Date Published: July 1, 2019
Publisher: Public Library of Science
Author(s): Ya-Yao Huang, Ming-Jang Chiu, Ruoh-Fang Yen, Chia-Ling Tsai, Hao-Yu Hsieh, Ching-Hung Chiu, Chi-Han Wu, Ling-Wei Hsin, Kai-Yuan Tzen, Cheng-Yi Cheng, Kuo-Hsing Ma, Chyng-Yann Shiue, Chin-Tu Chen.
[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/μmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 μSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) μSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.
Alzheimer’s disease (AD) is one of the most frequent causes of death and disability worldwide, and has a significant clinical and socio-economic impact. It is the most common form of dementia in individuals over 65 y and accounts for 50–60% of dementia cases. AD is characterized by the degeneration of neurons in the hippocampus and cortex, and the appearance of β-amyloid plaques and neurofibrillary tangles, both of which appear many years before the onset of symptoms of cognitive impairment [1–5]. Although the precise cause of AD remains unclear, it is most likely due to multiple etiologies such as neuronal apoptosis, inflammatory responses, and alterations in various receptors and enzymes. Thus, several PET imaging agents that target multiple mechanisms such as various receptors, enzymes, and β–amyloids have been developed [6, 7] for monitoring the response of AD drug therapy non-invasively and facilitating AD drugs development. Among these, β–amyloid imaging agents have improved the ascertainment of early stages of AD. Unfortunately, the levels of β–amyloid do not correlate as closely to the clinical phenotype as do tau proteins [8–10]. Thus, for the past few years, development of tau imaging agents is among the most active areas of research in molecular imaging of neurodegenerative diseases. This has led to the development of [18F]T807 ([18F]AV-1451) [11, 12], [18F]T808 ([18F]AV-680) [13, 14], [11C]PBB3 , [18F]THK5105 [16, 17], [18F]THK523 [18–20], [18F]THK5117 [16, 21], [18F]THK5351 ([18F]GE-216) , [18F]RO6958548, [11C]RO6931643, [11C]RO6924963 [23–27] and most recently, [18F]MK-6240  and [18F]PI-2620  as tau imaging agents for clinical studies of AD pathophysiology. Among these, [18F]T807 is the most widely used tau imaging agent in clinical studies [12, 30–34]. In addition to several AD clinical studies, [18F]T807 has also been applied to studies of chronic traumatic encephalopathy , frontotemporal dementia (FTD) , Parkinson’s disease , and primary progressive aphasia .
With this one-pot two-step synthesis of the [18F]T807 injection using a FXFN module, a GMP-compliant [18F]T807 injection can be automatically produced with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Preliminary study in an AD patient showed that [18F]T807 bound to tau protein, and clinical studies are in progress for imaging tauopathies in humans.