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The availability of tau PET radioligands enables quantitative assessment of tau density and distribution in the human brain. We evaluated the kinetics of a novel radioligand, (18)F-RO-948 (previously referred to as (18)F-RO6958948), and its ability to identify tau positivity in individual patients with mild Alzheimer disease (AD). Methods: Eleven subjects with amyloid-positive mild AD, 5 amyloid-negative older control subjects (OC), and 5 younger control subjects (YC) completed 1 or 2 (4 AD and 5 OC) PET scans with (18)F-RO-948 for 90, 120, or 200 min. The kinetics of the radioligand was evaluated with standard compartmental and noncompartmental models (with plasma data in 70% of cases), tissue-reference methods, and SUV ratio. These approaches were applied to assess the ability of (18)F-RO-948 to discriminate AD subjects from OC subjects. Results: The plasma reference graphical analysis appeared to be the optimal method of quantification for (18)F-RO-948, yielding strictly time-consistent values of distribution volume and distribution volume ratio at 90 min against the analyses at 120 and 200 min. The reference tissue graphical analysis and SUV ratio were cross-validated against plasma reference graphical analysis. Test–retest evaluation showed excellent reproducibility. A proposed novel index of tau load, the regional tau-positive fraction, showed high values in the medial and lateral temporal and parietal regions in AD and successfully separated AD subjects from OC and YC subjects with a significant margin. Conclusion: (18)F-RO-948 appears to be a promising radioligand for quantitative imaging of tau in the brain of AD patients.

(11)C-RO-963, (11)C-RO-643, and (18)F-RO-948 (previously referred to as (11)C-RO6924963, (11)C-RO6931643, and (18)F-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 (11)C-RO-963, (11)C-RO-643, or (18)F-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 (18)F-RO-948 for evaluation of test–retest variability. Four AD subjects underwent a repeated (18)F-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 (18)F-RO-948. Results: In younger controls, SUV(peak) was observed in the temporal lobe with values of approximately 3.0 for (11)C-RO-963, 1.5 for (11)C-RO-643, and 3.5 for (18)F-RO-948. Over all brain regions and subjects, the trend was for (18)F-RO-948 to have the highest SUV(peak), followed by (11)C-RO-963 and then (11)C-RO-643. Regional analysis of SUV ratio and total distribution volume for (11)C-RO-643 and (18)F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that (11)C-RO-643 had lower brain entry than either (11)C-RO-963 or (18)F-RO-948 and that (18)F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on (18)F-RO-948. Both voxelwise and region-based analysis of (18)F-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: (18)F-RO-948 demonstrates characteristics superior to (11)C-RO-643 and (11)C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of (18)F-RO-948 compare favorably with other existing tau PET tracers.

Tau aggregates and amyloid-β (Aβ) plaques are key histopathologic features in Alzheimer disease (AD) and are considered targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. This article describes the preclinical in vitro and in vivo characterization of 3 novel compounds—RO6958948, RO6931643, and RO6924963—that bind specifically to tau aggregates and have the potential to become PET tracers for future human use. Methods: RO6958948, RO6931643, and RO6924963 were identified as high-affinity competitors at the 3H-T808 binding site on native tau aggregates in human late-stage AD brain tissue. Binding of tritiated compounds to brain tissue sections of AD patients and healthy controls was analyzed by macro- and microautoradiography and by costaining of tau aggregates and Aβ plaques on the same tissue section using specific antibodies. All 3 tracer candidates were radiolabeled with a PET nuclide and tested in vivo in tau-naïve baboons to assess brain uptake, distribution, clearance, and metabolism. Results: 3H-RO6958948, 3H-RO6931643, and 3H-RO6924963 bound with high affinity and specificity to tau aggregates, clearly lacking affinity for concomitant Aβ plaques in human AD Braak V tissue sections. The specificity of all 3 radioligands for tau aggregates was supported, first, by binding patterns in AD sections comparable to the tau-specific radioligand 3H-T808; second, by very low nonspecific binding in brain tissue devoid of tau pathology, excluding significant radioligand binding to any other central nervous system target; and third, by macroscopic and microscopic colocalization and quantitative correlation of radioligand binding and tau antibody staining on the same tissue section. RO6958948, RO6931643, and RO6924963 were successfully radiolabeled with a PET nuclide at high specific activity, radiochemical purity, and yield. After intravenous administration of 18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 to baboons, PET scans indicated good brain entry, rapid washout, and a favorable metabolism pattern. Conclusion: 18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 are promising PET tracers for visualization of tau aggregates in AD. Head-to-head comparison and validation of these tracer candidates in AD patients and healthy controls will be reported in due course.