Synthesis, characterization, and monkey PET studies of [18F]MK‐1312, a PET tracer for quantification of mGluR1 receptor occupancy by MK‐5435

Abstract Two moderately lipophilic, high affinity ligands for metabotropic glutamate receptor subtype 1 (mGluR1) were radiolabeled with a positron‐emitting radioisotope and evaluated in rhesus monkey as potential PET tracers. Both ligands were radiolabeled with fluorine‐18 via nucleophilic displacement of the corresponding 2‐chloropyridine precursor with [ 18 F]potassium fluoride. [ 18 F] MK‐1312 was found to have a suitable signal for quantification of mGluR1 receptors in nonhuman primates and was more thoroughly characterized. In vitro autoradiographic studies with [ 18 F] MK‐1312 in rhesus monkey and human brain tissue slices revealed an uptake distribution consistent with the known distribution of mGluR1, with the highest uptake in the cerebellum, moderate uptake in the hippocampus, thalamus, and cortical regions, and lowest uptake in the caudate and putamen. In vitro saturation binding studies in rhesus monkey and human cerebellum homogenates confirmed that [ 18 F] MK‐1312 binds to a single site with a B max / K d ratio of 132 and 98, respectively. PET studies in rhesus monkey with [ 18 F] MK‐1312 showed high brain uptake and a regional distribution consistent with in vitro autoradiography results. Blockade of [ 18 F] MK‐1312 uptake with mGluR1 allosteric antagonist MK‐5435 dose‐dependently reduced tracer uptake in all regions of gray matter to a similarly low level of tracer uptake. This revealed a large specific signal useful for determination of mGluR1 receptor occupancy in rhesus monkey. Taken together, these results are promising for clinical PET studies with [ 18 F] MK‐1312 to determine mGluR1 occupancy of MK‐5435. Synapse 2011. © 2010 Wiley‐Liss, Inc.