Radiosynthesis and quality control testing of the tau imaging positron emission tomography tracer [¹⁸F]PM‐PBB3 for clinical applications

Abstract

Recently, we produced 11C‐labeled 2‐((1E,3E)‐4‐(6‐(methylamino)pyridin‐3‐yl)buta‐1,3‐dienyl)benzo[d]thiazol‐6‐ol ([11C]PBB3) as a clinically useful positron emission tomography (PET) tracer for in vivo imaging of tau pathologies in the human brain. To overcome the limitations (i.e., rapid in vivo metabolism and short half‐life) of [11C]PBB3, we further synthesized 18F‐labeled 1‐fluoro‐3‐((2‐((1E,3E)‐4‐(6‐(methylamino)pyridine‐3‐yl)buta‐1,3‐dien‐1‐yl)benzo[d]thiazol‐6‐yl)oxy)propan‐2‐ol ([18F]PM‐PBB3). [18F]PM‐PBB3 is also a useful tau PET tracer for imaging tau pathologies. In this study, we developed a routine radiosynthesis and quality control testing of [18F]PM‐PBB3 for clinical applications. [18F]PM‐PBB3 was synthesized by direct 18F‐fluorination of the tosylated derivative, followed by removal of the protecting group. [18F]PM‐PBB3 was obtained with sufficient radioactivity (25 ± 6.0% of the nondecay‐corrected radiochemical yield at the end of synthesis, EOS), radiochemical purity (98 ± 0.6%), and molar activity (350 ± 94 GBq/μmol at EOS; n = 53). Moreover, [18F]PM‐PBB3 consistently retained >95% of radiochemical purity for 60 min without undergoing photoisomerization using a new UV‐cutoff light (yellow light) fixed in the hot cell to monitor the synthesis. All the results of the quality control testing for the [18F]PM‐PBB3 injection complied with our in‐house quality control and quality assurance specifications. We have accomplished >200 production runs of [18F]PM‐PBB3 in our facility for various research purposes.

Automated radiosynthesis of two 18F-labeled tracers containing 3-fluoro-2-hydroxypropyl moiety, [18F]FMISO and [18F]PM-PBB3, via [18F]epifluorohydrin

“… a At the end of synthesis (EOS) b n = 8 c the average result using 18 F-fluorination in our routine radiosynthesis d n = 11 e the result using 18 F-fluorination ( n = 53) (Kawamura et al 2021 ) …”

“…The solution of [ 18 F]PM-PBB3 was passed through a Millex-GV filter to obtain [ 18 F]PM-PBB3 as an injectable solution. The preparative HPLC and formulation were performed under UV-cut light (< 500 nm wavelength cutoff, ECOHiLUX HES-YF; Iris Oyama, Sendai, Japan) to prevent the photoisomerization of [ 18 F]PM-PBB3, because [ 18 F]PM-PBB3 underwent rapid photoisomerization upon exposure to fluorescent light (Kawamura et al 2021 ).…”

“…The 18 F-3-fluoro-2-hydroxypropyl ( 18 F-FHP) moiety was used instead of the aforementioned conventional 18 F-fluoroalkyl moieties. Many PET tracers containing the 18 F-FHP moiety have been developed, some of which have been used in clinical studies, such as [ 18 F]FMISO (Bruehlmeier et al 2004 ; Eschmann et al 2005 ), [ 18 F]THK-5351 (Harada et al 2016 ; Tago et al 2016 ), [ 18 F]FC1195S (Byun et al 2017 ; Lee et al 2016 ; Yang et al 2016 ), [ 18 F]SMBT-1 (Harada et al 2021 ), and [ 18 F]PM-PBB3 (Tagai et al 2021 ; Kawamura et al 2021 ) (Fig. 1 ).…”

“…To synthesize these PET tracers, direct 18 F-fluorination of the corresponding tosylate or triflate precursor with [ 18 F]F − is a conventional method. Among these, [ 18 F]FMISO as a PET imaging agent for tumor hypoxia (Oh et al 2005 ; Tang et al 2005 ), and [ 18 F]PM-PBB3 as a PET imaging agent for tau pathology (Kawamura et al 2021 ) have been prepared by direct 18 F-fluorination using tosylate precursors and [ 18 F]F − , followed by the removal of the protecting group. The direct 18 F-fluorination was achieved within the same reaction vessel using an automated synthesizer.…”

“…The direct 18 F-fluorination was achieved within the same reaction vessel using an automated synthesizer. Moreover, the one-step radiolabeling technique for 18 F-labeled tracers could be readily transferred to other PET centers for multisite studies using the same study protocol (Kawamura et al 2016 , 2021 ; Mori et al 2017 ). In fact, automated radiosynthesis of [ 18 F]PM-PBB3 by direct 18 F-fluorination has been transferred to a dozen PET centers in Japan, China, Taiwan, and the USA (Hsu et al 2020 ; Su et al 2020 ; Weng et al 2020 ).…”