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

Recently, a novel series of 2-phenyl-pyrazolo[1,5-a]pyrimidine-acetamides 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 tosyl-oxy derivative (NN-diethyl-2- (2- (4- (2-toluene-sulfonyl-oxy-ethoxy)phenyl) -5,7-dimethyl-pyrazolo [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-methoxy-phenyl)-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 tosyl-oxy-for-fluorine nucleophilic aliphatic substitution), which has been fully automated on our Zymate-XP robotic system. It involves: (A) reaction of K[F-18]F-Kryptofix 222 with the tosyl-oxy precursor (4.5-5.0 mg, 8.2-9.1 μmol) at 165 degrees C for 5 min in dimethyl sulfoxide (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(TM) RP18. Typically, 5.6-7.4 GBq of [F-18]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 (R)-based formulation included), starting from a 37 GBq[F-18]fluoride batch (overall non-decay-corrected and isolated radiochemical yield: 15-20%). (authors)