGlu; Test–retest; F]PSS232; [; Positron emission tomography
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-014-2883-7

Purpose A novel, 18 F-labelled metabotropic glutamate receptor subtype 5 (mGlu 5 ) derivative of [ 11 C]ABP688 ([ 11 C] 1 ), [ 18 F]PSS232 ([ 18 F] ] 5 ), was evaluated in vitro and in vivo for its potential as a PET agent and was used in test–retest reliability studies Methods The radiosynthesis of [ 18 F] 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 mGlu 5 and mGlu 1 , 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 . Results [ 18 F] 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 mGlu 5 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 [ 18 F] 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. Conclusion The new mGlu 5 radiotracer, [ 18 F] 5 , showed specific and selective in vitro and in vivo properties and is a promising radioligand for PET imaging of mGlu 5 in humans.