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Imaging HDACs In Vivo: Cross-Validation of the [11C]Martinostat Radioligand in the Pig Brain

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 emissi...

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Bibliographic Details
Published in:Molecular imaging and biology 2020-06, Vol.22 (3), p.569-577
Main Authors: Donovan, L. L., Magnussen, J. H., Dyssegaard, A., Lehel, S., Hooker, J. M., Knudsen, G. M., Hansen, H. D.
Format: Article
Language:English
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Summary: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 [ 11 C]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 [ 11 C]Martinostat. We quantified [ 11 C]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 [ 11 C]Martinostat PET quantification. Results [ 11 C]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 V T . 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 V T 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 [ 11 C]Martinostat provides a good in vivo measure of the cerebral HDAC1–3 protein levels.
ISSN:1536-1632
1860-2002
DOI:10.1007/s11307-019-01403-9