PET Imaging of Brain mGlu1 Receptors Using [11]LY2428703

Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors that respond to glutamate by activating proteins inside nerve cells that affect cell metabolism, thereby fine-tuning the signals sent between cells to maintain balance in neuronal activity. mGluR receptor subtype 1 (mGluR1s) are located in several brain regions, including the cerebellum, hippocampus, olfactory bulb, and basal ganglia. mGluR1 activation stimulates phospholipase C, resulting in phosphoinositide hydrolysis and increased intracellular Ca(2+) levels. Detailed study of mGluR1s has heretofore been hindered by the lack of high affinity and of selective ligands for this receptor subtype.

The present protocol will use a new PET ligand [C(11)]mGlu1 to 1) perform kinetic brain imaging to quantify mGluR1 binding parameters in brain and determine the reliability and reproducibility of these measures in 15 healthy volunteers (Phase 1); and 2) if the tracer proves successful in Phase 1, we will estimate radiation-absorbed doses of [C(11)]mGlu1 in healthy human subjects by performing whole body imaging (Phase 2).

Successful development of a PET ligand to image mGlurR1 would have a strong impact on clinical management of brain disorders characterized by disruptions in glutamatergic transmission, including anxiety and stress disorders, drug addiction, epilepsy, Huntington s disease, and Parkinson s disease.