title: Synthesis, radiolabelling and in vitro and in vivo evaluation of a novel fluorinated ABP688 derivative for the PET imaging of metabotropic glutamate receptor subtype 5.
abstract: (E)-3-(Pyridin-2-ylethynyl)cyclohex-2-enone O-(2-(3-(18)F-fluoropropoxy)ethyl) oxime ([(18)F]-PSS223) was evaluated in vitro and in vivo to establish its potential as a PET tracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5). [(18)F]-PSS223 was obtained in 20% decay corrected radiochemical yield whereas the non-radioactive PSS223 was accomplished in 70% chemical yield in a S(N)2 reaction of common intermediate mesylate 8 with potassium fluoride. The in vitro binding affinity of [(18)F]-PSS223 was measured directly in a Scatchard assay to give K(d) = 3.34 ± 2.05 nM. [(18)F]-PSS223 was stable in PBS and rat plasma but was significantly metabolized by rat liver microsomal enzymes, but to a lesser extent by human liver microsomes. Within 60 min, 90% and 20% of [(18)F]-PSS223 was metabolized by rat and human microsome enzymes, respectively. In vitro autoradiography on horizontal rat brain slices showed heterogeneous distribution of [(18)F]-PSS223 with the highest accumulation in brain regions where mGluR5 is highly expressed (hippocampus, striatum and cortex). Autoradiography in vitro under blockade conditions with ABP688 confirmed the high specificity of [(18)F]-PSS223 for mGluR5. Under the same blocking conditions but using the mGluR1 antagonist, JNJ16259685, no blockade was observed demonstrating the selectivity of [(18)F]-PSS223 for mGluR5 over mGluR1. Despite favourable in vitro properties of [(18)F]-PSS223, a clear-cut visualization of mGluR5-rich brain regions in vivo in rats was not possible mainly due to a fast clearance from the brain and low metabolic stability of [(18)F]-PSS223.
authors.affiliation: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences of ETH Zurich Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland.
authors.forename: Selena Milicevic
authors.initials: SM
authors.lastname: Sephton
authors.forename: Patrick
authors.initials: P
authors.lastname: Dennler
authors.forename: Dominique S
authors.initials: DS
authors.lastname: Leutwiler
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Wanger-Baumann
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
keywords: PET imaging; [11C]-ABP688; [18F]-FDEGPECO; [18F]-PSS223; autoradiography; mGluR5; microsome enzymes