Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain
Bioorganic & Medicinal Chemistry Letters
Positron emission tomography SAHA Brain Epigenetics Brain permeability a b s t r a c t Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza Ò ), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study
... etic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([ 18 F]Fluoroacetamido)-1-hexanoicanilide ([ 18 F]FAHA) was recently developed as a HDAC substrate and shows moderate blood-brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate-and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [ 18 F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration. Published by Elsevier Ltd. Gene expression is regulated, in part, through enzyme catalyzed epigenetic modifications targeting both the DNA and its associated histone proteins. 1 For example, histone acetyl transferases (HATs) catalyze the acetylation of the lysine residues of histone proteins removing the positive charge and rendering the DNA more accessible to transcription initiation complexes and RNA polymerase. In contrast, histone deacetylases (HDACs) typically catalyze the hydrolysis of the acetyl groups from lysine residues of histone proteins condensing the chromatin and repressing gene expression. 2 Because the folding process induced by the deacetylation of histones represses the expression of genes which are involved in critical metabolic processes such as apoptosis, cell-cycle arrest and differentiation, HDAC has become an important molecular target in drug development.     The discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA, Fig. 1) , 7,8 an antifungal antibiotic with anticancer activity, has stimulated the development of inhibitors of HDAC including Vorinostat (SAHA, Fig. 1 ) which was recently approved by FDA for the treatment of cutaneous T cell lymphoma (CTCL) and other cancers. 9 HDAC inhibitors are also of interest in the study and treatment of a number of CNS disorders including depression, addiction and neurodegenerative diseases. 4, 10, 11 In fact, valproic acid, a class I HDAC inhibitor, 6 is one of the most widely used and effective antiseizure medications, which we recently showed its poor blood-brain barrier (BBB) penetration explaining the high doses needed for therapeutic efficacy. 12 For this reason, the development of brain penetrant radiotracers for positron emission tomography (PET) imaging of HDAC in the brain would advance the study of this important epigenetic marker as well as the measurement of target engagement during HDAC inhibitor therapy. Only a handful of HDAC active compounds including HDAC inhibitor drugs have been radiolabeled with either F-18 (t 1/2 : 110 min) or C-11 (t 1/2 : 20.4 min) and evaluated for specificity for 0960-894X/$ -see front matter Published by Elsevier Ltd. http://dx.