An Automated Multidose Synthesis of the Potentiometric PET Probe 4-[18F]Fluorobenzyl-Triphenylphosphonium ([18F]FBnTP)
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The aim of this study was the automated synthesis of the mitochondrial membrane potential sensor 4-[18F]fluorobenzyl-triphenylphosphonium ([18F]FBnTP) on a commercially available synthesizer in activity yields (AY) that allow for imaging of multiple patients.
A three-pot, four-step synthesis was implemented on the ELIXYS FLEX/CHEM radiosynthesizer (Sofie Biosciences) and optimized for radiochemical yield (RCY), radiochemical purity (RCP) as well as chemical purity during several production runs (n = 24). The compound was purified by solid-phase extraction (SPE) with a Sep-Pak Plus Accell CM cartridge, thereby avoiding HPLC purification.
Under optimized conditions, AY of 1.4–2.2 GBq of [18F]FBnTP were obtained from 9.4 to 12.0 GBq [18F]fluoride in 90–92 min (RCY = 28.6 ± 5.1 % with n = 3). Molar activities ranged from 80 to 99 GBq/μmol at the end of synthesis. RCP of final formulations was > 99 % at the end of synthesis and > 95 % after 8 h. With starting activities of 23.2–33.0 GBq, RCY decreased to 16.1 ± 0.4 % (n = 3). The main cause of the decline in RCY when high amounts of [18F]fluoride are used is radiolytic decomposition of [18F]FBnTP during SPE purification.
In initial attempts, the probe was synthesized with RCY < 0.6 % when starting activities up to 44.6 GBq were used. Rapid radiolysis of the intermediate 4-[18F]fluorobenzaldehyde and the final product [18F]FBnTP during purification was identified as the main cause for low yields in high-activity runs. Radiolytic decomposition was hindered by the addition of radical scavengers during synthesis, purification, and formulation, thereby improving AY and RCP. The formulated probe in injectable form was synthesized without the use of HPLC and passed all applicable quality control tests.
Key words4-[18F]Fluorobenzyl-triphenylphosphonium [18F]FBnTP Mitochondrial metabolism Positron emission tomography 4-[18F]fluorobenzaldehyde Radiolysis Antioxidants Solid-phase extraction purification
We would like to thank Dr. Michael E. Phelps for support and guidance with this study; Dr. Roger Slavik, Krzysztof Bobinski, and Daniel Yeh for providing [18F]fluoride; Dr. Jason Lee, Dr. Tove Olafsen, and Charles Zamilpa for their help with the small animal imaging; and Dr. Michael van Dam, Jeffrey Collins as well as Krzysztof Bobinski for valuable technical input.
The authors gratefully acknowledge the support from NIH through program, research, and training grants (CA186842, CA208642 and CA086306) and the support from the Department of Energy (DE-SC0012353).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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