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

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

J Adam Hendricks  1 , Edmund J Keliher, Brett Marinelli, Thomas Reiner, Ralph Weissleder, Ralph Mazitschek
Affiliations

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

J Adam Hendricks et al. J Med Chem. .

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.

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Figures

Figure 1
Figure 1
Structures of HDAC inhibitors and HDAC imaging agents.
Figure 2
Figure 2
a) Dose-response profile for 1b and 2 against HDACs1-3 and 6; b) Analytical Radio-HPLC traces.
Figure 3
Figure 3
(a) Blood half-life of 1a following i.v. and (b) p.o. administration; c) biodistribution; d) blood half-life determined by dynamic PET-scan (%ID/g - Injected Dose per Gram of Tissue; SUV - standardized uptake value).
Figure 4
Figure 4
a) Dynamic PET-CT following i.v. administration of 1a in C57BL/6 mouse; b) PET-CT scan of tumor xenograft before and after competition with `cold' SAHA, blue dotted line indicates tumor perimeter; c) Time dependent distribution of 1a.
Scheme 1
Scheme 1
Synthesis of 1b (a) Methyl 8-chloro-8-oxooctanoate, Et3N, CH2Cl2, rt, 1hr, 54%; b) 50% NH2OH(aq), 1 N NaOH(MeOH), rt, 12hr, 65%.
Scheme 2
Scheme 2
Synthesis of 1a (a) 1. K2CO, K222,18F (n.c.a.), DMSO, 120 °C microwave, 5 min; 2. C18 isolation, MeOH elution. 78% (b) 1. NaBH4, 10% Pd/C,rt., 10 min; 2. LiChrolut EN isolation, THF elution, Na2SO4/Celite drying. 58% (c) Methyl 8-chloro-8-oxooctanoate, rt, 5 min. (d) 1. 50% NH2OH(aq), 1 N NaOH(MeOH), rt, 3min min; 2. HPLC Purification, concentration; 3. Reconstitution into vehicle (88% two steps).
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