Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases

Abstract

Epigenetic alterations of gene expression have emerged as a key factor in several neurodegenerative diseases. In particular, inhibitors targeting histone deacetylases (HDACs), which are enzymes responsible for deacetylation of histones and other proteins, show therapeutic effects in animal neurodegenerative disease models. However, the details of the interaction between changes in HDAC levels in the brain and disease progression remain unknown. In this review, we focus on recent advances in development of radioligands for HDAC imaging in the brain with positron emission tomography (PET). We summarize the results of radiosynthesis and biological evaluation of the HDAC ligands to identify their successful results and challenges. Since 2006, several small molecules that are radiolabeled with a radioisotope such as carbon-11 or fluorine-18 have been developed and evaluated using various assays including in vitro HDAC binding assays and PET imaging in rodents and non-human primates. Although most compounds do not readily cross the blood-brain barrier, adamantane-conjugated radioligands tend to show good brain uptake. Until now, only one HDAC radioligand has been tested clinically in a brain PET study. Further PET imaging studies to clarify age-related and disease-related changes in HDACs in disease models and humans will increase our understanding of the roles of HDACs in neurodegenerative diseases.

Keywords: histone deacetylase; imaging; neurodegenerative disease; positron emission tomography; radioligand.

Figure 1

Chemical structure of SAHA. Three groups that constitute a typical HDAC inhibitor are indicated.

Scheme 1

Radiosynthesis of [¹⁸F]1.

Figure 2

Chemical structure of [¹⁸F]FACE.

Scheme 2

Radiosynthesis of [¹⁸F]2 and [¹⁸F]3.

Scheme 3

Radiosynthesis of [¹⁸F]4.

Scheme 4

Radiosynthesis of [¹⁸F]5.

Scheme 5

Radiosynthesis of [¹¹C]6 and [¹¹C]7.

Scheme 6

Radiosynthesis of [¹¹C]8. * Non-decay corrected.

Figure 3

The total volume of distribution (V_T) images from [¹¹C]8 PET in baboon brains. Robust brain uptake (top) of [¹¹C]8 was decreased by pre-treatment with unlabeled 8 (bottom). (Reproduced from Wang et al. J Med Chem; published by The American Chemical Society, 2014 [68]).

Scheme 7

Radiosynthesis of [¹⁸F]9–11.

Scheme 8

Radiosynthesis of [¹⁸F]12. * Non-decay corrected.

Scheme 9

Radiosynthesis of [¹¹C]13–15.

Scheme 10

Radiosynthesis of [¹¹C]16–18. * Non-decay corrected.

Scheme 11

Radiosynthesis of [¹¹C]19 and [¹¹C]20.

Scheme 12

Radiosynthesis of [⁶⁴Cu]21.

Scheme 13

Radiosynthesis of [¹¹C]22.

Scheme 14

Radiosynthesis of [¹¹C]23 and [¹¹C]24.

Figure 4

[¹¹C]8 PET images in a first-in-human study. (A) Brain SUV images averaged from 60 to 90 min p.i. of [¹¹C]8 (174 MBq). PET images are overlaid on MRI; (B) [¹¹C]8 SUVR images of eight individual subjects. SUV_{60–90 min} was normalized to white matter as a reference. (Reproduced with permission from Wey et al. Sci Transl Med; The American Association for the Advancement of Science, 2016 [28]).