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Utility of Translocator Protein (18 kDa) as a Molecular Imaging Biomarker to Monitor the Progression of Liver Fibrosis.

ABSTRACT: Hepatic fibrosis is the wound healing response to chronic hepatic injury caused by various factors. In this study, we aimed to evaluate the utility of translocator protein (18 kDa) (TSPO) as a molecular imaging biomarker for monitoring the progression of hepatic fibrosis to cirrhosis. Model rats were induced by carbon tetrachloride (CCl4), and liver fibrosis was assessed. Positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[(18)F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]-acetamide ([(18)F]FEDAC), a radioprobe specific for TSPO, was used for noninvasive visualisation in vivo. PET scanning, immunohistochemical staining, ex vivo autoradiography, and quantitative reverse-transcription polymerase chain reaction were performed to elucidate the relationships among radioactivity uptake, TSPO levels, and cellular sources enriching TSPO expression in damaged livers. PET showed that uptake of radioactivity in livers increased significantly after 2, 4, 6, and 8 weeks of CCl4 treatment. Immunohistochemistry demonstrated that TSPO was mainly expressed in macrophages and hepatic stellate cells (HSCs). TSPO-expressing macrophages and HSCs increased with the progression of liver fibrosis. Interestingly, the distribution of radioactivity from [(18)F]FEDAC was well correlated with TSPO expression, and TSPO mRNA levels increased with the severity of liver damage. TSPO was a useful molecular imaging biomarker and could be used to track the progression of hepatic fibrosis to cirrhosis with PET.

SUBMITTER: Hatori A

PROVIDER: S-EPMC4661446 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:UNLABELLED:11C-PBR28 PET can detect the 18-kDa translocator protein (TSPO) expressed within macrophages. However, quantitative evaluation of the signal in brain tissue from donors with multiple sclerosis (MS) shows that PBR28 binds the TSPO with high affinity (binding affinity [Ki], ?4 nM), low affinity (Ki, ?200 nM), or mixed affinity (2 sites with Ki, ?4 nM and ?300 nM). Our study tested whether similar binding behavior could be detected in brain tissue from donors with no history of neurologic disease, with TSPO-binding PET ligands other than 11C-PBR28, for TSPO present in peripheral blood, and with human brain PET data acquired in vivo with 11C-PBR28. METHODS:The affinity of TSPO ligands was measured in the human brain postmortem from donors with a history of MS (n=13), donors without any history of neurologic disease (n=20), and in platelets from healthy volunteers (n=13). Binding potential estimates from thirty-five 11C-PBR28 PET scans from an independent sample of healthy volunteers were analyzed using a gaussian mixture model. RESULTS:Three binding affinity patterns were found in brains from subjects without neurologic disease in similar proportions to those reported previously from studies of MS brains. TSPO ligands showed substantial differences in affinity between subjects classified as high-affinity binders (HABs) and low-affinity binders (LABs). Differences in affinity between HABs and LABs are approximately 50-fold with PBR28, approximately 17-fold with PBR06, and approximately 4-fold with DAA1106, DPA713, and PBR111. Where differences in affinity between HABs and LABs were low (?4-fold), distinct affinities were not resolvable in binding curves for mixed-affinity binders (MABs), which appeared to express 1 class of sites with an affinity approximately equal to the mean of those for HABs and LABs. Mixed-affinity binding was detected in platelets from an independent sample (HAB, 69%; MAB, 31%), although LABs were not detected. Analysis of 11C-PBR28 PET data was not inconsistent with the existence of distinct subpopulations of HABs, MABs, and LABs. CONCLUSION:With the exception of 11C-PK11195, all TSPO PET ligands in current clinical application recognize HABs, LABs, and MABs in brain tissue in vitro. Knowledge of subjects' binding patterns will be required to accurately quantify TSPO expression in vivo using PET.

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Utility of Translocator Protein (18 kDa) as a Molecular Imaging Biomarker to Monitor the Progression of Liver Fibrosis.

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