Determination of Fragmentation Schemes and Metabolites of Fluorinated Histone Deacetylase Inhibitors for Use as Positron Emission Tomography Imaging Agents Using HPLC-MS/MS
High performance liquid chromatography coupled with tandem mass spectrometry was developed and validated as a method for the analysis of fluorinated histone deacetylase inhibitors (F-HDACi), and then employed to study their metabolism in biosystems. Four HDACi analogs labeled with the positron emission nuclide 18F constitute a group of potential positron emission tomography imaging agents, which were developed by the Institute of Nuclear Energy Research (INER) and coded as INER-1577 #1, #2, #3, and #4 during animal studies for the diagnosis of dementia. The performance of the method was found to be suitable for the determination of analog #3, and it was employed to determine the structures and fragmentation mechanisms of all four analogs and to study the biotransformations of analogs #3 and #4. The results indicated that the method used for the determination of analog #3 was suitable for determining the abundance of the analogs in chemical and biochemical tests with high precision, accuracy, reproducibility, and recovery. Weaknesses in the chemical bonding of the analogs were found to involve the fluoro, dimethylamino, and benzamide groups in a fragmentation mechanism deduced via tandem mass spectrometry. The metabolites of analogs #3 and #4 in rat liver microsomes and rat plasma were also identified to clarify their characteristic behaviors in biosystems. The major product of analogs #3 in liver microsomes was produced by hydroxylation of the benzylic carbon atom, but in rat plasma the metabolites of analog #3 were produced by hydrolysis of the benzamide group to give a diaminobiphenyl compound with the simultaneous replacement of a fluorine atom by a hydroxyl group. The metabolites of analog #4 in liver microsomes were produced by hydroxylation of the benzylic carbon atom and hydrolysis of the benzamide bond. The results of the studies characterized the chemical and biochemical behaviors of the series F-HADCi analogs.
References
[1]
Small, G.W., Siddarth, P., Kepe, V., Ercoli, L.M., Burggren, A.C., Bookheimer, S.Y., Miller, K.J., Kim, J., Lavretsky, H., Huang, S.C. and Barrio, J.R. (2012) Prediction of Cognitive Decline by Positron Emission Tomography of Brain Amyloid and Tau. Archives of Neurology, 69, 215-222.
https://doi.org/10.1001/archneurol.2011.559
[2]
Lu, F.M. and Yuan, Z. (2015) PET/SPECT Molecular Imaging in Clinical Neuroscience: Recent Advances in the Investigation of CNS Diseases. Quantitative Imaging in Medicine and Surgery, 5, 433-447.
[3]
Asbury, C. (2011) Brain Imaging Technologies and Their Applications in Neuroscience. The DANA Foundation.
https://dana.org/uploadedFiles/Pdfs/brainimagingtechnologies.pdf
[4]
Arora, A. and Bhagat, N. (2016) Insight into the Molecular Imaging of Alzheimer’s Disease. International Journal of Biomedical Imaging, 2016, 17.
https://doi.org/10.1155/2016/7462014
[5]
Zwergel, C., Stazi, G., Valente, S. and Mai, A. (2016) Histone Deacetylase Inhibitors: Updated Studies in Various Epigenetic-Related Diseases. Journal of Clinical Epigenetics, 2, 7.
[6]
Marks, P.A. and Dokmanovic, M. (2005) Histone Deacetylase Inhibitors: Discovery and Development as Anticancer Agents. Expert Opinion on Investigational Drugs, 14, 1497-1511. https://doi.org/10.1517/13543784.14.12.1497
[7]
Ceacci, E. and Minucci, S. (2016) Inhibition of Histone Deacetylases in Cancertherapy: Lessons from Leukaemia. British Journal of Cancer, 114, 605-611.
https://doi.org/10.1038/bjc.2016.36
[8]
Kirkpatrick, B. (2015) HDAC Inhibitor Could Sharpen Memory and Treat Cancer.
https://www.whatisepigenetics.com/hdac-inhibitor-could-sharpen-memory-and-treat-cancer/
[9]
Weinhold, B. (2006) Epigenetics: The Science of Change. Environmental Health Perspectives, 114, A160-A167. https://doi.org/10.1289/ehp.114-a160
[10]
Volmar, C.H. and Wahlestedt, C. (2015) Histone Deacetylases (HDACs) and Brain Function. Neuroepigenetics, 1, 20-27. https://doi.org/10.1016/j.nepig.2014.10.002
[11]
Xu, K., Dai, X.L., Huang, H.C. and Jiang, Z.F. (2011) Targeting HDACs: A Promising Therapy for Alzheimer’s Disease. Oxidative Medicine and Cellular Longevity, 2011, Article ID: 143269.
[12]
Levenson, J.M. and Sweatt, J.D. (2005) Epigenetic Mechanisms in Memory Formation. Nature Reviews Neuroscience, 6, 108-118. https://doi.org/10.1038/nrn1604
[13]
Yang, S.S., Zhang, R., Wang, G. and Zhang, Y.F. (2017) The Development Prospection of HDAC Inhibitors as a Potential Therapeutic Direction in Alzheimer’s Disease. Translational Neurodegeneration, 6, 19.
https://doi.org/10.1186/s40035-017-0089-1
[14]
Lu, X., Wang, L., Yu, C., Yu, D. and Yu, G. (2015) Histone Acetylation Modifiers in the Pathogenesis of Alzheimer’s Disease. Frontiers in Cellular Neuroscience, 9, 226.
https://doi.org/10.3389/fncel.2015.00226
[15]
Selenica, M.L., Benner, L., Housley, S.B., Manchec, B., Lee, D.C., Nash, K.R., Kalin, J., Bergman, J.A., Kozikowski, A., Gordon, M.N. and Morgan, D. (2014) Histone Deacetylase 6 Inhibition Improves Memory and Reduces Total Tau Levels in a Mouse Model of Tau Deposition. Alzheimer’s Research & Therapy, 6, 12.
http://alzres.com/content/6/1/12
https://doi.org/10.1186/alzrt241
[16]
Couto, P.J. and Millis, R.M. (2015) PET Imaging of Epigenetic Influences on Alzheimer’s Disease. International Journal of Alzheimer’s Disease, 2015, Article ID: 575078. https://doi.org/10.1155/2015/575078
[17]
Yeh, H.H., Tian, M., Hinz, R., Young, D., Shavrin, A., Mukhapadhyay, U., Flores, L.G., Balatoni, J., Soghomonyan, S., Jeong, H.J. and Pal, A. (2013) Imaging Epigenetic Regulation by Histone Deacetylases in the Brain Using PET/MRI with 18F-FAHA. Neuroimagine, 64, 630-639.
https://doi.org/10.1016/j.neuroimage.2012.09.019
[18]
Mottamal, M., Zheng, S., Huang, T.L. and Wang, G. (2015) Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents. Molecules, 20, 3898-3941. https://doi.org/10.3390/molecules20033898
[19]
Li, M.H., Shiue, C.Y., Chang, H.C. and Chu, H.H. (2017) Compounds of Imaging Agent with HDAC Inhibitor for Treatment of Alzheimer Syndrome and Method of Synthesis Thereof. US9, 603, 950B1.
[20]
Li, M.H., Shiue, C.Y., Chang, H.C. and Chu, H.H. (2018) Compound and Analogs for Tracing Histone Acetylation Inhibitors PET Imaging for Diagnosis and Treatment of Tumors. Patent has been approved by USA and Taiwan.
[21]
Portychova, L. and Schug, K.A. (2017) Instrumentation and Applications of Electrochemistry Coupled to Mass Spectrometry for Studying Xenobiotic Metabolism: A Review. Analytical Chimica Acta, 993, 1-21.
https://doi.org/10.1016/j.aca.2017.08.050
[22]
Chen, W.H. (2017) Determination of the Metabolites of FEONM, an Alzheimer’s Disease Radio-Imaging Diagnosis Agent in Various Biosystems Using LC/Tandem Mass Spectrometry. EC Pharmacology and Toxicology, 4, 40-50.
[23]
Mammalian Liver Microsomesguidelines for Use, TF000017 Rev 1.0, Supplied by BD Biosciences.
[24]
Cyprotex Co. In Vitro “ADME & PK—Plasma Stability”.
http://www.cyprotex.com/admepk/in-vitro-metabolism/plasmastability
[25]
Seto, E. and Yoshida, M. (2014) Erasers of Histone Acetylation: The Histone Deacetylase Enzymes. Cold Spring Harbor Perspective in Biology, 6, a018713.
https://doi.org/10.1101/cshperspect.a018713
[26]
Kuevi, U.A., Atohoun, G.S.Y., Kpotin, A.G., Kpota-Hounguè, A.T., Burke, L.A. and Mensah, J.B. (2014) DFT Study of Benzamide Coordination with Zinc (II). International Research Journal of Pure & Applied Chemistry, 4, 339-351.
https://doi.org/10.9734/IRJPAC/2014/7645
[27]
Kantharaj, E. and Jayaraman, R. (2011) Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer Therapy: Drug Metabolism and Pharmacokinetic Properties, Chapter 5. In: Rundfeldt, C., Ed., Drug Development—A Case Study Based Insight into Modern Strategies, InTech, Rijeka, 101-120.
http://www.meipharma.com/sites/default/files/Drug%20Development%20%282011%29.pdf
