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 (NN-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide, K(i)=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 (NN-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. [(18)FIDPA-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[(18)F]F-Kryptofix 222 with the tosyloxy precursor (4.5-5.0 mg, 8.2-9.1 mu mol) at 165 degrees C for 5 min in dimethyl sufloxide (0.6ml.) followed by (B) C18 PrepSep cartridge pre-purification and finally (C) semi-preparative high-performance liquid chromatography (HPLC) purification on a Waters X-Terra(TM) RP18. Typically, 5.6-7.4 GBq of [(18)F]DPA-714 (> 95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/mu mol within 85-90 min (HPLC purification and SepPak (R)-based formulation included), starting from a 37GBq [(18)F]fluoride batch (overall non-decay-corrected and isolated radiochemical yield: 15-20%).