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 f. ex. in Parkinson disease (PD) results in an imbalance of other neurotransmitters, mostly
excitatory. Metabotropic glutamate receptors (mGluR)s 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 of 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 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 disorder, like Parkinson’s disease,
schizophrenia or drug addiction.

Grant Number: 5R01NS124777-04
NIH Institute/Center: NIH
Principal Investigator: ANNA-LIISA BROWNELL