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Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers
- Source :
- Synapse (New York, N.Y.). 56(4)
- Publication Year :
- 2005
-
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.
- Subjects :
- Cerebellum
Fluorine Radioisotopes
Time Factors
Metabolite
Receptor, Metabotropic Glutamate 5
Statistics as Topic
Hippocampus
In Vitro Techniques
Receptors, Metabotropic Glutamate
Cellular and Molecular Neuroscience
chemistry.chemical_compound
In vivo
medicine
Animals
Humans
Carbon Radioisotopes
Brain Chemistry
Brain Mapping
Binding Sites
Dose-Response Relationship, Drug
Chemistry
Metabotropic glutamate receptor 5
Brain
Macaca mulatta
Magnetic Resonance Imaging
In vitro
Rats
medicine.anatomical_structure
nervous system
Biochemistry
Metabotropic glutamate receptor
Positron-Emission Tomography
Microsome
Microsomes, Liver
Autoradiography
Excitatory Amino Acid Antagonists
Subjects
Details
- ISSN :
- 08874476
- Volume :
- 56
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Synapse (New York, N.Y.)
- Accession number :
- edsair.doi.dedup.....1e2323df20093e5a056b4e10870cf300