Synthesis and Evaluation of 18F-INER-1577-3 as a Central Nervous System (CNS) Histone Deacetylase Imaging Agent

Author(s): Ming-Hsin Li*, Han-Chih Chang, Chun-Fang Feng, Hung-Wen Yu, Chyng-Yann Shiue

Journal Name: Current Medical Imaging
Formerly: Current Medical Imaging Reviews

Volume 16 , Issue 8 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Epigenetic dysfunction is implicated in many neurologic, psychiatric and oncologic diseases. Consequently, histone deacetylases (HDACs) inhibitors have been developed as therapeutic and imaging agents for these diseases. However, only a few radiotracers have been developed as HDACs imaging agents for the central nervous system (CNS). We report herein the synthesis and evaluation of [18F]INER-1577-3 ([18F]5) as an HDACs imaging agent for CNS.

Methods: [18F]INER-1577-3 ([18F]5) was synthesized by two methods: one-step (A) and two-step (B) methods. Briefly, radiofluorination of the corresponding precursors (11, 12) with K[18F]/K2.2.2 followed by purifications with HPLC gave ([18F]5). The quality of [18F]INER- 1577-3 synthesized by these methods was verified by HPLC and TLC as compared to an authentic sample. The inhibitions of [18F]INER-1577-3 and related HDACs inhibitors on tumor cells growth were carried out with breast cancer cell line 4T1 and MCF-7. The whole-body and brain uptake of [18F]INER-1577-3 in rats and AD mice were determined using a micro-PET scanner and the data was analyzed using PMOD.

Results: The radiochemical yield of [18F]INER-1577-3 synthesized by these two methods was 1.4 % (Method A) and 8.8% (Method B) (EOB), respectively. The synthesis time was 115 min and 100 min, respectively, from EOB. The inhibition studies showed that INER-1577-3 has a significant inhibitory effect in HDAC6 and HDAC8 but not HDAC2. PET studies in rats and AD mice showed a maximum at about 15 min postinjection for the whole brain of a rat (0.47 ± 0.03 %ID/g), SAMP8 mice (5.63 ± 1.09 %ID/g) and SAMR1 mice (7.23 ± 1.21 %ID/g).

Conclusion: This study showed that INER-1577-3 can inhibit tumor cell growth and is one of a few HDACs inhibitors that can penetrate the blood-brain barrier (BBB) and monitor HDAC activities in AD mice. Thus, [18F]INER-1577-3 may be a potent HDACs imaging agent, especially for CNS.

Keywords: Epigenetic modifications, histone deacetylases, [18F]INER-1577-3, histone deacetylases imaging agents, PET imaging, AD mice.

[1]
Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 2007; 8(5): 355-67.
[http://dx.doi.org/10.1038/nrn2132 ] [PMID: 17453016]
[2]
Rudenko A, Tsai LH. Epigenetic modifications in the nervous system and their impact upon cognitive impairments. Neuropharmacology 2014; 80: 70-82.
[http://dx.doi.org/10.1016/j.neuropharm.2014.01.043 ] [PMID: 24495398]
[3]
Rudenko A, Tsai LH. Epigenetic regulation in memory and cognitive disorders. Neuroscience 2014; 264: 51-63.
[http://dx.doi.org/10.1016/j.neuroscience.2012.12.034 ] [PMID: 23291453]
[4]
Sen N. Epigenetic regulation of memory by acetylation and methylation of chromatin: Implications in neurological disorders, aging, and addiction. Neuromolecular Med 2015; 17(2): 97-110.
[http://dx.doi.org/10.1007/s12017-014-8306-x ] [PMID: 24777294]
[5]
Sun H, Kennedy PJ, Nestler EJ. Epigenetics of the depressed brain: Role of histone acetylation and methylation. Neuropsychopharmacology 2013; 38(1): 124-37.
[http://dx.doi.org/10.1038/npp.2012.73 ] [PMID: 22692567]
[6]
Konsoula Z, Barile FA. Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders. J Pharmacol Toxicol Methods 2012; 66(3): 215-20.
[http://dx.doi.org/10.1016/j.vascn.2012.08.001 ] [PMID: 22902970]
[7]
Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CT. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 2009; 32(11): 591-601.
[http://dx.doi.org/10.1016/j.tins.2009.06.002 ] [PMID: 19775759]
[8]
Juo YY, Gong XJ, Mishra A, et al. Epigenetic therapy for solid tumors: From bench science to clinical trials. Epigenomics 2015; 7(2): 215-35.
[http://dx.doi.org/10.2217/epi.14.73 ] [PMID: 25942532]
[9]
Kazantsev AG, Thompson LM. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 2008; 7(10): 854-68.
[http://dx.doi.org/10.1038/nrd2681 ] [PMID: 18827828]
[10]
D’Mello SR. Histone deacetylases as targets for the treatment of human neurodegenerative diseases. Drug News Perspect 2009; 22(9): 513-24.
[http://dx.doi.org/10.1358/dnp.2009.22.9.1437959 ] [PMID: 20072728]
[11]
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; 54(15): 5576-82.
[http://dx.doi.org/10.1021/jm200620f ] [PMID: 21721525]
[12]
Hooker JM, Kim SW, Alexoff D, et al. Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using positron emission tomography. ACS Chem Neurosci 2010; 1(1): 65-73.
[http://dx.doi.org/10.1021/cn9000268 ] [PMID: 20657706]
[13]
Mukhopadhyay U, Tong WP, Gelovani JG, Alauddin MM. Radiosynthesis of 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) for PET imaging of histone deacetylase (HDAC). J Labelled Comp Radiopharm 2006; 49(11): 997-1006.
[http://dx.doi.org/10.1002/jlcr.1122]
[14]
Reid AE, Hooker J, Shumay E, et al. Evaluation of 6-([(18)F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain. Nucl Med Biol 2009; 36(3): 247-58.
[http://dx.doi.org/10.1016/j.nucmedbio.2008.12.005 ] [PMID: 19324270]
[15]
Schroeder FA, Wang C, Van de Bittner GC, et al. PET imaging demonstrates histone deacetylase target engagement and clarifies brain penetrance of known and novel small molecule inhibitors in rat. ACS Chem Neurosci 2014; 5(10): 1055-62.
[http://dx.doi.org/10.1021/cn500162j ] [PMID: 25188794]
[16]
Wang C, Schroeder FA, Wey HY, et al. In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs. J Med Chem 2014; 57(19): 7999-8009.
[http://dx.doi.org/10.1021/jm500872p ] [PMID: 25203558]
[17]
Li MH, Shiue CY, Chang HC, Chu HH. Synthesis of [18F]benzamide ([18F]INER-1577) as Histone Deacetylase (HDACs) Imaging Agent. Society of Nuclear Medicine and Molecular Imaging 2016 Annual Meeting 2016. Jun 11-15. 2664.
[18]
Thomae D, Morley TJ, Hamill T, Carroll VM, Papin C, Twardy NM, et al. Automated one-step radiosynthesis of the CB1 receptor imaging agent [(18) F]MK-9470. J Labelled Comp Radiopharm 2014; 57(10): 611-4.
[http://dx.doi.org/10.1002/jlcr.3219 ] [PMID: 25156811]
[19]
Seo YJ, Muench L, Reid A, et al. Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain. Bioorg Med Chem Lett 2013; 23(24): 6700-5.
[http://dx.doi.org/10.1016/j.bmcl.2013.10.038 ] [PMID: 24210501]
[20]
Fuchikami M, Yamamoto S, Morinobu S, Okada S, Yamawaki Y, Yamawaki S. The potential use of histone deacetylase inhibitors in the treatment of depression. Prog Neuropsychopharmacol Biol Psychiatry 2016; 64: 320-4.
[http://dx.doi.org/10.1016/j.pnpbp.2015.03.010 ] [PMID: 25818247]
[21]
Mielcarek M, Zielonka D, Carnemolla A, Marcinkowski JT, Guidez F. HDAC4 as a potential therapeutic target in neurodegenerative diseases: A summary of recent achievements. Front Cell Neurosci 2015; 9: 42.
[http://dx.doi.org/10.3389/fncel.2015.00042 ] [PMID: 25759639]
[22]
Harrison IF, Dexter DT. Epigenetic targeting of histone deacetylase: Therapeutic potential in Parkinson’s disease? Pharmacol Ther 2013; 140(1): 34-52.
[http://dx.doi.org/10.1016/j.pharmthera.2013.05.010 ] [PMID: 23711791]
[23]
Didonna A, Opal P. The promise and perils of HDAC inhibitors in neurodegeneration. Ann Clin Transl Neurol 2015; 2(1): 79-101.
[http://dx.doi.org/10.1002/acn3.147 ] [PMID: 25642438]
[24]
Wang C, Eessalu TE, Barth VN, et al. Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain. Am J Nucl Med Mol Imaging 2013; 4(1): 29-38.
[PMID: 24380043]
[25]
Seo YJ, Kang Y, Muench L, et al. Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors. ACS Chem Neurosci 2014; 5(7): 588-96.
[http://dx.doi.org/10.1021/cn500021p ] [PMID: 24780082]
[26]
Cosín-Tomás M, Alvarez-López MJ, Sanchez-Roige S, et al. Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise. Front Aging Neurosci 2014; 6: 51.
[PMID: 24688469]


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 8
Year: 2020
Published on: 08 October, 2019
Page: [978 - 990]
Pages: 13
DOI: 10.2174/1573405615666191008160809

Article Metrics

PDF: 25
HTML: 2