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 [¹⁸F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer's disease to age-matched healthy controls.

Methods: [¹⁸F] JNJ-64326067 PET scans were acquired for 90 min and then from 120 to 180 min in 5 participants with [¹⁸F]-florbetapir PET amyloid positive probable AD (73 ± 9 years) and 5 [¹⁸F]-florbetapir PET amyloid negative healthy controls (71 ± 7 years). Whole-body [¹⁸F] 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 [¹⁸F] 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: [¹⁸F] JNJ-64326067 could be useful for detection and quantitation of tau aggregates.

Keywords: Alzheimer’s disease; Isoquinoline; PET; Tau aggregates.

Fig. 1

Individual MRI (top), 60–90 min (middle), and 120–180 min (bottom). PET SUVr images from HV Subjects 13 (a), and 10 (b), and AD subjects 6 (c) and 11 (d). Signal in the occipital cortex in subject 10 underlie the location of pellets in the skull from a shotgun accident as a youth

Fig. 2

a Representative [¹⁸F] JNJ-64326067 SUV time-activity curves HV and AD subjects. b [¹⁸F]JNJ-64326067 SUVr time-activity curves from the same HV and AD subjects. Abbreviations: medial frontal cortex (FL_Mid_L), inferior lateral temporal cortex (TL_InfLat_L), posterior cingulate (Cing_Post_L)

Fig. 3

Regional SUVr values for all AD and HV subjects: cortical (a) and subcortical and mesial regions (b). FL frontal, OL occipital, TL temporal, Cing cingulate. Box represents the interquartile range (IQR); i.e., 25th–75th percentiles. Inside the box: median (horizontal line), mean (circle). Whiskers cover the data within 1.5 IQR. Circles outside the whiskers show the observations beyond the reach of the whiskers. Results for right and left were similar; left regions only are depicted for clarity

Fig. 4

Regional DVR values for all AD and HV subjects: cortical (a) and subcortical and mesial regions (b). Abbreviations are the same as in Fig. 3. Results for right and left were similar; left regions only are depicted for clarity

Fig. 5

Correlation of [¹⁸F] JNJ-64326067 DVR using 90 min of data, SUVr averaged between 30 and 60, 60–90, and 120–180 min with DVR using 180 min of data. DVR was estimated using LGA. The ventral cerebellum reference region was used for both SUVr and DVR. These regressions were done using regional values in AD subjects 06, 11, and 14

Fig. 6

Bland–Altman plots of SUVr vs. DVR. Bland–Altman plots of SUVr vs. DVR for a 60–90 min and b 120–180 min for AD subjects 06, 11, and 14. Each point shows a pair of (SUVr, DVR) measures taken in the same subject × region. The x-coordinate is the average of (SUVr, DVR), and the y-coordinate is the difference (SUVr-DVR). The black horizontal line through y = 0: reference where SUVr = DVR. Above this line SUVr>DVR, and vice versa. The red horizontal line represents the trough of the mean of all difference observations. The red dotted lines indicate the 95% threshold for the differences (i.e., mean ± 2SD)