Characterization of 3 Novel Tau Radiopharmaceuticals 11C-RO-963 11C-RO-643 and 18F-RO-948 in Healthy Controls and in Alzheimer Subjects

摘要

¹¹C-RO-963, ¹¹C-RO-643, and ¹⁸F-RO-948 (previously referred to as ¹¹C-RO6924963, ¹¹C-RO6931643, and ¹⁸F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. >Methods: Amyloid PET–positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of ¹¹C-RO-963, ¹¹C-RO-643, or ¹⁸F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with ¹⁸F-RO-948 for evaluation of test–retest variability. Four AD subjects underwent a repeated ¹⁸F-RO-948 scan 6–22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41–67 y) each underwent 1 whole-body dosimetry scan with ¹⁸F-RO-948. >Results: In younger controls, SUVpeak was observed in the temporal lobe with values of approximately 3.0 for ¹¹C-RO-963, 1.5 for ¹¹C-RO-643, and 3.5 for ¹⁸F-RO-948. Over all brain regions and subjects, the trend was for ¹⁸F-RO-948 to have the highest SUVpeak, followed by ¹¹C-RO-963 and then ¹¹C-RO-643. Regional analysis of SUV ratio and total distribution volume for ¹¹C-RO-643 and ¹⁸F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that ¹¹C-RO-643 had lower brain entry than either ¹¹C-RO-963 or ¹⁸F-RO-948 and that ¹⁸F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on ¹⁸F-RO-948. Both voxelwise and region-based analysis of ¹⁸F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, F(1,21) = 45, P < 10⁻⁵). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of P < 0.001, cluster size > 50). >Conclusion: ¹⁸F-RO-948 demonstrates characteristics superior to ¹¹C-RO-643 and ¹¹C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of ¹⁸F-RO-948 compare favorably with other existing tau PET tracers.