Head-to-head comparison of tau positron emission tomography tracers [18F]flortaucipir and [18F]RO948

Abstract

Purpose: [¹⁸F]flortaucipir binds to paired helical filament tau and accurately identifies tau in Alzheimer's disease (AD). However, "off-target" binding interferes with the quantification of [¹⁸F]flortaucipir in several brain regions. Recently, other tau PET tracers have been developed. Here, we compare [¹⁸F]flortaucipir with the novel tau tracer [¹⁸F]RO948 head-to-head in vivo.

Methods: We included 18 participants with AD, three with amyloid-β-positive amnestic mild cognitive impairment, and four healthy controls. All underwent [¹⁸F]flortaucipir (80-100 min) and [¹⁸F]RO948 (70-90) PET scans within approximately 1 month. Four study participants underwent 0-100-min dynamic scanning. Standardized uptake value ratios (SUVRs) were created using an inferior cerebellar reference region.

Results: Neocortical tracer retention was highly comparable using both SUVR and distribution volume ratio-1 values obtained from dynamic scans. However, [¹⁸F]RO948 retention was significantly higher in the entorhinal cortex and lower in the basal ganglia, thalamus, and choroid plexus compared with [¹⁸F]flortaucipir. Increased off-target binding was observed with age for both tracers. Several cases exhibited strong [¹⁸F]RO948 retention in the skull/meninges. This extra-cerebral signal, however, did not affect diagnostic accuracy and remained relatively unchanged when re-examining a subsample after 1 year. Kinetic modeling showed an increase in [¹⁸F]flortaucipir SUVR over the scanning interval, compared with a plateau for [¹⁸F]RO948.

Conclusion: [¹⁸F]RO948 and [¹⁸F]flortaucipir bound comparably in neocortical regions, but [¹⁸F]RO948 showed higher retention in the medial temporal lobe and lower intracerebral "off-target" binding. Time-dependent bias of SUVR estimates may prove less of a factor with [¹⁸F]RO948, compared with previous tau ligands.

Keywords: Alzheimer’s disease; Head-to-head; Neurodegeneration; PET; Tau.

Fig. 1

Comparison of [¹⁸F]flortaucipir (FTP) and [¹⁸F]RO948 parametric BP_ND (Logan DVR-1) images (a, c) and regional SUV, SUVR, and SUVR vs DVR data (b, d) in two cases with AD dementia with high tau burden. Stage I/II, entorhinal cortex; stage III/IV, temporal/limbic cortex; stage V/VI, neocortex. CP, choroid plexus; BG, basal ganglia; FTP, Flortaucipir; ITC, inferior temporal cortex

Fig. 2

Comparison of [¹⁸F]flortaucipir (FTP) and [¹⁸F]RO948 parametric BP_ND (Logan DVR-1) images (a, c) and regional SUV, SUVR, and SUVR vs DVR data (b, d) in two cases with AD dementia with more limited tau burden. Stage I/II, entorhinal cortex; stage III/IV, temporal/limbic cortex; stage V/VI, neocortex. CP, choroid plexus; BG, basal ganglia; FTP, Flortaucipir; ITC, inferior temporal cortex

Fig. 3

Representative [¹⁸F]flortaucipir (FTP) and [¹⁸F]RO948 images for two patients with AD dementia, one patient with MCI due to AD, and one cognitively healthy individual

Fig. 4

Comparison of SUVRs of [¹⁸F]flortaucipir (FTP) and [¹⁸F]RO948 in selected cortical ROIs (a). Correlations of [¹⁸F]flortaucipir and [¹⁸F]RO948 retentions in composite ROIs corresponding to regions of Braak stages (b). Scatter plot of all FreeSurfer-derived cortical, basal ganglia, and choroid plexus ROIs for both tracers (c). Braak imaging: stage I/II, entorhinal cortex; stage III/IV, temporal/limbic cortex; stage V/VI, neocortex; I–IV, temporal meta-ROI

Fig. 5

Comparison of SUVR of [¹⁸F]flortaucipir (FTP) and [¹⁸F]RO948 in ROIs covering typical sites of [¹⁸F]flortaucipir off-target binding regions (a). Voxelwise comparison where [¹⁸F]flortaucipir exhibited higher retention than [¹⁸F]RO948 and yielded significant voxels in the striatum and the thalamus (b). Association of tracer retention in the basal ganglia with age in this study’s sample (n = 25; some data points are hidden behind other data points) (c) and in the whole BioFINDER 1 cohort ([¹⁸F]flortaucipir; n = 212) and BioFINDER 2 cohort ([¹⁸F]RO948 n = 465) (d)

Fig. 6

Quantification of [¹⁸F]RO948 and [¹⁸F]flortaucipir (FTP) uptake in an ROI covering the skull bone and the meninges (a). Comparison between [¹⁸F]RO948 retention at baseline and after 1 year (b)