The proposed research involves characterizing the novel Positron Emission Tomography (PET) radioligand, 3- (6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime ([11C]ABP688), an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5), in humans. A large body of diverse evidence implicates mGluR5 in the pathophysiology of depression. In addition, mGluR5 dysfunction has been associated with disorders such as anxiety, schizophrenia, addiction, Parkinson's disease, and fragile X syndrome. As focus intensifies on mGluR5, it is becoming increasingly important to establish reliable methods of imaging this receptor. PET provides visualization of neuroreceptor systems in living human brain, making PET an ideal modality to quantify mGluR5 in vivo. To this end, [11C]ABP688, a highly selective allosteric antagonist of the mGluR5 in vitro with high selectivity for mGluR5 in vivo, has recently been developed for use in humans. Quantification of mGluR5 variation by [11C]ABP688 could serve many purposes, from a possible indicator of depression or other disorders, to a potential monitor of treatment effectiveness in an individual, to providing personalized information prior to treatment about potential therapeutic outcomes. However, as with any newly developed PET tracer, [11C]ABP688 must be properly characterized in humans in order to provide accurate quantification of its target. Therefore, I will define and perform a protocol to characterize [11C]ABP688, which can be generalized to any novel PET ligand. Through the proposed study, structured meetings with my mentors (leaders in the field of PET research of psychiatric patient populations), as well as coursework and regular meetings with project contributors, I will expand my expertise in neurobiology, radiochemistry, PET imaging and analysis, clinical assessment, and affective disorders. In doing so, I will not only enhance the current knowledge of [11C]ABP688 and mGluR5, but also learn a set procedures for developing and using PET tracers that I can employ as an independent investigator. Specifically, I plan to: (1) Determine the optimal modeling techniques and scanning time for [11C]ABP688, to ensure reliable and accurate quantification. Intra- individual binding variation will be established using these optimal methods. (2) Examine methods to calculate a full plasma input function without an arterial line, improving subject comfort and decreasing scan cost. Using mathematical approaches, it may be possible to model arterial input from either venous samples or sinogram data. Eliminating the need for arterial lines may reduce current barriers to widespread PET use in addressing public health issues. (3) Investigate sensitivity of [11C]ABP688 to endogenous glutamate to determine if this ligand can be used to monitor glutamate level variations in neurologic and psychiatric disorders. (4) Compare mGluR5 distribution and density in depressed and control subjects. This will provide insight into the mechanism of mGluR5 dysfunction in depression. The goal of these studies is an increased knowledge of mGluR5 and the development of much needed reliable mGluR5 PET imaging methods.
The studies outlined in this proposal will be used to develop a reliable method of imaging a receptor in the brain that may be altered in depressed patients. Accurate measurements of this receptor may be used as a diagnostic indicator of depression, allowing earlier interventions, or may help predict or monitor treatment response. This would allow personalization of treatment for depression and related disorders.
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