Abstract Purpose 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, ¹⁸FCHL-2205 and ¹⁸FT008, have recently entered clinical use. Direct comparison is needed to guide radiotracer selection for future translational studies. Methods Dynamic PET imaging was performed using either ¹⁸FCHL-2205 or ¹⁸FT008 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. Results ¹⁸FCHL-2205 and ¹⁸FT008 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 ¹⁸FCHL-2205 relative to ¹⁸FT008. Healthy rats showed a similar pattern, with ¹⁸FCHL-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 ¹⁸FCHL-2205 compared to ¹⁸FT008. In TgF344-AD rats, brain uptake increased by 1.9-fold with ¹⁸FCHL-2205 versus 1.6-fold with ¹⁸FT008 compared to wild-type controls. In C24H-overexpressing mice, ¹⁸FCHL-2205 detected measurable increases in brain signal in several brain regions (up to 1.5-fold), while ¹⁸FT008 did not in the same animals. Conclusion Across species and models, both radioligands demonstrated appropriate characteristics for imaging C24H in vivo. However, ¹⁸FCHL-2205 generally displayed higher specific binding and appeared more sensitive to detect moderate increases in C24H expression.
Goutal et al. (Sat,) studied this question.