Clinical evaluation of [18F] JNJ-64326067, a novel candidate PET tracer for the detection of tau pathology in Alzheimer’s disease

Abstract

Purpose The accumulation of misfolded tau is a common feature of several neurodegenerative disorders, with Alzheimer’s disease (AD) being the most common. Earlier we identified JNJ-64326067, a novel isoquinoline derivative with high affinity and selectivity for tau aggregates from human AD brain. We report the dosimetry of [ 18 F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer’s disease to age-matched healthy controls. Methods [ 18 F] JNJ-64326067 PET scans were acquired for 90 min and then from 120 to 180 min in 5 participants with [ 18 F]-florbetapir PET amyloid positive probable AD (73 ± 9 years) and 5 [ 18 F]-florbetapir PET amyloid negative healthy controls (71 ± 7 years). Whole-body [ 18 F] JNJ-64326067 PET CT scans were acquired in six healthy subjects for 5.5 h in 3 scanning sessions. Brain PET scans were visually reviewed. Regional quantification included kinetic analysis of distribution volume ration (DVR) estimated by Logan graphical analysis over the entire scan and static analysis of SUVr in late frames. Both methods used ventral cerebellar cortex as a reference region. Results One of the healthy controls had focal areas of PET signal in occipital and parietal cortex underlying the site of a gunshot injury as an adolescent; the other four healthy subjects had no tau brain signal. Four of the 5 AD participants had visually apparent retention of [ 18 F] JNJ-64326067 in relevant cortical regions. One of the AD subjects was visually negative. Cortical signal in visually positive subjects approached steady state by 120 min. Temporal and frontal cortical SUVr/DVR values in visually positive AD subjects ranged from 1.21 to 3.09/1.2 to 2.18 and from 0.92 to 1.28/0.91 to 1.16 in healthy controls. Whole-body effective dose was estimated to be 0.0257 mSv/MBq for females and 0.0254 mSv/MBq for males. Conclusions [ 18 F] JNJ-64326067 could be useful for detection and quantitation of tau aggregates. Electronic supplementary material The online version of this article (10.1007/s00259-020-04880-1) contains supplementary material, which is available to authorized users.

Evaluation of [18F]-JNJ-64326067-AAA tau PET tracer in humans

“…[ 18 F]-JNJ-067 is a new tau PET tracer with a demonstrated ability to differentiate between AD and HC participants. 47 The goal of this study was to evaluate the performance of [ 18 F]-JNJ-067 using a more diverse cohort of HC, MCI, AD, and PSP participants, and to explore different approaches to quantitation of data. Although there are a handful of tau tracers currently in use, researchers are still searching for an ideal tau tracer that fulfills all of the following: binds to its target with a high dynamic range; has no or minimal offtarget signal; reaches a steady state within a half-life; and has a high test-retest reliability.…”

“…The initial study of [ 18 F]-JNJ-067 showed this tracer has a high affinity for aggregated tau (K i ¼ 2.4 nM), low offtarget binding to amyloid and MAO enzymes shown using autoradiography in human brain tissue, and favorable kinetics in mice and monkeys. 46 Subsequently a study by Schmidt et al 47 evaluated [ 18 F]-JNJ-067 PET data collected for three hours from 5 HC and 5 AD subjects. In that study, 1.5 hours of data acquisition produced distribution volume ratios that were highly correlated with DVRs obtained in 3 hours of scanning (r 2 ¼.99), with large effect sizes in distinguishing AD participants from controls.…”

PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research

“…Designers of these new generation tracers are focusing on improving in vivo characteristics such as higher selectivity, faster brain penetration/washout, and less off-target binding. Preliminary studies for these newer tracers have shown promising results (Declercq et al, 2017 ; Kuwabara et al, 2018 ; Guehl et al, 2019 ; Rombouts et al, 2019 ; Teng et al, 2019 ; Schmidt et al, 2020 ).…”

Single and Combined Neuroimaging Techniques for Alzheimer’s Disease Detection

“…Observation of fMRI techniques will help detect dementia and change in neuron connections, determining the change in brain function. On the other hand, the level of amyloid deposition in certain parts of the brain, which can be seen by amyloid PET biomarker, will help to survey AD severity for patients [5]. However, especially in cases of dementia diagnosis, mentioned biomarkers could not help accurately identify or predict cognitive deterioration due to individual threshold differences in each subject [6].…”