PET Imaging of Bromodomain and Extra-Terminal Domain Inhibitors for the Noninvasive Assessment of Metabolic Changes in the Liver and Brain of Early-Stage Alcoholic Liver Disease

Abstract

Alcoholic liver disease (ALD) has a significant impact on human health and is one of the leading causes of liver disease mortality. The early and exact diagnosis of ALD is very important since the early stage of disease progression can be reversible. Although ALD can be evaluated by ultrasound, CT, or MRI, there is still no imaging technique sufficient in the diagnosis of early-stage ALD. Of the current studies, epigenetic modulation plays a significant role in the development and progression of ALD. In this work, we evaluate whether BRDs play a vital role in the early-stage ALD using our new PET imaging probe of BET proteins, [11C]­CW22. PET/CT imaging of [11C]­CW22 and [18F]­FDG was used to identify early-stage lesions of livers and brains in the mice model. We found that the average uptake values of livers and brains in early-stage ALD were significantly increased for [11C]­CW22 PET/CT imaging but only slightly changed in [18F]­FDG PET/CT imaging. Consistently, we also found that BRD 3, 4 protein expression levels were significantly higher in the liver and brain tissues of early-stage ALD. Furthermore, through Pmod software, we found that [11C]­CW22 PET/CT uptakes in the brain stem, cerebellum, and midbrain were significantly up-regulated in the early-stage ALD. In conclusion, BRDs were important mediators of damage in early-stage ALD. [11C]­CW22 PET/CT imaging can detect the early-phase alcohol-induced damage of livers and brains, which will likely lead to human trials in the future.

Noninvasive Positron Emission Tomography Imaging of SIRT1 in a Model of Early-Stage Alcoholic Liver Disease

“…All commercially available reagents were used without further purification unless otherwise stated. Mouse models of early-stage ALD were generated as previously described . The criteria for the evaluation of mouse models of early-stage ALD were as follows: unkempt and lusterless hair, diminished activity, slow reaction, and slowly increasing weight.…”

“…Mouse models of early-stage ALD were generated as previously described. 28 The criteria for the evaluation of mouse models of early-stage ALD were as follows: unkempt and lusterless hair, diminished activity, slow reaction, and slowly increasing weight. We measured the diet feed in each cage during the whole study by assessing feed weight and weighed the mice every 3 days.…”

Bromodomain and extraterminal protein-targeted probe enables tumour visualisation in vivo using positron emission tomography

“…For example, [ 11 C]CW22 imaging identified brain lesions in a mouse model of early-stage alcohol liver disease. 8 Despite the mounting interest in BET inhibitors as cancer therapeutic agents, the direct targeting of BET proteins for molecular imaging of solid tumours has not been reported. A BET-targeted imaging agent could enable quantification of BET protein expression in cancer and in future could predict response to BET inhibitor therapy.…”