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Simplified radiosynthesizer programming

Introduction

In recent years, the development of automated radiosynthesizers that can produce a variety of different probes with minimal human intervention or radiation exposure has aimed to simplify routine synthesis of PET probes, especially for the clinic. As such, these synthesizers can be operated by technicians and do not require a highly trained radiochemist. Additionally, some automated systems can be configured to prepare different PET probes and thus also act as valuable tools for researchers developing new synthesis protocols for novel probes. In order to be useful to chemists, these systems must also provide an intuitive and easy-to-use software interface for the creation and modification of synthesis programs.

There are a variety of radiochemical synthesizers on the market with a range of features and capabilities. However, the software that drives these systems tends to be overly complex and requires a deep understanding of the system internals.  The programming interfaces are typically designed with the engineer rather than the radiochemist in mind, requiring lengthy programs to be created from sequences of low-level, non-intuitive hardware operations (e.g. such as switching individual valves, turning heaters or pumps on or off, etc.). In some cases, the user is even responsible for adding steps to update the graphical representation/schematic of the system.  

The complexity of developing synthesis programs is not a concern for routine production, where fixed programs are run on a regular basis, but becomes a significant hurdle for radiochemists, who frequently develop and optimize automated synthesis protocols for novel probes.

Results

Unit Operations Concept

In light of these unnecessarily complex approaches, we have created software to perform radiochemistry on our radiosynthesizer platforms with the goal of being intuitive and easy to use. To facilitate the creation and modification of programs, this software is based on high-level unit operations designed to make intuitive sense to a chemist. A small number of adjustable parameters for each of these operations provide considerable flexibility to implement diverse syntheses and optimize conditions but do not require a detailed understanding of fluidics and low-level hardware architecture. Examples of these unit operations are ‘ADD’ which adds any reagent to any reaction vessel, ‘REACT’ which performs a reaction under sealed conditions, and ‘TRANSFER’ which transfers the contents of one reaction vessel to another with an optional cartridge purification step.

ARC-P Software

This concept was originally explored in the context of the ARC-P modular radiosynthesizer. Each module contained a microcontroller that communicated via an RS-485 bus to software running on a PC. A program running on the PC performed device discovery on the bus and populated a tab-based GUI permitting access to start and stop high-level "commands" supported by each module. Each tab corresponded to a single module and was labeled by the type of module and its unique address. The user could drag the tabs into an intuitive arrangement/order. The GUI also support memorization of manual synthesis protocols in real time for editing and playback of these protocols.

These projects are available on Google Code:

ELIXYS Software

This concept was further refined and modernized in the context of the ELIXYS radiosynthesizer. The client software uses a drag-and-drop interface to further simplify the programming process and is designed to run on multi-touch tablets and phones. The server software that runs the instrument supports multiple client connections simultaneously, to allow others to watch the current synthesis run for increased transparency and oversight, and is tolerant of failures of client devices without impacting a production run in progress.

A new synthesis protocol is created in two stages: (1) the reagents that will be used in the synthesis are described, and (2) the program is built by stringing together an ordered sequence of unit operations. Unit operations are added to the program by simply dragging them from a toolbar and dropping them on a 'filmstrip' representing the protocol being created.

The software was found to dramatically reduce the number of program steps, speeding up the processes of creating and debuggin programs.

Synthesizer/Software   Tracer Operation Count 
ELIXYS [F-18]FDG  18 unit operations 
ELIXYS  D-[F-18]FAC  42 unit operations 
ELIXYS  L-[F-18]FMAU  42 unit operations 
ELIXYS  [F-18]SFB  15 unit operations 
ELIXYS  [F-18]FLT  15 unit operations 
ELIXYS  [F-18]Fallypride  12 unit operations 
Synthera  [F-18]FDG  227 program steps 
Synthera [F-18]FLT  241 program steps 
Synthera [F-18]SFB  206 program steps 
FASTlab  [F-18]FDG  335 program steps 
Explora RN [F-18]FLT 72 program steps 

Current Status and Future Directions

Development and enhancement of the ELIXYS software is still ongoing at Sofie Biosciences, Inc. Modifications are being made to support new hardware features, and new software features for tracer development and clinical production are being integrated.

Related Publications

  • H. Herman, G. Flores, K. Quinn, M. Eddings, S. Olma, M. D. Moore, H. Ding, K. P. Bobinski, M. Wang, D. Williams, D. Wiliams, C. K.-F. Shen, M. E. Phelps, and R. M. van Dam, “Plug-and-play modules for flexible radiosynthesis,” Applied Radiation and Isotopes, vol. 78, pp. 113–124, Aug. 2013.
  • M. Lazari, K. M. Quinn, S. B. Claggett, J. Collins, G. J. Shah, H. E. Herman, B. Maraglia, M. E. Phelps, M. D. Moore, and R. M. van Dam, “ELIXYS - a fully automated, three-reactor high-pressure radiosynthesizer for development and routine production of diverse PET tracers,” EJNMMI Res, vol. 3, no. 1, p. 52, Dec. 2013.
  • S. B. Claggett, K. M. Quinn, M. Lazari, M. D. Moore, and R. M. van Dam, “Simplified programming and control of automated radiosynthesizers through unit operations,” EJNMMI Research, vol. 3, no. 1, p. 53, Jul. 2013.

Team Members and Collaborators

Current:

  • Joshua Thompson (collaborator from Sofie Biosciences)
  • Alex Crane (collaborator from Sofie Biosciences)
  • Melissa Moore (visiting scientist from Sofie Biosciences)
  • Brandon Maraglia (visiting scientist from Sofie Biosciences)

Former:

  • Shane Claggett (postdoctoral scholar)
  • Henry Herman (staff engineer)
  • Kevin Quinn (staff researcher)
  • Luis Fuentes (staff software developer)
  • Gaurav Shah (postdoctoral scholar; later visiting scientist from Sofie Biosciences)
  • Mark Lazari (graduate student)