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

• Published in: Nuclear medicine and biology 2010-11, Vol.37 (8), p.917-925
• Main Authors: Liu, Yajing, Zhu, Lin, Plössl, Karl, Choi, Seok Rye, Qiao, Hongwen, Sun, Xiaotao, Li, Song, Zha, Zhihao, Kung, Hank F
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alzheimer Disease - diagnostic imaging; Alzheimer's Disease; Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Animals; Automated radiosynthesis; Automation; Autoradiography; Biological and medical sciences; Brain - diagnostic imaging; Brain imaging; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Ethylene Glycols - chemical synthesis; Ethylene Glycols - chemistry; Halogenation; Humans; Isotope Labeling; Medical sciences; Mice; Mice, Transgenic; Neurology; Organic mental disorders. Neuropsychology; Plaque, Amyloid - diagnostic imaging; Positron-Emission Tomography - methods; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Pyridines - chemical synthesis; Pyridines - chemistry; Radiochemistry; Radiochemistry - methods; Radiology; Solid-phase extraction
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2010.05.001

Abstract Introduction Accumulation of β -amyloid (A β ) aggregates in the brain is linked to the pathogenesis of Alzheimer's disease (AD). Imaging probes targeting these A β 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 A β 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). Methods 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/K2 CO3 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). Results 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 A β plaques (IC50=1–4 μM, a concentration several order of magnitude higher than the expected pseudo carrier concentration in the brain). Conclusions 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.