R01NS124777

Simultaneous PET/PHMR Studies on Interplay of mGlu/Dopamine Receptors in PD-Like Neurodegeneration - Abstract

Research of the brain receptor functions holds a promise to provide better diagnostic tools and drugs that could be tailored for the individual needs, thereby eliminating or reducing side effects and even providing a way for prevention of diseases.

Increasing understanding of receptor functions is revealing complex and dynamic interactions between neurotransmitter systems. In the basal ganglia, dopamine (DA) regulation of glutamate (GLU) neurotransmission is complex, and the loss of DA-mediated inhibition in the striatum, for example in Parkinson's disease (PD), results in an imbalance of other neurotransmitters, mostly excitatory.

Metabotropic glutamate receptors (mGluRs) are activated when there is excess GLU in the synaptic cleft and therefore act as sensors and modulators when or where GLU transmission is enhanced. This functional specificity makes them attractive pharmacological targets. The prevalent localization of mGluRs in the striatum and limbic system supports their role in modulating DA and GLU-dependent signaling and synaptic plasticity within the basal ganglia cortico-subcortical loops.

A recent failure of the first clinical trial focusing on agonizing mGluR4 function inspired this project to investigate the fundamentals of dopaminergic and glutamatergic interplay in PD-like neurodegeneration.

We have developed high-level imaging instrumentation and techniques as well as unique ligands to conduct quantitative in vivo imaging studies of dopaminergic and glutamatergic neurofunction. We have earlier developed radioligands for PET imaging of dopamine transporters as well as pharmacological MRI (PHMRI) to investigate dopamine release. Recently, we have developed allosteric modulators as PET imaging ligands for mGluR4 (presynaptic receptor) and mGluR5 (postsynaptic receptor) and characterized them in experimental animal models.

Now, we are proposing to combine the PHMR imaging of amphetamine-induced dopamine release or excessive synaptic glutamate concentration induced by agonizing mGluR4 with MG4P027 (N-(4-chloro-3-((fluoromethyl-D2)thio)phenyl)picolinamide) or antagonizing mGluR5 function with MTEP ((2-methyl-1,3-thiazo-4-yl)ethynyl pyridine) with simultaneous PET imaging of mGluR4, mGluR5, and dopamine D2 receptor function to investigate degeneration-induced modulation of dopaminergic and glutamatergic neurotransmission using an α-synuclein rat model of PD and its additional 6-OHDA lesioned counterpart (combination model).

Real-time imaging of receptor modulation will challenge the present theories of signaling and synaptic plasticity during degenerative processes. The results of this receptor modulation can be readily utilized in the drug development for dopamine-glutamate regulation related disorders, like Parkinson's disease, schizophrenia, or drug addiction.

The General Hospital Corporation

NOT APPLICABLE

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Boston, Massachusetts 021142621 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 394% from $689,722 to $3,407,541.