Optimization of automated radiosynthesis of [18F]AV-45: a new PET imaging agent for Alzheimer's disease

Accumulation of β-amyloid (Aβ) aggregates in the brain is linked to the pathogenesis of Alzheimer's disease (AD). Imaging probes targeting these Aβ aggregates in the brain may provide a useful tool to facilitate the diagnosis of AD. Recently, [(18)F]AV-45 ([(18)F]5) demonstrated high binding to the Aβ aggregates in AD patients. To improve the availability of this agent for widespread clinical application, a rapid, fully automated, high-yield, cGMP-compliant radiosynthesis was necessary for production of this probe. We report herein an optimal [(18)F]fluorination, de-protection condition and fully automated radiosynthesis of [(18)F]AV-45 ([(18)F]5) on a radiosynthesis module (BNU F-A2).The preparation of [(18)F]AV-45 ([(18)F]5) was evaluated under different conditions, specifically by employing different precursors (-OTs and -Br as the leaving group), reagents (K222/K(2)CO(3) vs. tributylammonium bicarbonate) and deprotection in different acids. With optimized conditions from these experiments, the automated synthesis of [(18)F]AV-45 ([(18)F]5) was accomplished by using a computer-programmed, standard operating procedure, and was purified on an on-line solid-phase cartridge (Oasis HLB).The optimized reaction conditions were successfully implemented to an automated nucleophilic fluorination module. The radiochemical purity of [(18)F]AV-45 ([(18)F]5) was >95%, and the automated synthesis yield was 33.6 ± 5.2% (no decay corrected, n=4), 50.1 ± 7.9% (decay corrected) in 50 min at a quantity level of 10-100 mCi (370-3700 MBq). Autoradiography studies of [(18)F]AV-45 ([(18)F]5) using postmortem AD brain and Tg mouse brain sections in the presence of different concentration of "cold" AV-136 showed a relatively low inhibition of in vitro binding of [(18)F]AV-45 ([(18)F]5) to the Aβ plaques (IC50=1-4 μM, a concentration several order of magnitude higher than the expected pseudo carrier concentration in the brain).Solid-phase extraction purification and improved labeling conditions were successfully implemented into an automated synthesis module, which is more convenient, highly efficient and simpler in operation than using a semipreparative high-performance liquid chromatography method. This new, automated procedure for preparation of [(18)F]AV-45 ([(18)F]5) is suitable for routine clinical application.