ELIXYS - a fully automated, three-reactor high-pressure radiosynthesizer for development and routine production of diverse PET tracers

Abstract

BackgroundAutomated radiosynthesizers are vital for routine production of positron-emission tomography tracers to minimize radiation exposure to operators and to ensure reproducible synthesis yields. The recent trend in the synthesizer industry towards the use of disposable kits aims to simplify setup and operation for the user, but often introduces several limitations related to temperature and chemical compatibility, thus requiring reoptimization of protocols developed on non-cassette-based systems. Radiochemists would benefit from a single hybrid system that provides tremendous flexibility for development and optimization of reaction conditions while also providing a pathway to simple, cassette-based production of diverse tracers.MethodsWe have designed, built, and tested an automated three-reactor radiosynthesizer (ELIXYS) to provide a flexible radiosynthesis platform suitable for both tracer development and routine production. The synthesizer is capable of performing high-pressure and high-temperature reactions by eliminating permanent tubing and valve connections to the reaction vessel. Each of the three movable reactors can seal against different locations on disposable cassettes to carry out different functions such as sealed reactions, evaporations, and reagent addition. A reagent and gas handling robot moves sealed reagent vials from storage locations in the cassette to addition positions and also dynamically provides vacuum and inert gas to ports on the cassette. The software integrates these automated features into chemistry unit operations (e.g., React, Evaporate, Add) to intuitively create synthesis protocols. 2-Deoxy-2-[18F]fluoro-5-methyl-β-l-arabinofuranosyluracil (l-[18F]FMAU) and 2-deoxy-2-[18F]fluoro-β-d-arabinofuranosylcytosine (d-[18F]FAC) were synthesized to validate the system.Resultsl-[18F]FMAU and d-[18F]FAC were successfully synthesized in 165 and 170 min, respectively, with decay-corrected radiochemical yields of 46% ± 1% (n = 6) and 31% ± 5% (n = 6), respectively. The yield, repeatability, and synthesis time are comparable to, or better than, other reports. d-[18F]FAC produced by ELIXYS and another manually operated apparatus exhibited similar biodistribution in wild-type mice.ConclusionThe ELIXYS automated radiosynthesizer is capable of performing radiosyntheses requiring demanding conditions: up to three reaction vessels, high temperatures, high pressures, and sensitive reagents. Such flexibility facilitates tracer development and the ability to synthesize multiple tracers on the same system without customization or replumbing. The disposable cassette approach simplifies the transition from development to production.

A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[18F]fluoro‐β‐d‐arabinofuranosyl)cytosine (18F‐FAC)

“…Our overall synthesis time (168 minutes) is similar to that reported one for 18 F-FAC. [11] Even though early 18 F-introduction gives a higher radiochemical yield, its automation is more difficult and the reliability and reproducibility is less easy to maintain. In addition, the radiochemical yield and overall radiosynthesis time of our methods might be further improvable using other synthesizers; alternatively one could obtain the same amount of labelled nucleoside product by starting with a higher 18 F-activity.…”

“…recently presented a newly designed radiosynthesis module system which furnished the nucleoside analogues 18 F-FMAU and 18 F-FAC in good overall radiochemical yields (46% and 31% respectively, decay-corrected) and with acceptable reproducibility following early stage fluoride introduction. [11] Overall synthesis times were reported to be 165-170 minutes in each case. The flexible radio-synthesizers developed are described as being suitable for both the development and production of different radiotracers for applications in PET.…”

“…Calculated electron density Ω of selected cytidine (4)(5)(6)(7)(8) and uridine derivatives (9)(10)(11) [a] Quantum chemically calculated net charge at the 2-carbonyl oxygen. …”

Fully Automated Production of Diverse 18F-Labeled PET Tracers on the ELIXYS Multireactor Radiosynthesizer Without Hardware Modification

“…To address these current challenges in automated radiosynthesis, we combined the benefits of both classes and have developed a fully-automated three-reactor radiosynthesizer (ELIXYS) that is based on a disposable-cassette design but is capable of handling high reaction temperatures and pressures ( 7 ). The unique reagent delivery and vial sealing mechanisms allow fluidic connections to be dynamically configured in software, rather than hardware, to accommodate diverse synthesis protocols without need for any custom plumbing modifications.…”

“…This allows for a single disposable cassette design to be used for developing and reliably producing a wide variety of PET tracers encompassing a broad range of reaction conditions and complexities. The system is, therefore, suitable for both novel tracer development and also supports routine production of multiple tracers on a single system ( 7 ).…”