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

• Published in: European journal of nuclear medicine and molecular imaging 2020-09, Vol.47 (10), p.2429-2439
• Main Authors: Arakawa, Ryosuke, Takano, Akihiro, Stenkrona, Per, Stepanov, Vladimir, Nag, Sangram, Jahan, Mahabuba, Grybäck, Per, Bolin, Martin, Chen, Laigao, Zhang, Lei, He, Ping, Villalobos, Anabella, McCarthy, Timothy J., Halldin, Christer, Varrone, Andrea
• Format: Article
• Language: English
• Subjects: Adult; Alzheimer's disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Brain; Brain - diagnostic imaging; Cardiology; Cerebellum; Computed tomography; Correlation coefficients; Cortex (cingulate); Dosimeters; Dosimetry; Fluorine isotopes; Humans; Imaging; Male; Medical imaging; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Neurodegenerative diseases; Neuroimaging; Neurology; Nuclear Medicine; Oncology; Original; Original Article; Orthopedics; Pancreas; Positron emission; Positron emission tomography; Positron Emission Tomography Computed Tomography; Primates; Radiation dosage; Radioisotopes; Radiology; Radiometry; Radiopharmaceuticals; Reliability analysis; Reproducibility of Results; Secretase; Tissue Distribution; Tomography; Tomography, X-Ray Computed; β-Site APP-cleaving enzyme 1
• ISSN: 1619-7070; 1619-7089; 1619-7089
• DOI: 10.1007/s00259-020-04739-5

Purpose Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer’s disease. [ 18 F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [ 18 F]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 [ 18 F]PF-06684511 in healthy volunteers. Methods Five 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 ( V T ) 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 V T were calculated as reliability measures. Results In 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. V T (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 V T (2TCM) were 16.5% (12.4–20.5%) and 0.496 (0.291–0.644). Conclusion The ED of [ 18 F]PF-06684511 was similar to other 18 F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of V T was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [ 18 F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. Trial registration EudraCT 2016-001110-19 (registered 2016-08-08)