Novel ⁶⁴Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases

Abstract

We report the design, synthesis, and biological evaluation of a 64 Cu-labeled histone deacetylase (HDAC) imaging probe, which was obtained by introduction of metal chelator through click reaction of HDAC inhibitor CUDC-101 and then radiolabeled with 64 Cu. The resulting 64 Cu-labeled compound 7 ([ 64 Cu]7) was identified as a positron emission tomography (PET) imaging probe to noninvasively visualize HDAC expression in vivo. Cell based competitive assay established the specific binding of [ 64 Cu]7 to HDACs. Biodistribution and small-animal microPET/CT studies further showed that [ 64 Cu]7 had high tumor to background ratio in the MDA-MB-231 xenograft model, a triple-negative breast cancer with high expression of HDACs. To our knowledge, [ 64 Cu]7 thus represents the first 64 Cu-labeled PET HDAC imaging probe, which exhibits nanomolar range binding affinity and capability to imaging HDAC expression in triple-negative breast cancer in vivo.

A Tyrosine Kinase Inhibitor–Based High-Affinity PET Radiopharmaceutical Targets Vascular Endothelial Growth Factor Receptor

“…ZD-G2-DOTA and ZD-G1-DOTA were radiolabeled using procedures described in our previously published report (32). Briefly, 185 MBq (5 mCi) of 64 CuCl 2 in 0.1 M HCl were diluted by adding 300 mL of 0.1 M ammonium acetate (pH 5.6).…”

Cell cycle arrest induced by inhibitors of epigenetic modifications in maize (Zea mays) seedling leaves: characterization of the process and possible mechanisms involved

“…Thus, TSA is a useful tool for analysing histone modifications in regulatory mechanisms of the cell cycle. 7‐(4‐(3‐ethynylphenylamino)‐7‐methoxyquinazolin‐6‐yloxy)‐N‐hydroxyheptanamide (CUDC‐101) can inhibit HDAC activity in a different way (Meng et al ., ).…”

Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain

“…Several previously studied radiolabeled hydroxamite HDAC inhibitors, including [ 125/131 I]-SAHA [ 29 ], [ 11 C]MS-275 [ 30 ], [ 18 F]SAHA [ 31 ], [ 18 F]FESAHA [ 32 ], and [ 64 Cu]CUDC-101 [ 33 ] demonstrated poor accumulation in the brain due to inability to efficiently cross the BBB. Other hydroxamite-based HDAC inhibitors containing more lipophilic capping groups, such as the adamantyl in [ 11 C]martinostat, demonstrated efficient cellular membrane and BBB penetration of this radiotracer, as well as efficient visualization and quantification of HDACs class I expression levels in the brain and other organs in non-human primates [ 34 ].…”