Histone deacetylase (HDAC) inhibitors (HDACIs) have long been studied and shown promises in the treatment of various neurodegenerative disorders including Huntington’s disease (HD). Based on many demonstrated potentials of HDACIs in mitigating various diseases, we evaluated the utility of [18F]FAHA, a radiolabeled derivative of suberoylanilide hydroxamic acid (SAHA), as a PET imaging agent for characterizing HDAC activity in a non-human primate model and a R6/2 transgenic mouse model of HD. We were aiming at HD as a potential first application, and therefore also examined the expression of HDAC and acetyl histone (AH) in brains of HD patients. This thesis describes that [18F]FAHA was metabolized rapidly to [18F]FACE in both blood plasma and brain. Kinetic analysis indicated that peripherally generated [18F]FACE contributed to the total brain activity. We therefore used a dual-input function model to analyze the kinetics of tracer accumulation and inhibition by SAHA in rhesus monkeys. Parametric images demonstrated the inhibition of HDAC activity in the brain by SAHA in a dose-dependent manner. Huntington’s mice (R6/2) showed a gradual increase of [18F]FAHA accumulation in all organs including the brain with age. In human tissue we found significant losses of acetyl histons expression from cells in the caudate nucleus and Purkinje cells of the cerebellum in HD, while the level of HDAC 5 was increased in these cells. The data obtained in rhesus monkeys indicated that PET imaging with [18F]FAHA could be used as a pharmacodynamic biomarker of the inhibition of class IIa HDACs by HDACIs in the brain and facilitate the development and clinical translation of novel class-IIa HDACIs.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:574280 |
| Date | January 2013 |
| Creators | Yeh, Hsin-Hsien |
| Contributors | Mann, David; Herholz, Karl; Hinz, Rainer |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/utility-and-validation-of-the-histone-deacetylase-hdac-substrate-18ffaha-as-a-positron-emission-tomography-pet-imaging-biomarker-in-nonhuman-primates-and-hd-transgenic-mice-for-evaluation-of-neurodegenerative-diseases-and-hdac-inhibitor-treatment(69cbe9a1-aa64-45d6-947f-9368eabb071c).html |
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