Positive allosteric modulators as PET imaging ligands for mGluR4

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DESCRIPTION (provided by applicant): Half a million Americans suffer from Parkinson's disease (PD) incurring health cost of $6 billion in a year. There are several other neurological disorders with extremely high cost for treatment, but in this context the focus is on the disorders, which have strong connection to glutamate neurotransmission. Glutamate is the most abundant neurotransmitter in the brain and likely mediates more than 50% of all the synapses. The recent brain research has shown that metabotropic glutamate receptors (mGluRs) are involved in several neurological disorders including PD. Developing highly selective competitive agonists and antagonists for specific mGluR subtypes has been difficult, because of the high conservation of the orthosteric glutamate binding site across members of this receptor family and the restricted structural requirements for pharmacophores that occupy the binding pocket. Lack of specific in vivo imaging agents has limited the precise characterization of the physiological and pathological roles of individual mGluRs thus hampering drug development. Recently several non-competitive structurally diverse mGluR ligands have been published. These ligands, positive, negative and neutral modulators, bind to the allosteric binding sites located in the seven strand transmembrane domain. We have previously synthesized and radiolabeled several allosteric modulators for group I mGluR5 and characterized them as PET imaging ligands in preclinical studies. We have used all these ligands to investigate modulation of glutamatergic and dopaminergic receptor function in mouse, rat and primate PD models. We have shown that deficit in dopamine transporter function, the ultimate biomarker of PD-like degeneration, is accompanied with enhanced expression of mGluR5. mGlu5 receptors are localized postsynaptically providing information of glutamate, which is transported through the synapse. However, glutamate is released from the presynaptic site of the neuron, making presynaptic location equally if not more prominent to investigate neurotransmission. Thus, group III mGlu4 receptors localized presynaptically are important contributors for glutamate neurotransmission, especially since positive allosteric modulators can potentiate orthosteric agonist of mGluR4 to inhibit the release of neurotransmitters such as GABA and thus balance neurotransmission through direct and indirect pathways in PD. However, there is no in vivo imaging ligand available for mGluR4. Our ultimate goal is to synthesize positive allosteric compounds as specific PET imaging ligands for mGluR4. Precisely, we are proposing to synthesize precursors and develop radiolabeling techniques for mGluR4 positive allosteric modulators using 2-pyridylamide derivatives as lead compounds and investigate a role of presynaptic mGluR4 in glutamatergic neurotransmission. Our research effort is to develop imaging ligands for the receptor systems, what are totally lacking of any in vivo imaging approach. The successful accomplishment can open new research strategies for early diagnosis and novel therapies for the disorders, which do not have yet therapy.