Radiosynthesis of [18F]DPA‐714, a selective radioligand for imaging the translocator protein (18 kDa) with PET

Recently, a novel series of 2‐phenylpyrazolo[1,5‐a]pyrimidineacetamides has been reported as selective ligands of the translocator protein (18 kDa). Within this series, DPA‐714 (N,N‐diethyl‐2‐(2‐(4‐(2‐fluoroethoxy)phenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide, Ki=7.0 nM) is a compound, which had been designed with a fluorine atom in its structure, allowing labelling with fluorine‐18 (half‐life: 109.8 min) and in vivo imaging using positron emission tomography. DPA‐714 and its tosyloxy derivative (N,N‐diethyl‐2‐(2‐(4‐(2‐toluenesulfonyloxyethoxy)phenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide) as precursor for the labelling with fluorine‐18 were synthesized in two steps from DPA‐713 (N,N‐diethyl‐2‐(2‐(4‐methoxyphenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide) and obtained in 32 and 42% yields, respectively. [18F]DPA‐714 was synthesized using a simple one‐step process (a tosyloxy‐for‐fluorine nucleophilic aliphatic substitution), which has been fully automated on our Zymate‐XP robotic system. It involves: (A) reaction of K[18F]F‐Kryptofix®222 with the tosyloxy precursor (4.5–5.0 mg, 8.2–9.1 µmol) at 165°C for 5 min in dimethyl sufloxide (0.6 mL) followed by (B) C18 PrepSep cartridge pre‐purification and finally (C) semi‐preparative high‐performance liquid chromatography (HPLC) purification on a Waters X‐Terra™ RP18. Typically, 5.6–7.4 GBq of [18F]DPA‐714 (>95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and SepPak®‐based formulation included), starting from a 37 GBq [18F]fluoride batch (overall non‐decay‐corrected and isolated radiochemical yield: 15–20%).