CHAPTER 10:mGlu4 PET Ligands as Enablers of Target Biology Understanding

Identifying the biological origin of a disease and the potential targets for intervention are some of the first steps in the discovery of a medicine. The metabotropic glutamate receptor 4 (mGlu4) has lately received much attention due to its potential role in various neuronal diseases such as Parkinson’s disease (PD) and other disorders. To better understand the role of mGlu4 in health and disease conditions, we were interested in developing an mGlu4-selective radiotracer for in vivo studies. Herein we discuss our efforts to develop novel mGlu4 positron emission tomography (PET) radiotracers from mGlu4 positive allosteric modulators (PAMs). We have investigated the biology of this receptor in vitro using cells expressing mGlu4, as well as in vivo, using the 6-hydroxydopamine (6-OHDA)-lesion rat model of Parkinson’s disease. Results of cell studies showed the important role of endogenous glutamate in inducing changes in the affinity of allosteric modulators of mGlus. Results from PET imaging studies showed the interplay between presynaptic mGlu4 and postsynaptic mGlu5 expression in the lesioned side of the brain, while the results of pharmacological MRI studies of the hemodynamic response showed enhanced signal changes in cortical areas in the lesioned side after challenge with mGlu4 PAMs or mGlu5 negative allosteric monitors (NAMs).