title: In vivo PET imaging of histone deacetylases by 18F-suberoylanilide hydroxamic acid (18F-SAHA).
abstract: Histone deacetylases (HDACs) are a group of enzymes that modulate gene expression and cell state by deacetylation of both histone and non-histone proteins. A variety of HDAC inhibitors (HDACi) have already undergone clinical testing in cancer. Real-time in vivo imaging of HDACs and their inhibition would be invaluable; however, the development of appropriate imaging agents has remained a major challenge. Here, we describe the development and evaluation of (18)F-suberoylanilide hydroxamic acid ((18)F-SAHA 1a), a close analogue of the most clinically relevant HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). We demonstrate that 1a has near identical biochemical activity profiles to that of SAHA and report findings from pharmacokinetic studies. Using a murine ovarian cancer model, we likewise show that HDAC inhibitor target binding efficacy can be quantitated within 24 h of administration. 1a thus represents the first (18)F-positron emission tomography (PET) HDAC imaging agent, which also exhibits low nanomolar potency and is pharmacologically analogous to a clinically relevant HDAC inhibitor.
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Massachusetts 02114, United States.
authors: J Adam
authors: JA
authors: Hendricks
authors: Edmund J
authors: EJ
authors: Keliher
authors: Brett
authors: B
authors: Marinelli
authors: Thomas
authors: T
authors: Reiner
authors: Ralph
authors: R
authors: Weissleder
authors: Ralph
authors: R
authors: Mazitschek
mesh_terms: D000818:Animals; D005462:Fluorine Radioisotopes; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids; D051379:Mice; D008810:Mice, Inbred C57BL; D000077337:Vorinostat
chemical_list: D005462:Fluorine Radioisotopes; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D006655:Histone Deacetylases