A report of the automated radiosynthesis of the tau positron emission tomography radiopharmaceutical, [¹⁸F]-THK-5351

Abstract

The radiotracer, [ F]-THK-5351, is a highly selective and high-binding affinity PET imaging agent for aggregates of hyper-phosphorylated tau protein. Our report is a simplified 1-pot, 2-step radiosynthesis of [ F]-THK-5351. This report is broadly applicable for routine clinical production and multi-center trials on account of favorable half-life of flourine-18 and the use of a commercially available radiosynthesis module, the GE TRACERlab™ FX . First, the O-THP protected tosyl precursor underwent nucleophilic fluorinating reaction with potassium cryptand fluoride ([ F] fluoride (K[ F]/K )) in Dimethyl sulfoxide at 110°C for 10 minutes followed by O-THP removal by using diluted hydrochloric acid (HCl) at same temperature. [ F]-THK-5351 was purified via semi-preparative high-performance liquid chromatography and formulated by using 10% EtOH, United States Pharmacopeia (USP) in 0.9% sodium chloride for injection, USP and an uncorrected radiochemical yield of 21 ± 3.5%, with a specific activity of 153.11 ± 25.9 GBq/μmol (4138 ± 700 mCi/μmol) at the end of synthesis (63 minutes; n = 3).

Characterization of the radiosynthesis and purification of [18F]THK-5351, a PET ligand for neurofibrillary tau

“…These issues could be mitigated to varying extents by further QMA conditioning (data not shown), eluting the intermediate tC18 cartridge into a smaller external vial to avoid eluted product from sticking to the sides of the vessel, and using a manual addition line for precursor to minimize residual losses. Even without these modifications, decay-corrected yields using comparable precursor masses were similar to those previously reported,(Neelamegam et al, 2017) although the total synthesis time was 20 minutes longer in the current work.…”

“…[ 18 F]THK-5351 decay-corrected radiochemical yields post-HPLC purification were 23%, 48%, and 55%, using precursor masses of 0.1, 0.2, and 0.5 mg, respectively. These data suggest that adequate [ 18 F]THK-5351 radiochemical yields can be achieved using 6–30 times less precursor mass than previously described (3.0 mg) (Harada et al, 2016a; Neelamegam et al, 2017). …”

“…The crude product is purified using a combination of solid phase extraction(s) (SPE) and high-pressure liquid chromatography (HPLC) prior to final drug formulation. Previously reported methods provide adequate radiochemical yields and molar activity, but require 3 mg of THK-5352 (Harada et al, 2016b; Neelamegam et al, 2017; Okamura et al, 2013). In this report, we show that reasonable radiochemical yields can be achieved with ≤0.5 mg of precursor.…”