PT - JOURNAL ARTICLE AU - Dean F. Wong AU - Robert A. Comley AU - Hiroto Kuwabara AU - Paul B. Rosenberg AU - Susan M. Resnick AU - Susanne Ostrowitzki AU - Cristina Vozzi AU - Frank Boess AU - Esther Oh AU - Constantine G. Lyketsos AU - Michael Honer AU - Luca Gobbi AU - Gregory Klein AU - Noble George AU - Lorena Gapasin AU - Kelly Kitzmiller AU - Josh Roberts AU - Jeff Sevigny AU - Ayon Nandi AU - James Brasic AU - Chakradhar Mishra AU - Madhav Thambisetty AU - Abhay Mogekar AU - Anil Mathur AU - Marilyn Albert AU - Robert F. Dannals ED - Borroni, Edilio ED - Hopkins, Johns TI - First in-human PET study of 3 novel tau radiopharmaceuticals: [<sup>11</sup>C]RO6924963, [<sup>11</sup>C]RO6931643, and [<sup>18</sup>F]RO6958948 AID - 10.1101/296764 DP - 2018 Jan 01 TA - bioRxiv PG - 296764 4099 - http://biorxiv.org/content/early/2018/04/23/296764.short 4100 - http://biorxiv.org/content/early/2018/04/23/296764.full AB - Background [11C]RO-963, [11C]RO-643 and [18F]RO-948 (previously referred 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 (1,2). Here we describe the first human evaluation of these novel radiotracers.Methods Amyloid PET positive Alzheimer’s disease (AD) patients and young healthy subjects (YC) each received two 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 in 11 healthy controls (HC) and 11 AD. Regions were defined on MRI, and PET data were quantified by plasma reference graphical analysis (for VT) and target cerebellum ratio (SUVR60-90). SUVR images were also analyzed voxelwise. Five older healthy subjects (OC) each received two scans with [18F]RO-948 for evaluation of test-retest variability. Four AD subjects received a repeat [18F]RO-948 scan over about 1 year. Six additional HC (3M: 3F; 41-67y) each received one whole body dosimetry scan with [18F]RO-948.Results In YC, peak SUV values were 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 that [18F]RO-948 had the highest peak SUV value, followed by [11C]RO-963, and then [11C]RO-643. Regional analysis of SUVR and VT for [11C]RO-643 and [18F]RO-948 clearly discriminated AD and HC groups. Compartmental modeling confirmed that [11C]RO-643 had lower brain entry than both [18F]RO-963 and [18F]RO-948, and [18F]RO-948 showed a better contrast between (predicted) areas of high vs low tau accumulation. Thus, our subsequent analysis focused on [18F]RO-948. Both voxelwise and region-based analysis of [18F]RO-948 binding in HC vs AD revealed multiple areas where AD and HC significantly differed. Of 22 high-binding regions, 13 showed significant group difference (following ANOVA, F=45, p&lt;10-5). Voxelwise analysis also revealed a set of symmetrical clusters where AD&gt;HC (threshold of p&lt;0.001, cluster size k&gt;50).Conclusions [18F]RO-948 demonstrates superior characteristics to [11C]RO-643 and [18F]RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of RO-948 compare favorably with existing other tau PET tracers.