TY - JOUR T1 - <em>In vivo</em> characterization of metabotropic glutamate 2 and 5 receptors in Alzheimer’s Disease JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 217 LP - 217 VL - 61 IS - supplement 1 AU - Gengyang Yuan AU - Ramesh Neelamegam AU - Sevda Lule AU - Chuzhi Pan AU - Xiying Qu AU - Anna-Liisa Brownell Y1 - 2020/05/01 UR - http://jnm.snmjournals.org/content/61/supplement_1/217.abstract N2 - 217Objectives: Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease that causes memory loss, cognitive decline and changes in behavior. Currently, there is no cure for AD and the available treatments only offer symptomatic benefits without preventing its progression. Metabotropic glutamate receptors (mGluRs) have been implicated in numerous neurodegenerative disorders, including AD. However, understanding of the mGluRs relation to the pathology of AD remains limited due to the lack of sufficient in vivo evidences. We investigated expression and functional changes in AD-like degeneration using in vivo PET imaging studies of mGluR2 and mGluR5 and subsequent behavioral experiments in the control and triple transgenic mouse models (3X-Tg) of AD. mGluR2 has mainly presynaptic location while mGluR5 has post-synaptic location. Methods: Seven 3X-Tg AD mice and seven control mice were used for this purpose. The mGluR2-specific radiotracer [11C]mG2P001 and the highly mGluR5 selective [18F]FPEB were employed to map the brain distribution of mGluR2 and mGluR5, respectively. PET imaging was done in anesthetized mice with the PET/CT scanner, Triumph II. The region of interests (ROIs) were analyzed by ASIPro. The averaged radioactivity uptake (0-10 min) for each radiotracer was generated to compare signal changes in the brain areas in control and disease models. The Morris Water Maze (MWM) test was carried out at the age of 12-month to assess the hippocampal-dependent spatial learning and memory associated with alteration of mGluR2 &amp; 5 function. Results: Accumulation of [11C]mG2P001 was detected in the cerebellum, colliculus, subiculum, hippocampus, thalamus, striatum and cortex while accumulation of [18F]FPEB was mainly in the cortex, striatum, hippocampus and hypothalamus, but not cerebellum. The averaged radioactivity uptake of [11C]mG2P001 and [18F]FPEB in their indicated brain areas showed significant radioactivity reduction in the AD mice compared to the control mice. The reduction of [11C]mG2P001 ranged from 11.6% in striatum to 29.0% in subiculum. Whereas, a higher radioactivity reduction was seen for [18F]FPEB, ranging from 18.3% in thalamus to 35.1% in cortex. The MWM test showed a maximum increased latency of 49% for AD mice, indicating their memory loss and cognitive impairment. Conclusions: Although mGluR2 and mGluR5 have different synaptic location and functional mechanism both [11C]mG2P001 and [18F]FPEB showed significantly decreased radioactivity in their specific receptor binding regions in AD mice model compared to that of the control group. The MWM behavior test further indicated the reduced hippocampal radioactivity attributed to the observed cognitive/memory impairment among AD mice, where 19.3% and 34.3% radioactivity decrease were seen for [11C]mG2P001 and [18F]FPEB in hippocampus, respectively. In addition, the aberrant changes of [11C]mG2P001 in subiculum, where the first accumulation of amyloid beta plaques was observed, in this AD model might bear a therapeutic potential. Our studies provide an in vivo evidence that alteration in the mGluR 2 &amp; 5 occupying brain regions might contribute to AD pathology. Acknowledgements: The research was supported by NIH grants R01EB021708 and R01NS100164. ER -