1 research outputs found
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
(E)-3-(Pyridin-2-ylethynyl)cyclohex-2-enone O-(2-(3-18F-fluoropropoxy)ethyl) oxime ([18F]-PSS223) was evaluated
in vitro and in vivo to establish its potential as a PET tracer for imaging metabotropic glutamate receptor subtype
5 (mGluR5). [18F]-PSS223 was obtained in 20% decay corrected radiochemical yield whereas the non-radioactive
PSS223 was accomplished in 70% chemical yield in a SN2 reaction of common intermediate mesylate 8 with potassium
fluoride. The in vitro binding affinity of [18F]-PSS223 was measured directly in a Scatchard assay to give Kd =
3.34 ± 2.05 nM. [18F]-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 [18F]-PSS223 was
metabolized by rat and human microsome enzymes, respectively. In vitro autoradiography on horizontal rat brain
slices showed heterogeneous distribution of [18F]-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 [18F]-PSS223 for mGluR5. Under the same blocking conditions but using
the mGluR1 antagonist, JNJ16259685, no blockade was observed demonstrating the selectivity of [18F]-PSS223
for mGluR5 over mGluR1. Despite favourable in vitro properties of [18F]-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 [18F]-PSS223