In vitro and in vivo evaluation of [18F]-FDEGPECO as a PET tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5).

(E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone O-2-(2-(18)F-fluoroethoxy)ethyl oxime, ([(18)F]-FDEGPECO), a novel high affinity radioligand for the metabotropic glutamate receptor subtype 5 (mGluR5) was assessed for its potential as a PET imaging agent. In vitro autoradiography on rat brain slices resulted in a heterogeneous and displaceable binding to mGluR5-rich brain regions. [(18)F]-FDEGPECO showed high stability in rat plasma and brain homogenate as well as in human plasma and microsomes. Good blood-brain barrier passage was predicted from an in vitro transport assay with P-glycoprotein-transfected hMDR1-MDCK cells. In vivo PET imaging on rats revealed specific uptake of radioactivity in the mGluR5-rich brain regions such as hippocampus, striatum and cortex while the cerebellum, a region with low mGluR5-expression, showed negligible uptake. Blockade experiments by co-injection of [(18)F]-FDEGPECO and M-MPEP (6mg/kg), an antagonist for mGluR5, reduced the level of radioactivity in mGluR5-regions to that of the cerebellum, pointing to an effective blockade of specifically bound [(18)F]-FDEGPECO. Postmortem biodistribution studies at 15min p.i. confirmed the distribution pattern observed in PET. HPLC analysis of rat brain extracts indicated that 98.5% and 91% of the total radioactivity were parent compound at 5min and 17min p.i., respectively. Taken together, the high affinity and the high in vivo specificity of [(18)F]-FDEGPECO for mGluR5 in the rat brain as well as the lack of in vivo defluorination make this new [(18)F]-labeled ABP688 derivative a suitable ligand for the preclinical PET imaging of mGluR5. These favorable characteristics warrant further evaluation in humans.