In Vivo PET Imaging of Histone Deacetylases by 18F-Suberoylanilide Hydroxamic Acid (18F-SAHA)

• Published in: Journal of medicinal chemistry 2011-08, Vol.54 (15), p.5576-5582
• Main Authors: Hendricks, J. Adam, Keliher, Edmund J, Marinelli, Brett, Reiner, Thomas, Weissleder, Ralph, Mazitschek, Ralph
• Format: Article
• Language: English
• Subjects: Animals; Fluorine Radioisotopes; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; Hydroxamic Acids; Mice; Mice, Inbred C57BL
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200620f

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 18F-suberoylanilide hydroxamic acid (18F-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 18F-positron emission tomography (PET) HDAC imaging agent, which also exhibits low nanomolar potency and is pharmacologically analogous to a clinically relevant HDAC inhibitor.