Low Uptake of [18F]Flutemetamol in the Mouse Brain Prevents Non-invasive Quantification of Myelin

Abstract

Direct in vivo imaging of myelin would greatly benefit research on demyelinating diseases such as multiple sclerosis but remains technically challenging. This study evaluated whether the amyloid-β radiotracer [18F]Flutemetamol is suitable for PET/CT imaging of myelin in the murine cuprizone model of demyelination. Male C57BL/6 mice were fed 0.3% cuprizone for five weeks (n = 5) or control chow (n = 5) and subsequently underwent a 90 min dynamic [18F]Flutemetamol PET/CT scan with a retest scan two days later. PET data were analyzed using region-of-interest-based quantification with an image-derived input function; volume of distribution (VT) was estimated by Logan graphical analysis, and percentage injected dose per milliliter (% ID/mL) was calculated as a simplified uptake measure. Demyelination was independently validated by MRI and histology. Cuprizone treatment induced significant body weight loss and robust region-specific demyelination of the corpus callosum, confirmed by reduced myelin marker expression, increased astroglial and microglial activation, and corresponding MRI changes. In contrast, in vivo [18F]Flutemetamol PET showed rapid radiotracer washout, low brain retention, and high variability. Estimated VT values were very low and did not differ between control and cuprizone-treated mice. Similarly, % ID/mL failed to detect group differences in any analyzed brain region and showed high test−retest variability. Despite histologically confirmed demyelination and corresponding T2-weighted MRI signal alterations, [18F]Flutemetamol PET/CT did not provide sufficient sensitivity or quantitative robustness to detect myelin loss in vivo. This negative finding might reflect a combination of tracer-related and methodological limitations, including limited spatial resolution and uncertainties in quantitative modeling, and therefore does not allow a definitive conclusion regarding the intrinsic suitability of [18F]Flutemetamol for preclinical myelin imaging.