PT - JOURNAL ARTICLE AU - Shao, Tuo AU - Yu, Qingzhen AU - Liang, Steven TI - <strong>Molecular imaging of murine hepatic encephalopathy with cannabinoid receptor type I targeted [<sup>18</sup>F]MK-9470 by positron emission tomography</strong> DP - 2020 May 01 TA - Journal of Nuclear Medicine PG - 194--194 VI - 61 IP - supplement 1 4099 - http://jnm.snmjournals.org/content/61/supplement_1/194.short 4100 - http://jnm.snmjournals.org/content/61/supplement_1/194.full SO - J Nucl Med2020 May 01; 61 AB - 194Objectives: Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of both acute and chronic liver failure. The endocannabinoid system has been implicated in the pathogenesis of liver disease and HE. Overexpression of cannabinoid receptor type I (CB1) is a hallmark of hepatic fibrosis and neuroinflammation both in the liver and brain. [18F]MK-9470 is a selective, high-affinity, inverse agonist for the CB1 receptor and can be used for positron emission tomography (PET) imaging. In this study, we evaluated whether CB1 could be targeted as an imaging biomarker for noninvasive diagnosis and staging of HE, using PET with a CB1 radioligand [18F]MK-9470. Methods: We selecte 10 days-BDL (mild) and 21 days-BDL as HE model. We used PET to assess changes in CB1 binding of [18F]MK-9470 in the brain and liver of mice with bile duct ligation (BDL)-induced hepatic encephalopathy compared with controls. We co-injected cold MK-9470 with [18F]MK-9470 to assess the specific binding of the radiotracer. We performed behavioral tests including locomotor activity test, object recognition test (ORT) and object location test (OLT) to assess neurological dysfunction. We performed western blot and immunofluorescence to assess CB1and microglia (ionized calcium binding adaptor molecule 1, Iba1) expression in the brain hippocampus. Autoradiography was performed to evaluate the tracer uptake in brain sections. Results: Our results indicate that liver damage and memory impairments were found in BDL-induced HE. Thus, we found that following BDL, there is fibrotic lesions stained in the portal area by Sirius red staining (Fig. 1A). Locomotor activity test demonstrated the number of crossings per one minute in the open field arena for the BDL group decreased compared to the Sham group. ORT and OLT testing revealed that the cognitive index of the BDL mice was significantly reduced when compared to the sham group ((ORT: mild p&lt;0.05; severe p&lt;0.01; OLT: mild p&lt;0.05; severe p&lt;0.01) (Fig. 1B). Immunofluorescence results demonstrating overexpression of CB1 (red) and microglia marker Iba1 (green) in the brain hippocampus of BDL model (Fig. 1C). PET imaging with [18F]MK-9470 showed high uptake in the brain of BDL mice compared with shams. Blocking studies demonstrated specific binding of radiotracer to CB1 (Fig. 1D). Current diagnosis of HE is based on the patient’s history and clinical evidence of liver disease; arterial ammonia concentration; CT scan of head (No diagnostic features are discernible on CT in patients with chronic low-grade HE). Given this situation, it will be the first study that using CB1 as a marker to diagnose HE in PET scan, systematically validates [18F] MK-9470 imaging in HE by performing a spatially precise correlative analysis of PET/CT imaging, histopathology, CB1 expression and behavioral examination in preclinical rodent models. Conclusions: PET with [18F]MK-9470 can be used to noninvasively visualize overexpression of CB1 both in brain and liver for the potential ascertainment and assessment of hepatic encephalopathy.