INTRODUCTION: 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). 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/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). 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 Aβ 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.
INTRODUCTION: 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 ADpatients. 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/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). 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 Aβ 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.
Authors: E D Agdeppa; V Kepe; J Liu; S Flores-Torres; N Satyamurthy; A Petric; G M Cole; G W Small; S C Huang; J R Barrio Journal: J Neurosci Date: 2001-12-15 Impact factor: 6.167
Authors: Rajesh Goswami; Datta E Ponde; Mei-Ping Kung; Catherine Hou; Mike R Kilbourn; Hank F Kung Journal: Nucl Med Biol Date: 2006-08 Impact factor: 2.408
Authors: William E Klunk; Henry Engler; Agneta Nordberg; Yanming Wang; Gunnar Blomqvist; Daniel P Holt; Mats Bergström; Irina Savitcheva; Guo-feng Huang; Sergio Estrada; Birgitta Ausén; Manik L Debnath; Julien Barletta; Julie C Price; Johan Sandell; Brian J Lopresti; Anders Wall; Pernilla Koivisto; Gunnar Antoni; Chester A Mathis; Bengt Långström Journal: Ann Neurol Date: 2004-03 Impact factor: 10.422
Authors: Chester A Mathis; Yanming Wang; Daniel P Holt; Guo-Feng Huang; Manik L Debnath; William E Klunk Journal: J Med Chem Date: 2003-06-19 Impact factor: 7.446
Authors: Kristina Herfert; Julia G Mannheim; Laura Kuebler; Sabina Marciano; Mario Amend; Christoph Parl; Hanna Napieczynska; Florian M Maier; Salvador Castaneda Vega; Bernd J Pichler Journal: Mol Imaging Biol Date: 2020-04 Impact factor: 3.488
Authors: V Camus; P Payoux; L Barré; B Desgranges; T Voisin; C Tauber; R La Joie; M Tafani; C Hommet; G Chételat; K Mondon; V de La Sayette; J P Cottier; E Beaufils; M J Ribeiro; V Gissot; E Vierron; J Vercouillie; B Vellas; F Eustache; D Guilloteau Journal: Eur J Nucl Med Mol Imaging Date: 2012-01-18 Impact factor: 9.236