Designing group specific PET ligands for mGluR2

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ABSTRACT: Positive allosteric modulators of metabotropic glutamate group II receptor, mGluR2 are the subject of intensive research due to their promising therapeutic potential for a range of neurological disorders such as Alzheimer’s (AD) and Parkinson's disease, schizophrenia and addiction. Positive allosteric modulators are small molecules capable of enhancing agonist-mediated receptor activity while possessing no intrinsic agonist activity have recently been described for mGluR2. Relative to classical mGluR agonists, these molecules offer improved selectivity versus other mGluRs and chemical tractability, and may reduce receptor desensitization. Alzheimer's disease (AD) is a neurodegenerative brain disorder that develops over a period of years and causes progressive memory loss and cognitive decline. Schizophrenia is a chronic and disabling disease and the World Health Organization has identified this mental disease as one of the ten most debilitating diseases affecting human beings. Cause of these diseases is still unknown. Anxiety and stress-related disorders including posttraumatic stress disorder, obsessive-compulsive disorder, phobias and panic disorders are major public health issue. Drug abuse related brain disorders have significant economic cost. The combined costs of brain related illnesses, including costs of lost productivity, lost earnings due to illness, and social costs are estimated to be a 1.5 trillion dollars annually in USA. All the above neurological disorders are affected by glutamate neurotransmission and modulation of mGluR2. There has been clinical trials of using mGluR2 related drugs for the treatment of Schizophrenia. As well it has been suggested that in AD suppression of group II signaling may be a therapeutic strategy to selectively reduce or block synaptic amyloid β42 generation. However, there is a lack of specific in vivo imaging ligand for mGluR2 to investigate therapeutic response. We have earlier developed glycine- based PET imaging ligands for mGluR2/3 using a prodrug approach. After the brief evaluation of the receptor functions, we concluded that to achieve receptor specificity for mGluR2 the compound has to be a noncompetitive allosteric modulator. Based on our previous experience we propose to develop selective and sensitive PET imaging ligands for group II mGluR2s. We propose to synthesize several benzimidazole derivatives as positive allosteric modulators and select 4-5 compounds from binding assays and develop them as noncompetitive PET imaging ligands for mGluR2. The mGluR2 subgroup selectivity and sensitivity of the developed ligands will be tested in specific transfected cell lines and in experimental animals. Two best ligands will be selected for quantitative imaging and kinetic modeling using primate model and combined PET/MR imaging to simultaneously acquire dynamic PET data with anatomical information to obtain accurate values for local expression of mGluR2 to be applied in future translational and clinical research.