Head-to-head comparison of [¹⁸F]CHL2205 versus [¹⁸F]T008 as PET radioligands to study brain cholesterol homeostasis in rodent models and nonhuman primates.

Abstract

Cholesterol 24-hydroxylase (C24H) is central to brain cholesterol metabolism and is thought to be altered in many neurodegenerative diseases, including Alzheimer's disease (AD). Only two fluorinated C24H-targeting PET radioligands, [¹⁸F]CHL-2205 and [¹⁸F]T008, have recently entered clinical use. Direct comparison is needed to guide radiotracer selection for future translational studies. Dynamic PET imaging was performed using either [¹⁸F]CHL-2205 or [¹⁸F]T008 in parallel conditions in cynomolgus macaques, healthy rats, the TgF344-AD rat model, and C24H-overexpressing mice. Arterial blood sampling enabled full kinetic modeling in healthy rats and nonhuman primates. An image-derived input function was validated in rats, and the specific binding was evaluated under C24H saturation using soticlestat. [¹⁸F]CHL-2205 and [¹⁸F]T008 showed similar metabolism profiles in either macaques or rats. In macaques, brain uptake values (V_T, Logan plot analysis) were 1.6-fold higher for [¹⁸F]CHL-2205 relative to [¹⁸F]T008. Healthy rats showed a similar pattern, with [¹⁸F]CHL-2205 exhibiting 1.5-fold higher brain V_T. In rats, soticlestat blockade revealed C24H-specific binding for both ligands, with an estimated binding potential (BPND) 1.3-fold higher for [¹⁸F]CHL-2205 compared to [¹⁸F]T008. In TgF344-AD rats, brain uptake increased by 1.9-fold with [¹⁸F]CHL-2205 versus 1.6-fold with [¹⁸F]T008 compared to wild-type controls. In C24H-overexpressing mice, [¹⁸F]CHL-2205 detected measurable increases in brain signal in several brain regions (up to 1.5-fold), while [¹⁸F]T008 did not in the same animals. Across species and models, both radioligands demonstrated appropriate characteristics for imaging C24H in vivo. However, [¹⁸F]CHL-2205 generally displayed higher specific binding and appeared more sensitive to detect moderate increases in C24H expression.