Tau PET imaging with ¹⁸F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study

Abstract

18 F-PI-2620 is a PET tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer disease (AD) and other neurodegenerative disorders. Preclinically, 18 F-PI-2620 binds to both 3-repeat and 4-repeat tau isoforms. The purpose of this firstin-humans study was to evaluate the ability of 18 F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess the safety and tolerability of this new tau PET tracer. Methods: Participants with a clinical diagnosis of probable AD and healthy controls (HCs) underwent dynamic 18 F-PI-2620 PET imaging for 180 min. 18 F-PI-2620 binding was assessed visually and quantitatively using distribution volume ratios (DVR) estimated from noninvasive tracer kinetics and SUV ratio (SUVR) measured at different time points after injection, with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC subjects, as well as DVR and SUVR correlations and effect size (Cohen's d) over time. Results: 18 F-PI-2620 showed peak brain uptake around 5 min after injection and fast washout from nontarget regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD subjects than in HCs. Very low background signal was observed in HCs. 18 F-PI-2620 administration was safe and well tolerated. SUVR time-activity curves in most regions and subjects achieved a secular equilibrium after 40 min after injection. A strong correlation (R 2. 0.93) was found between noninvasive DVR and SUVR for all imaging windows starting at more than 30 min after injection. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18 F-PI-2620 uptake in neocortical regions significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC subjects demonstrated a high image quality and excellent signal-to-noise ratio of 18 F-PI-2620 PET for imaging tau deposition in AD subjects. Noninvasive quantification using DVR and SUVR for 30-min imaging windows between 30 and 90 min after injection-for example, 45-75 min-provides robust and significant discrimination between AD and HC subjects. 18 F-PI-2620 uptake in expected regions correlates strongly with neurocognitive performance.

Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury

“…Therefore, most classification schemes, such as ATN [12], list [ 18 F]FDG-PET as a surrogate of neuronal injury together with atrophy in structural magnetic resonance imaging and total tau in cerebrospinal fluid. Our findings clearly demonstrate that dualphase [ 18 F]PI-2620-PET cannot only provide information on "T" [22] but has also the potential to facilitate assessment of "N".…”

“…Thus, we aimed to investigate the potential of the secondgeneration tau-PET ligand [ 18 F]PI-2620 [22] as an additional (in addition to detecting tau pathology) biomarker of neuronal injury. We validated early-phase [ 18 F]PI-2620 data against [ 18 F]FDG-PET and focused on optimizing dynamic or coffee break acquisition protocols for tau-PET imaging with dual biomarker information.…”

Imaging α-synuclein pathologies in animal models and patients with Parkinson’s and related diseases

“…Molecular imaging modalities, as exemplified by positron emission tomography (PET), have enabled visualization of amyloid β (Klunk et al, 2004) and tau (Maruyama et al, 2013; Chien et al, 2014; Wong et al, 2018; Betthauser et al, 2019; Mueller et al, 2019; Sanabria Bohórquez et al, 2019; Tagai et al, 2020) deposits in the brain of living patients with Alzheimer’s disease (AD) and allied disorders along with mouse models of these illnesses. A significant subset of the PET probes for these proteinopathies is a self-fluorescent β-sheet ligand and is applicable to intravital two-photon laser fluorescence microscopy of the animal models.…”

Evaluation of Imaging Windows for Tau PET Imaging Using 18F-PI2620 in Cognitively Normal Individuals, Mild Cognitive Impairment, and Alzheimer’s Disease Patients

“…5,6 Despite their intensive development for precise selective binding to tau protein deposition, these first-generation tau tracers still demonstrate the variation binding called "off-target," with the lack of selectivity for tau binding. The newly developed tau tracer, 18 F-PI-2620, binding to all types of tau deposits (3 R, 4 R, and 3R/4 R) in vitro and its effective binding (with a lower off-target binding) to tau, is considered as high potential tau binding tracer. 7,8 While drawing attention to the clinical use of 18 F-PI2620 as a second generation of tau imaging radiotracer, there are evidently quite a few optimized acquisition protocols.…”

“…The appropriate uptake-timing is defined as the most stable period of radiotracer retention in the brain. Hence, this study aimed to define the post-injection stable period for a high accuracy protocol in cognitively normal individuals, mild cognitive impairment (MCI) and AD patients, using 18 F-PI 2620.…”