The goal of this career development proposal is to develop a sensitive PET probe for in vivo imaging of mGluR3, which might provide valuable insight to elucidate key biochemical mechanisms in the pathogenesis of Alzheimer's disease (AD) while providing me an excellent opportunity to grow as an independent scientist. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate central nervous system (CNS), which mediates more than 50% of all synapses. The glutamatergic neurotransmission plays important roles in various brain functions, including motor control, learning and memory, cognition, and neural development. AD is a devastating neurodegenerative disorder that triggers a complex cascade leading to synaptic alterations, neurotransmitter deficiencies, and cognitive failure. Treatment of AD is the largest unmet need in neurology. Only four drugs (three cholinesterase inhibitors and memantine) are approved for the treatment of AD, and none of them has shown significant disease-modifying activity. Our understanding of the etiology and pathobiology of AD-related neurodegeneration remains limited. The studies show that mGluR3 is increasingly linked to age-related cognitive disorders, which are expected to stimulate the production of TGF-?, rescue memory deficits and to stimulate the activity of ?-secretase. It is the activation of mGluR3 not mGluR2 to induce neuroprotection, while activation of mGluR2 may lead neurotoxicity. Presently, PET imaging has an increasing role in the diagnosis of AD. However, the potential of PET strongly depends on the availability of suitable PET radiotracers. Even, as a very promising target for AD and other CNS disorders, there is no PET ligand for imaging of mGluR3. There is tremendous need for specific and selective imaging ligands to verify the drug targets and to investigate mGluR3 in physiological and pathological processes. The potential impact of an mGluR3 PET tracer will be major to investigate underlying pathology of AD and enhance drug development. Here we propose to develop mGluR3-selective PET imaging ligands based on the allosteric modulators, with aims to evaluate the reported lead compounds, to carry out SAR study, to optimize the lead with respect to affinity, selectivity, metabolic stability and other pharmacological properties, to radiolabel the optimized ligands, and to demonstrate proof of concept in animal models. Specifically, we will develop fluorine-18 labeled PET tracers with optimized pharmacological properties for selectively imaging mGluR3 in vivo. We will study the expression, distribution and function of mGluR3 in normal and pathological conditions also using AD- mouse models. From the training perspective, the proposed work will allow me to extend my expertise in medicinal and organic chemistry to the development of PET imaging probes and characterize them in preclinical studies for neurological diseases, which could lead to improved diagnosis, treatment selection and monitoring disease progression while establishing me in the field of neurological molecular imaging.

Public Health Relevance

Alzheimer's Disease (AD), a devastating neurodegenerative disorder, triggers a complex cascade that leads to synaptic alterations, neurotransmitter deficiencies, and cognitive failure. Several mGluRs have been implicated in AD pathogenesis, and mGluR3 is increasingly linked to age-related cognitive disorders, which might be a superior target for AD. This career development proposal aims to develop an mGluR3-selective PET probe to noninvasively image mGluR3 function in vivo, which might provide valuable insight to differentiate and elucidate key biochemical mechanisms in AD pathogenesis while providing me an excellent opportunity to grow as an independent bio-scientist.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Quantitative Research Career Development Award (K25)
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Neuroscience of Aging Review Committee (NIA)
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Hsiao, John
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Massachusetts General Hospital
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