Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 24; pp. 6700 - 6705
• Main Authors: Seo, Young Jun, Muench, Lisa, Reid, Alicia, Chen, Jinzhu, Kang, Yeona, Hooker, Jacob M., Volkow, Nora D., Fowler, Joanna S., Kim, Sung Won
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2013; Elsevier
• Subjects: Anilides - chemistry; Animals; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain; Brain - diagnostic imaging; Brain - enzymology; Brain permeability; Carbon Radioisotopes - chemistry; Carbon-11; Chemistry; Chemistry, Medicinal; Chemistry, Organic; chromatin; drugs; Epigenetics; fluorine; Fluorine Radioisotopes - chemistry; Fluoroacetates - chemistry; gene expression; histone deacetylase; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; image analysis; Life Sciences & Biomedicine; metabolism; permeability; Permeability - drug effects; Pharmacology & Pharmacy; Physical Sciences; Positron emission tomography; Primates; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacology; SAHA; Science & Technology; Epigenetics; SAHA; Brain; Brain permeability; Carbon-11; Positron emission tomography; MS-275; DISORDERS; MECHANISMS; TRICHOSTATIN-A; POTENT; RADIOSYNTHESIS; ESTERS; INHIBITORS; EFFICIENT
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.10.038

Brain uptake of HDAC inhibitor and substrates. 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®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([18F]Fluoroacetamido)-1-hexanoicanilide ([18F]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 [18F]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.