Preclinical characterization of [18F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase
Tatsuki Koike, Cristian Constantinescu, Shuhei Ikeda, Toshiya Nishi, Eiji Sunahara, Maki Miyamoto, Patricia E. Cole, Olivier Barret, David Alagille, Caroline Papin, Thomas Morley, Krista Fowles, John Seibyl, Gilles Tamagnan, Takanobu Kuroita
Abstract
Abstract 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