With the recent advances in epigenetic research and improvement in our understanding of various epigenetic mechanisms, chromatin and DNA modifying enzymes, such as histone deacetylases (HDACs), histone methylases (HMs), and DNA methylating enzymes have emerged as important regulators of gene expression, development, physiology and life span. This presentation will cover a series of comprehensive imaging studies in rodents and non-human primates to assess the efficacy of novel radiolabeled agents non-invasive PET imaging of class-II and class-III histone deacetylase enzymes in the brain and other organs and tissues. The availability of novel HDAC class- and isoform-specific PET radiotracers will have a significant positive impact on the pace or research in the field of epigenetics.
Our group was first to develop a radiotracer for PET imaging of HDAC expression and activity, the 6-([18F]fluoroacetamido)-1-hexanoicanilide, termed 18F-FAHA . We have demonstrated, that after i.v. injection 18F-FAHA rapidly accumulates in the brain in rats and in rhesus macaques, and that the rate of 18F-FAHA accumulation in the brain is inhibited in a dose-dependent manner by HDAC inhibitor SAHA (vorinostat) [2,3]. Using quantitative PET/CT/MRI imaging and pharmacokinetic modeling, a dose-dependent nature of SAHA-induced reduction in 18F-FAHA accumulation in the baboon brain was demonstrated. Based on these initial studies, we developed a novel HDAC class IIa specific radiotracer 18F-trifluoroacetamido-1hexanoicanilide, termed 18F-TFAHA, and performed initial using PET/CT evaluation of this novel radiotracer in vivo in non-human primates. Currently, we are developing 18F-labeled agents for PET imaging of expression-activity of HDAC class-III enzymes called sirtuins (SIRTs) that are involved in a variety of physiological and pathophysiological processes, including lifespan regulation, nitrogen metabolism, fatty acid oxidation, and mitigating reactive oxygen species damage, cardiomyopathy, and neurodegenerative disiases.
These PET imaging agents will enable non-invasive and repetitive in vivo imaging of expression and activity of HDACs in the brain and different organs and tissues (including cancer) and help to understand the mechanisms of HDACs involvement in normal physiology and in the mechanisms of different diseases. The utilization of invasive biopsies of normal tissues (i.e., brain, heart, etc.) is prohibitive in humans due to obvious reasons of traumatism and morbidity. Therefore, PET/CT(MR) imaging using HDACs-specific substrate-type radiotracers should enable non-invasive monitoring of pharmacodynamics and therapeutic efficacy of novel HDACs-specific inhibitors (or activators) in experimental animals and in humans, and facilitate their translation into clinic.
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