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. 2023 Apr 27;66(8):5611-5621.
doi: 10.1021/acs.jmedchem.2c02064. Epub 2023 Apr 17.

High-Contrast PET Imaging with [18F]NT160, a Class-IIa Histone Deacetylase Probe for In Vivo Imaging of Epigenetic Machinery in the Central Nervous System

Nashaat Turkman  1   2   3 , Sulan Xu  1   2 , Chun-Han Huang  1   2   3 , Christopher Eyermann  2   4 , Julia Salino  1   2 , Palwasha Khan  1   2
Affiliations

High-Contrast PET Imaging with [18F]NT160, a Class-IIa Histone Deacetylase Probe for In Vivo Imaging of Epigenetic Machinery in the Central Nervous System

Nashaat Turkman et al. J Med Chem. .

Abstract

We utilized positron emission tomography (PET) imaging in vivo to map the spatiotemporal biodistribution/expression of class-IIa histone deacetylases (class-IIa HDACs) in the central nervous system (CNS). Herein we report an improved radiosynthesis of [18F]NT160 using 4-hydroxy-TEMPO which led to a significant improvement in radiochemical yield and molar activity. PET imaging with [18F]NT160, a highly potent class-IIa HDAC inhibitor, led to high-quality and high-contrast images of the brain. [18F]NT160 displayed excellent pharmacokinetic and imaging characteristics: brain uptake is high in gray matter regions, tissue kinetics are appropriate for a 18F-tracer, and specific binding for class-IIa HDACs is demonstrated by self-blockade. Higher uptake with [18F]NT160 was observed in the hippocampus, thalamus, and cortex while the uptake in the cerebellum was relatively low. Overall, our current studies with [18F]NT160 will likely facilitate the development and clinical translation of PET tracers for imaging of class-IIa HDACs biodistribution/expression in cancer and the CNS.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structures of radiolabeled class-IIa HDAC inhibitors.
Scheme 1
Scheme 1. Improved Radiosynthesis of [18F]NT160
Figure 2
Figure 2
Representative PET and PET/CT (fusion) images with [18F]NT160 of rat brain (summed 5–30 min): (A and B) coronal, (C and D) sagittal, and (E and F) transverse, respectively.
Figure 3
Figure 3
Time–activity curves of [18F]NT160 obtained from dynamic imaging for 60 min. (A) Brain, muscle, and heart; (B) hippocampus (Hip), cortex (Cortx), thalamus (TH), striatum (Str), and cerebellum (Cer).
Figure 4
Figure 4
Representative coronal PET images (summed, 5–30 min) with [18F]NT160 with the corresponding rat brain regions. Crt: Cortex, Cer: cerebellum, Th: thalamus, Hip: hippocampus, Str: striatum. The alignment for the images with the rat brain atlas was used to identify these regions of interest.,
Figure 5
Figure 5
(A) In vitro autoradiography with [18F]NT160 at baseline and (B) after pretreatment with NT160 (1.0 μM). (C) Brain histology obtained with HDAC4 antibody.
Figure 6
Figure 6
Time–activity curves obtained from dynamic imaging for 60 min: (A) whole brain; (B) hippocampus and cerebellum at baseline and after self-blocking. Cer: cerebellum, Hip: hippocampus.
Figure 7
Figure 7
Analytical HPLC chromatograms of [18F]NT160 obtained from (A) brain homogenates and (B) plasma. (C) Proposed blood metabolic pathway for M1 (radiometabolism of [18F]NT160 leads to [18F]1 (M1). (D and E) Inhibition of HDAC activity by compound 1 (M1) in HT-29 cells: (D) Inhibition of class-IIa HDAC and (E) inhibition of class-I/IIb. Compound 1 was screened side-by-side with SAHA and NT160.
Figure 8
Figure 8
Representative PET, CT, and PT/CT images (summed, 0–60 min) with [18F]1: (A and B) coronal, (C and D) sagittal, and (E and F) transverse, respectively. (G) Time–activity curve of [18F]1 in rat brain.
See this image and copyright information in PMC

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