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

• Published in: European journal of nuclear medicine and molecular imaging Vol. 49; no. 4; pp. 1148 - 1156
• Main Authors: Koike, Tatsuki, Constantinescu, Cristian C., Ikeda, Shuhei, Nishi, Toshiya, Sunahara, Eiji, Miyamoto, Maki, Cole, Patricia, Barret, Olivier, Alagille, David, Papin, Caroline, Morley, Thomas, Fowles, Krista, Seibyl, John, Tamagnan, Gilles, Kuroita, Takanobu
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2022; Springer Nature B.V
• Subjects: Animals; Autoradiography; Brain; Brain - diagnostic imaging; Brain - metabolism; Cardiology; Cerebellum; Cholesterol; Cholesterol 24-Hydroxylase - metabolism; Enzymes; Epilepsy; Fluorine isotopes; Homeostasis; Humans; Hydroxylase; Imaging; In vitro methods and tests; In vivo methods and tests; Macaca mulatta - metabolism; Medicine; Medicine & Public Health; Mice; Neostriatum; Neuroimaging; Nuclear Medicine; Occupancy; Oncology; Original; Original Article; Orthopedics; Piperidines; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Pyridines; Radiology; Seizures; Tomography; CH24H; Soticlestat; [; Cholesterol 24-hydroxylase; F; PET; 18F
• DOI: 10.1007/s00259-021-05565-z
• ISSN: 1619-7070

Purpose Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that plays a major role in brain cholesterol homeostasis by converting cholesterol into 24 S -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. Graphical abstract