Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers

Citations Over TimeTop 10% of 2005 papers

Abstract

Three metabotropic glutamate receptor subtype 5 (mGluR5) PET tracers have been labeled with either carbon-11 or fluorine-18 and their in vitro and in vivo behavior in rhesus monkey has been characterized. Each of these tracers share the common features of high affinity for mGluR5 (0.08-0.23 nM vs. rat mGluR5) and moderate lipophilicity (log P 2.8-3.4). Compound 1b was synthesized using a Suzuki or Stille coupling reaction with [11C]MeI. Compounds 2b and 3b were synthesized by a SNAr reaction using a 3-chlorobenzonitrile precursor. Autoradiographic studies in rhesus monkey brain slices using 2b and 3b showed specific binding in cortex, caudate, putamen, amygdala, hippocampus, most thalamic nuclei, and lower binding in the cerebellum. PET imaging studies in monkey showed that all three tracers readily enter the brain and provide an mGluR5-specific signal in all gray matter regions, including the cerebellum. The specific signal observed in the cerebellum was confirmed by the autoradiographic studies and saturation binding experiments that showed tracer binding in the cerebellum of rhesus monkeys. In vitro metabolism studies using the unlabeled compounds showed that 1a, 2a, and 3a are metabolized slower by human liver microsomes than by monkey liver microsomes. In vivo metabolism studies showed 3b to be long-lived in rhesus plasma with only one other more polar metabolite observed.

Related Papers

• → Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome(2011)101 cited
• → Astrocyte Glutamate Uptake and Signaling as Novel Targets for Antiepileptogenic Therapy(2020)67 cited
• → Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity(2017)51 cited
• → Heterodimerization of Calcium Sensing Receptors with Metabotropic Glutamate Receptors in Neurons(2001)155 cited
• → Metabotropic Glutamate Receptor 5/Homer Interactions Underlie Stress Effects on Fear(2010)71 cited