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EJNMMI Research
Published in: EJNMMI Research 1/2016

Open Access 01-12-2016 | Original research

Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors

Authors: Kazumi Koga, Jun Maeda, Masaki Tokunaga, Masayuki Hanyu, Kazunori Kawamura, Mari Ohmichi, Toshio Nakamura, Yuji Nagai, Chie Seki, Yasuyuki Kimura, Takafumi Minamimoto, Ming-Rong Zhang, Toshimitsu Fukumura, Tetsuya Suhara, Makoto Higuchi

Published in: EJNMMI Research | Issue 1/2016

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Abstract

Background

Histamine H3 receptor (H3R) is a potential therapeutic target of sleep- and cognition-related disorders. The purpose of the present study is to develop a novel positron emission tomography (PET) ligand for H3Rs from dihydroquinolinone derivatives, which we previously found to have high affinity with these receptors.

Methods

Six compounds were selected from a dihydroquinolinone compound library based on structural capability for 11C labeling and binding affinity for H3Rs. Their in vivo kinetics in the rat brain were examined in a comparative manner by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Chemicals with appropriate kinetic properties were then labeled with 11C and evaluated in rats and monkeys using PET.

Results

Of the six compounds, TASP0410457 (also diminutively called TASP457) and TASP0434988 exhibited fast kinetics and relatively high brain uptakes in ex vivo LC-MS/MS and were selected as candidate PET imaging agents. PET data in rat brains were mostly consistent with LC-MS/MS findings, and rat and monkey PET scans demonstrated that [11C]TASP0410457 was superior to [11C]TASP0434988 for high-contrast H3R PET imaging. In the monkey brain PET, distribution volume for [11C]TASP0410457 could be quantified, and receptor occupancy by a nonradioactive compound was measurable using this radioligand. The specific binding of [11C]TASP0410457 to H3Rs was confirmed by autoradiography using rat and monkey brain sections.

Conclusions

We developed [11C]TASP0410457 as a radioligand enabling a robust quantification of H3Rs in all brain regions and demonstrated the utility of ex vivo LC-MS/MS and in vivo PET assays for selecting appropriate imaging tracers. [11C]TASP0410457 will help to examine the implication of H3Rs in neuropsychiatric disorders and to characterize emerging therapeutic agents targeting H3Rs.
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Literature
1.
Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol. 2001;63:637–72.CrossRefPubMed
2.
Yanai K, Tashiro M. The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies. Pharmacol Ther. 2007;113:1–15.CrossRefPubMed
3.
Threlfell S, Cragg SJ, Imre K, Turi GF, Coen CW, Greenfield SA. H3Rs inhibit serotonin release in substantia nigra pars reticulata. J Neurosci. 2004;24:8704–10.CrossRefPubMed
4.
Garduno-Torres B, Trevino M, Gutierrez R, Arias-Montano JA. Presynaptic H3Rs regulate glutamate, but not GABA release in rat thalamus. Neuropharmacology. 2007;52:527–35.CrossRefPubMed
5.
Medhurst AD, Atkins AR, Beresford IJ, Brackenborough K, Briggs MA, Calver AR, et al. GSK189254, a novel H3 receptor antagonist that binds to H3Rs in Alzheimer’s disease brain and improves cognitive performance in preclinical models. J Pharmacol Exp Ther. 2007;321:1032–45.
6.
Schlicker E, Fink K, Hinterthaner M, Göthert M. Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors. Naunyn Schmiedebergs Arch Pharmacol. 1989;340:633–8.
7.
Brioni JD, Esbenshade TA, Garrison TR, Bitner SR, Cowart MD. Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer’s disease. J Pharmacol Exp Ther. 2011;336:38–46.CrossRefPubMed
8.
Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12:1068–75.
9.
Passani MB, Giannoni P, Bucherelli C, Baldi E, Blandina P. Histamine in the brain: beyond sleep and memory. Biochem Pharmacol. 2007;73:1113–22.
10.
11.
Ashworth S, Rabiner EA, Gunn RN, Pilsson C, Wilson AA, Comley RA, et al. Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET. J Nucl Med. 2010;51:1021–9.
12.
Jitsuoka M, Tsukahara D, Ito S, Tanaka T, Takenaga N, Tokita S, et al. Synthesis and evaluation of a spiro-isobenzofuranone class of H3R inverse agonists. Bioorg Med Chem Lett. 2008;18:5101–6.
13.
Van Laere KJ, Sanabria-Bohórquez SM, Mozley DP, Burns DH, Hamill TG, Van Hecken A, et al. 11C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists. J Nucl Med. 2014;55:65–72.
14.
Jucaite A, Takano A, Boström E, Jostell KG, Stenkrona P, Halldin C, et al. AZD5213: a novel H3R antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects. Int J Neuropsychopharmacol. 2013;16:1231–9.
15.
Ashworth S, Berges A, Rabiner EA, Wilson AA, Comley RA, Lai RYK, et al. Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET. Br J Pharmacol. 2014;171:1241–9.
16.
Pike VW, Rash KS, Chen Z, Pedregal C, Statnick MA, Kimura Y, et al. Synthesis and evaluation of radioligands for imaging brain nociceptin/orphanin FQ peptide (NOP) receptors with positron emission tomography. J Med Chem. 2011;54:2687–700.
17.
Joshi EM, Need A, Schaus J, Chen Z, Benesh D, Mitch C, et al. Efficiency gains in tracer identification for nuclear imaging: can in vivo LC-MS/MS evaluation of small molecules screen for successful PET tracers? ACS Chem Neurosci. 2014;5:1154–63.
18.
Mitch CH, Quimby SJ, Diaz N, Pedregal C, de la Torre MG, Jimenez A, et al. Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer. J Med Chem. 2011;54:8000–12.
19.
Zheng MQ, Nabulsi N, Kim SJ, Tomasi G, Lin S, Mitch C, et al. Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging. J Nucl Med. 2013;54:455–63.
20.
Pedregal C, Joshi EM, Toledo MA, Lafuente C, Diaz N, Martinez-Grau MA, et al. Development of LC-MS/MS-based receptor occupancy tracers and positron emission tomography radioligands for the nociceptin/orphanin FQ (NOP) receptor. J Med Chem. 2012;55:4955–67.
21.
Nakamura T, Masuda S, Fujino A, inventors. Taisho Pharmaceutical Co. Ltd., assignee. Dihydroquinolinone derivatives. PCT Int. Appl. WO2010090347
22.
Fukumura T, Suzuki H, Mukai K, Zhang MR, Yoshida Y, Kumata K, et al. Development of versatile synthesis equipment for multiple production of PET radiopharmaceuticals. J Label Compd Radiopharm. 2007;50:S202.
23.
Tai YC, Ruangma A, Rowland D, Siegel S, Newport DF, Chow PL, et al. Performance evaluation of the microPET focus: a third-generation microPET scanner dedicated to animal imaging. J Nucl Med. 2005;46:455–63.
24.
Oi N, Suzuki M, Terauchi T, Tokunaga M, Nakatani Y, Yamamoto N, et al. Synthesis and evaluation of novel radioligands for positron emission tomography imaging of the orexin-2 receptor. J Med Chem. 2013;56:6371–85.
25.
Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage. 1996;4(3 Pt 1):153–8.CrossRefPubMed
26.
Pillot C, Heron A, Cochois V, Tardivel-Lacombe J, Ligneau X, Schwartz JC, et al. A detailed mapping of the H3R and its gene transcripts in rat brain. Neuroscience. 2002;114:173–93.
27.
Obayashi S, Suhara T, Kawabe K, Okauchi T, Maeda J, Akine Y, et al. Functional brain mapping of monkey tool use. Neuroimage. 2001;14:853–61.
28.
Cunningham VJ, Rabiner EA, Slifstein M, Laruelle M, Gunn RN. Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab. 2010;30:46–50.PubMedCentralCrossRefPubMed
29.
Logan J, Carruthers NI, Letavic MA, Sands S, Jiang X, Shea C, et al. Blockade of the brain H3R by JNJ-39220675: preclinical PET studies with [11C]GSK189254 in anesthetized baboon. Psychopharmacology (Berl). 2012;223:447–55.
30.
Hamill TG, Sato N, Jitsuoka M, Tokita S, Sanabria S, Eng W, et al. Inverse agonist H3R PET tracers labelled with carbon-11 or fluorine-18. Synapse. 2009;63:1122–32.
31.
West RE Jr, Wu RL, Billah MM, Egan RW, Anthes JC. The profiles of human and primate [3H]N alpha-methylhistamine binding differ from that of rodents. Eur J Pharmacol. 1999;377:233–9.
Metadata
Title
Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors
Authors
Kazumi Koga
Jun Maeda
Masaki Tokunaga
Masayuki Hanyu
Kazunori Kawamura
Mari Ohmichi
Toshio Nakamura
Yuji Nagai
Chie Seki
Yasuyuki Kimura
Takafumi Minamimoto
Ming-Rong Zhang
Toshimitsu Fukumura
Tetsuya Suhara
Makoto Higuchi
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2016
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-016-0170-2

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