PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511

Ryosuke Arakawa,Akihiro Takano,Lei Zhang,Mahabuba Jahan,Laigao Chen,Ping He,Sangram Nag,Anabella Villalobos,Martin Bolin,Vladimir Stepanov,Timothy J Mccarthy,Per Grybäck,Andrea Varrone,Per Stenkrona,Christer Halldin

doi:10.1007/s00259-020-04739-5

Abstract

PurposeBeta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer’s disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers.MethodsFive subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures.ResultsIn the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4–20.5%) and 0.496 (0.291–0.644).ConclusionThe ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain.Trial registrationEudraCT 2016-001110-19 (registered 2016-08-08)

Highlights

Beta-secretase 1 (beta-site amyloid precursor protein (APP)– cleaving enzyme 1; BACE1) enzymatic activity is implicated in the pathophysiology of brain amyloid-beta (Aβ) accumulation in Alzheimer’s disease (AD)
We found that the effective dose (ED) in humans estimated from non-human primates (NHPs) data was 43 μSv/MBq, a value that is relatively high compared with the ED of other 18F radioligands [6]
We evaluated in healthy volunteers a novel positron emission tomography (PET) radioligand for brain imaging of BACE1, [18F]PF-06684511

Summary

Introduction

Beta-secretase 1 (beta-site amyloid precursor protein (APP)– cleaving enzyme 1; BACE1) enzymatic activity is implicated in the pathophysiology of brain amyloid-beta (Aβ) accumulation in Alzheimer’s disease (AD). We showed that [18F]PF-06684511 displays suitable kinetic properties in the brain of non-human primates (NHPs) and reported a dose-dependent blocking effect on [18F]PF-06684511 brain uptake by BACE1 inhibitors [5]. These data suggested that [18F]PF-06684511 is a promising PET radioligand for brain imaging of BACE1. We found that the effective dose (ED) in humans estimated from NHP data was 43 μSv/MBq, a value that is relatively high compared with the ED of other 18F radioligands [6]. The reasons for the high stomach uptake are not known, but the experimental setting such as the usage of anesthesia and the recumbent position of the NHP for long time might have played a role

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