TY - JOUR T1 - Assessment of pharmacokinetic modeling strategies for quantification of tau aggregates with [<sup>18</sup>F]MK6240 in human subjects JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 50 LP - 50 VL - 60 IS - supplement 1 AU - Nicolas Guehl AU - Dustin Wooten AU - Daniel Yokell AU - Sung-Hyun Moon AU - Maeva Dhaynaut AU - Katz Samantha AU - Kirsten Moody AU - Codi Gharagouzloo AU - Aurelie Kas AU - Keith Johnson AU - Georges El Fakhri AU - Marc Normandin Y1 - 2019/05/01 UR - http://jnm.snmjournals.org/content/60/supplement_1/50.abstract N2 - 50Objectives: [18F]MK6240 was developed for PET imaging of hyperphosphorylated tau protein which is implicated in Alzheimer’s disease. The goal of the present work was to extend previous in-human investigations for the evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with [18F]MK6240. This includes a characterization of modeling methods using compartment modeling and arterial blood sampling as the reference, the assessment of graphical and simplified methods, and the evaluation of parametric imaging methods. Methods: A total of 35 subjects, consisting of 18 healthy controls (CTRL), 11 subjects with mild cognitive impairment (MCI) and 6 with Alzheimer’s Disease (AD), underwent [18F]MK6240 PET scans. Dynamic PET data were measured for up to 135 min after injection of [18F]MK6240. Arterial blood samples were collected in 16 subjects (8 CTRLs, 6 MCIs and 2 AD) to determine [18F]MK6240 time courses in whole blood and plasma as well for determination of plasma free fraction (PFF). Radiometabolite analysis was performed on a subset of plasma samples. Dynamic PET images were registered to the Montreal Neurological Institute (MNI) template space using the subjects' MRI in order to allow delineation of regions of interest for extraction of time activity curves. Various compartment models as well as the Logan and multilinear analysis (MA1) graphical methods with arterial plasma input function were tested. Simplified non-invasive reference tissue methods were investigated including Logan distribution volume ratio (DVR), multilinear reference tissue method (MRTM2) and static SUV ratio (SUVR) using the cerebellum as a reference region. The outcomes of the reference region-based methods were compared to DVR estimates obtained from compartmental modeling with arterial plasma input function. Parametric images of [18F]MK6240 DVR and SUVR were computed and off-target binding was evaluated from those images. Results: Whole-blood:plasma ratio stabilized to 0.66±0.01 after 15 minutes (range: 0.56-0.81). Percent parent in plasma (%PP) followed a single exponential (T1/2: 5.43±0.68 min). Primarily polar metabolites were observed on HPLC. At 90 minutes, %PP ranged from 0-10%. No significant differences in PFF was found between CTRL and MCI/AD groups (p=0.4251, two-sample t-test). [18F]MK6240 in gray matter peaked quickly (SUV&gt;2 at ~3 minutes). The preferred compartmental model was a reversible two-tissue compartment model (2T4k1v) with the blood contribution vincluded as a model parameter. Regional total volume of distribution (VT) in gray matter of controls ranged from 3.3-6.9 mL.cm-3and 3.8-7.1 mL.cm-3in white matter. MCI and AD subjects demonstrated a very broad dynamic range of VT,with the highest regional VT found in the precuneus of an MCI subject with a VT of 53.9 mL.cm-3. DVR outcomes obtained from simplified methods as well as SUVR70-90min and SUVR90-120minwere highly correlated with DVR estimated from the 2T4k1v model but showed a marked underestimation at DVR&gt;3. Parametric images showed comparable features across quantification methods. Conclusions: [18F]MK6240 possesses good kinetic properties for quantification of hyperphosphorylated tau and presents a wide dynamic range of uptake across subjects. More studies will be needed in subjects with high [18F]MK6240 binding (DVR&gt;3) to fully elucidate the relationship between the outcomes of simplified methods and blood-based DVR measurements. Acknowledgments: NIH R01AG046396, S10OD018035, P41EB022544, and T32EB005876 ER -