L L Donovan1,2, J H Magnussen1, A Dyssegaard1, S Lehel3, J M Hooker4, G M Knudsen1,2, H D Hansen5. 1. Neurobiology Research Unit and Center for NeuroPharm, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen O, Denmark. 2. Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen N, Denmark. 3. PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, 2100, Copenhagen O, Denmark. 4. MGH/HST A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, 02129, USA. 5. Neurobiology Research Unit and Center for NeuroPharm, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen O, Denmark. hanne.d.hansen@nru.dk.
Abstract
PURPOSE: With the emerging knowledge about the impact of epigenetic alterations on behavior and brain disorders, the ability to measure epigenetic alterations in brain tissue in vivo has become critically important. We present the first in vivo/in vitro cross-validation of the novel positron emission tomography (PET) radioligand [11C]Martinostat in the pig brain with regard to its ability to measure histone deacetylase 1-3 (HDAC1-3) levels in vivo. PROCEDURES: Nine female Danish landrace pigs underwent 121-min dynamic PET scans with [11C]Martinostat. We quantified [11C]Martinostat uptake using both a simple ratio method and kinetic models with arterial input function. By the end of the scan, the animals were euthanized and the brains were extracted. We measured HDAC1-3 protein levels in frontal cortex, cerebellum vermis, and hippocampus and compared the protein levels and regional outcome values to the [11C]Martinostat PET quantification. RESULTS: [11C]Martinostat distributed widely across brain regions, with the highest uptake in the cerebellum vermis and the lowest in the olfactory bulbs. Based on the Akaike information criterion, the quantification was most reliably performed by Ichise MA1 kinetic modeling, but since the radioligand displayed very slow kinetics, we also calculated standard uptake value (SUV) ratios which correlated well with VT. The western blots revealed higher brain tissue protein levels of HDAC1/2 compared to HDAC3, and HDAC1 and HDAC2 levels were highly correlated in all three investigated brain regions. The in vivo SUV ratio measure correlated well with the in vitro HDAC1-3 levels, whereas no correlation was found between VT values and HDAC levels. CONCLUSIONS: We found good correlation between in vivo measured SUV ratios and in vitro measures of HDAC 1-3 proteins, supporting that [11C]Martinostat provides a good in vivo measure of the cerebral HDAC1-3 protein levels.
PURPOSE: With the emerging knowledge about the impact of epigenetic alterations on behavior and brain disorders, the ability to measure epigenetic alterations in brain tissue in vivo has become critically important. We present the first in vivo/in vitro cross-validation of the novel positron emission tomography (PET) radioligand [11C]Martinostat in the pig brain with regard to its ability to measure histone deacetylase 1-3 (HDAC1-3) levels in vivo. PROCEDURES: Nine female Danish landrace pigs underwent 121-min dynamic PET scans with [11C]Martinostat. We quantified [11C]Martinostat uptake using both a simple ratio method and kinetic models with arterial input function. By the end of the scan, the animals were euthanized and the brains were extracted. We measured HDAC1-3 protein levels in frontal cortex, cerebellum vermis, and hippocampus and compared the protein levels and regional outcome values to the [11C]Martinostat PET quantification. RESULTS: [11C]Martinostat distributed widely across brain regions, with the highest uptake in the cerebellum vermis and the lowest in the olfactory bulbs. Based on the Akaike information criterion, the quantification was most reliably performed by Ichise MA1 kinetic modeling, but since the radioligand displayed very slow kinetics, we also calculated standard uptake value (SUV) ratios which correlated well with VT. The western blots revealed higher brain tissue protein levels of HDAC1/2 compared to HDAC3, and HDAC1 and HDAC2 levels were highly correlated in all three investigated brain regions. The in vivo SUV ratio measure correlated well with the in vitro HDAC1-3 levels, whereas no correlation was found between VT values and HDAC levels. CONCLUSIONS: We found good correlation between in vivo measured SUV ratios and in vitro measures of HDAC 1-3 proteins, supporting that [11C]Martinostat provides a good in vivo measure of the cerebral HDAC1-3 protein levels.
Entities:
Keywords:
Brain; Epigenetics; HDAC1; HDAC2; HDAC3; Histone deacetylase; Martinostat; Pig; Positron emission tomography; Western blot
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