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Tytuł pozycji:

Preclinical characterization of [ 18 F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase.

Tytuł:
Preclinical characterization of [ F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase.
Autorzy:
Koike T; Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan. .
Constantinescu CC; Invicro, LLC, New Haven, CT, USA.
Ikeda S; Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
Nishi T; Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
Sunahara E; Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
Miyamoto M; Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
Cole P; Takeda Pharmaceuticals International Co, Cambridge, MA, USA.
Barret O; Invicro, LLC, New Haven, CT, USA.
Alagille D; Invicro, LLC, New Haven, CT, USA.
Papin C; Invicro, LLC, New Haven, CT, USA.
Morley T; Invicro, LLC, New Haven, CT, USA.
Fowles K; Yale PET Center, New Haven, CT, USA.
Seibyl J; Invicro, LLC, New Haven, CT, USA.
Tamagnan G; Invicro, LLC, New Haven, CT, USA.; Yale PET Center, New Haven, CT, USA.
Kuroita T; Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
Źródło:
European journal of nuclear medicine and molecular imaging [Eur J Nucl Med Mol Imaging] 2022 Mar; Vol. 49 (4), pp. 1148-1156. Date of Electronic Publication: 2021 Oct 15.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: Berlin : Springer-Verlag Berlin, 2002-
MeSH Terms:
Piperidines*
Positron-Emission Tomography*/methods
Animals ; Brain/diagnostic imaging ; Brain/metabolism ; Cholesterol 24-Hydroxylase/metabolism ; Humans ; Macaca mulatta/metabolism ; Mice ; Pyridines
References:
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Kolsch H, Lutjohann D, Ludwig M, et al. Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer’s disease. Mol Psychiatry. 2002;7:899–902. (PMID: 10.1038/sj.mp.4001109)
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Schonknecht P, Lutjohann D, Pantel J, et al. Cerebrospinal fluid 24S-hydroxycholesterol is increased in patients with Alzheimer’s disease compared to healthy controls. Neurosci Lett. 2002;324:83–5. (PMID: 10.1016/S0304-3940(02)00164-7)
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Nury T, Zarrouk A, Mackrill JJ, et al. Induction of oxiapoptophagy on 158N murine oligodendrocytes treated by 7-ketocholesterol-, 7β-hydroxycholesterol-, or 24(S)-hydroxycholesterol: protective effects of alpha-tocopherol and docosahexaenoic acid (DHA; C22:6 n-3). Steroids. 2015;99:194–203. (PMID: 10.1016/j.steroids.2015.02.003)
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Nishi T, Kondo S, Miyamoto M, et al. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice. Sci Rep. 2020;10:17081. (PMID: 10.1038/s41598-020-74036-6)
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Contributed Indexing:
Keywords: CH24H; Cholesterol 24-hydroxylase; PET; Soticlestat; [18F]
Substance Nomenclature:
0 (Piperidines)
0 (Pyridines)
1766MU795L (soticlestat)
EC 1.14.14.25 (Cholesterol 24-Hydroxylase)
Entry Date(s):
Date Created: 20211015 Date Completed: 20220426 Latest Revision: 20220428
Update Code:
20240104
PubMed Central ID:
PMC8921165
DOI:
10.1007/s00259-021-05565-z
PMID:
34651220
Czasopismo naukowe
Purpose: Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that plays a major role in brain cholesterol homeostasis by converting cholesterol into 24S-hydroxycholesterol. The selective CH24H inhibitor soticlestat (TAK-935) is being pursued as a drug for treatment of seizures in developmental and epileptic encephalopathies. Herein, we describe the successful discovery and the preclinical validation of the novel radiolabeled CH24H ligand (3-[ 18 F]fluoroazetidin-1-yl){1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl}methanone ([ 18 F]T-008) and its tritiated analog, [ 3 H]T-008.
Methods: In vitro autoradiography (ARG) studies in the CH24H wild-type (WT) and knockout (KO) mouse brain sections were conducted using [ 3 H]T-008. PET imaging was conducted in two adult rhesus macaques using [ 18 F]T-008. Each macaque received two test-retest baseline scans and a series of two blocking doses of soticlestat administered prior to [ 18 F]T-008 to determine the CH24H enzyme occupancy. PET data were analyzed with Logan graphical analysis using plasma input. A Lassen plot was applied to estimate CH24H enzyme occupancy by soticlestat.
Results: In ARG studies, binding of [ 3 H]T-008 was specific to CH24H in the mouse brain sections, which was not observed in CH24H KO or in wild-type mice after pretreatment with soticlestat. In rhesus PET studies, the rank order of [ 18 F]T-008 uptake was striatum > cortical regions > cerebellum, which was consistent with CH24H distribution in the brain. Pre-blocking with soticlestat reduced the maximum uptake and increased the washout in all brain regions in a dose-dependent manner. Calculated global occupancy values for soticlestat at a dose of 0.89 mg/kg were 97-98%, indicating maximum occupancy.
Conclusion: The preclinical in vitro and in vivo evaluation of labeled T-008 demonstrates that [ 18 F]T-008 is suitable for imaging CH24H in the brain and warrants further studies in humans.
(© 2021. The Author(s).)
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