Clinical Characterization of [ 18 F]T-008, a Cholesterol 24-Hydroxylase PET Ligand: Dosimetry, Kinetic Modeling, Variability, and Soticlestat Occupancy

• Published in: Journal of Nuclear Medicine Vol. 64; no. 12; pp. 1972 - 1979
• Main Authors: Constantinescu, Cristian C., Brown, Terry, Wang, Shining, Yin, Wei, Barret, Olivier, Jennings, Danna, Tauscher, Johannes
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01.12.2023
• Subjects: Brain; Cholesterol; Cholesterol 24-Hydroxylase; Dosimeters; Dosimetry; Female; Fluorine isotopes; Humans; Ligands; Male; Modelling; Neuroimaging; Pharmacokinetics; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Radioactive tracers; Radiometry; Seizures; cholesterol 24-hydroxylase; dose occupancy; developmental and epileptic encephalopathy; PET imaging; soticlestat
• ISSN: 0161-5505; 2159-662X; 1535-5667
• DOI: 10.2967/jnumed.123.265912

This series of studies characterized [ F]T-008, a PET radiotracer for imaging cholesterol 24-hydroxylase (CH24H), in healthy volunteers (ClinicalTrials.gov identifier NCT02497235). Assessments included radiation dosimetry, kinetic modeling, test-retest variability (TRT) evaluation, and a dose occupancy evaluation using soticlestat, a selective CH24H inhibitor. Soticlestat is currently in phase 3 development for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome. In the dosimetry study, 5 participants (3 men) underwent serial whole-body scans to estimate organ-absorbed doses and effective doses of [ F]T-008 using OLINDA/EXM 1.1. For the kinetic modeling and TRT study, 6 participants (all men) underwent two 210-min dynamic [ F]T-008 PET scans with arterial blood sampling. The regional total volume of distribution was estimated using a 1-tissue-compartment model, a 2-tissue-compartment model, and Logan graphic analysis. In the dose occupancy study, 11 participants (all men) underwent 120-min scans at baseline and 2 time points (peak and trough) after receiving single oral doses of soticlestat (50-600 mg). The relationship between effect-site soticlestat concentration and brain occupancy was evaluated with a specially developed pharmacokinetic model and a saturable maximal occupancy model. The estimated mean whole-body effective dose was 0.0292 mSv/MBq (SD, 0.00147 mSv/MBq). [ F]T-008 entered the brain rapidly, with a distribution consistent with known CH24H distribution densities. The 2-tissue-compartment model and Logan graphic analysis best described the tracer kinetics. The mean TRT for estimating total volume of distribution was 7%-15%. Single doses of soticlestat in the range 50-600 mg resulted in occupancies of 64%-96% at 2 h and 11%-79% at 24 h. The estimated half-maximal effect-site concentration of soticlestat was 5.52 ng/mL. [ F]T-008 is a suitable PET radiotracer for quantitatively analyzing CH24H in the human brain. Using [ F]T-008 and PET, we demonstrated that soticlestat was brain-penetrant and established target engagement by displacing [ F]T-008 in a dose-dependent manner in the brain.