An one-pot two-step automated synthesis of [18F]T807 injection, its biodistribution in mice and monkeys, and a preliminary study in humans.

Ya-Yao Huang,Chyng-Yann Shiue,Chia-Ling Tsai,Ruoh-Fang Yen,Cheng-Yi Cheng,Ching-Hung Chiu,Chi-Han Wu,Ming-Jang Chiu,Kai-Yuan Tzen,Kuo-Hsing Ma,Ling-Wei Hsin,Hao-Yu Hsieh,Chin-Tu Chen

doi:10.1371/journal.pone.0217384

Abstract

[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.

Highlights

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
Measurement of bacterial endotoxins was carried out using a Limulus amoebocyte lysate (LAL) test with Kinetic-QCL method (Lonza, Walkersville, MD, USA) and sterility test was performed with the proven method meeting the requirement of U.S. Pharmacopoeia (USP)
Shoup et al have developed a new method to synthesize [18F]T807 by radiofluorination of its t-Boc protected nitro- precursor with [18F]F- followed by on-line de-protection with HCl/HPLC to give [18F]T807 in 16–25% (EOB) in a synthesis time of 60 min (Fig 2) [40]

Summary

Introduction

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. 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 [15], [18F]THK5105 [16, 17], [18F]THK523 [18,19,20], [18F]THK5117 [16, 21], [18F]THK5351 ([18F]GE-216) [22], [18F] RO6958548, [11C]RO6931643, [11C]RO6924963 [23,24,25,26,27] and most recently, [18F]MK-6240 [28] and [18F]PI-2620 [29] as tau imaging agents for clinical studies of AD pathophysiology. In addition to several AD clinical studies, [18F]T807 has been applied to studies of chronic traumatic encephalopathy [35], frontotemporal dementia (FTD) [35], Parkinson’s disease [36], and primary progressive aphasia [37]

Methods

Results

Conclusion