In vivo PET imaging of histone deacetylases by 18F-suberoylanilide hydroxamic acid (18F-SAHA).

Article Details

Citation
Copy to clipboard

Hendricks JA, Keliher EJ, Marinelli B, Reiner T, Weissleder R, Mazitschek R

In vivo PET imaging of histone deacetylases by 18F-suberoylanilide hydroxamic acid (18F-SAHA).

J Med Chem. 2011 Aug 11;54(15):5576-82. doi: 10.1021/jm200620f. Epub 2011 Jul 18.

PubMed ID
21721525 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)9.7N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)16N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)21.8N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)57.3N/AN/ADetails