Flexible Radiosynthesizer

Overview

We have developed several generations of flexible radiosynthesizers to address the shortcomings of commercially-available radiosynthesizers, and have commercialized these through collaboration with Sofie Biosciences, Inc.

The first-generation, known as the Automated Radiochemistry Platform (ARC-P), was based on a modular approach consisting of reactor modules, reagent delivery modules, and purification modules. This system was designed to provide improved synthesis flexibility compared to other existing radiosynthesizers. A unique robotic mechanism was used in the reactor module to move each reaction vial among different fluidic interfaces for reagent delivery, evaporation, sealed reactions, or fluid transfers (see Figure 1). In the sealed reactor position, there is no tubing or valves in contact with the liquid or vapor in the reaction vial, enabling high pressures to be sustained (corresponding to high temperatures of desired volatile solvents such as acetonitrile). Flexibility was also enhanced by permitting an arbitrary number of reaction modules to be coupled into a single system. Modules were daisy-chained together (via power and communication cables) to a power-supply and laptop computer. The computer generated a simple interface for the system, where the unit operations of each module could be manually activated. The software can be 'taught' a sequence of operations to perform an automated synthesis.

Figure 1: (a) Schematic of reaction module. The reaction vessel is contained within a heating/cooling jacket that controls its temperature. Pneumatic actuators acting in the vertical direction and a stepper motor in the horizontal direction allow the vessel to be positioned at different fluidic interfaces (labeled “1”, “2” and “3”). A flat gasket material provides a gas-tight seal at each interface. Station “1” provides one or more lines for incoming reagents as well as a nitrogen stream and vacuum to facilitate evaporations. Station “2” provides a seal only and is for pressurized reactions. Station “3” provides nitrogen supply and a dip tube for transferring reagents out of the vessel into the next reaction or purification module. (b) Corresponding photograph of the PRM. The insets at top show details of the fluidic interfaces and gaskets.

The second-generation system, known as the ARC-PHS+, sought to reduce the complexity of the system and incorporate a disposable fluid path (suitable for clinical tracer production). Each reactor of this 3-reactor system had the same reactor functionality as the ARC-P, but the fluid paths (valves and tubing) for the various functions (reagent addition, evaporation, cartridge purification, gaskets for sealed reaction, product transfer dip tube) were implemented as disposable cassettes that were installed above each reactor. These cassette also contained positions to store all of the reagents needed for the synthesis, as well as stopcock valves and cartridges to perform intermediate purification operations. Disposable cassettes eliminate the need for cleaning, and simplify setup and operation of the system, especially in production settings. In addition, a simple but unique software interface was developed based on the concept of programming a synthesis via chemist-friendly unit operations. Each of these operations ("Add Reagent", "Evaporate", "React", "Transfer via Cartridge" (with "trap" and "elute" modes), etc.) has a number of simple parameters that the operator can set to define the precise behavior. A sequence of these unit operations can be created via dragging-and-dropping from a palette of operations to create the final synthesis program. Read more about this software approach here.

An additional benefit of the robotic mechanism to move the reactor among different functional positions is a high degree of flexibility in fluid path configuration. This enables most syntheses to be implemented on ELIXYS without ANY hardware modification at all. Other systems often require reconfiguration of fluid paths to implement different probes. Because of the high chance of leaks and connection errors, typically, these systems are dedicated for a single tracers, requiring a new synthesizer for each tracer and dramatically increasing the cost of production. On the flexible system, numerous probes can be made without any modification, enabling a single system to handle the production of many tracers.

The third- and subsequent generations of this system, known as ELIXYS, involved further refinements of the hardware and software to reduce cost, improve reliability and serviceability, and increase functionality of software (Figure 2). Automated programs have been developed to produce the following PET probes reliably on the ELIXYS. Additional analogs of FAC and several proprietary compounds have been successfully produced as well. An ELIXYS system is currently being used in the Crump Cyclotron and Radiochemistry Center for production and development of wide range of PET tracers.

The ELIXYS system has many features that address issues that arise in other radiosynthesizers:

Simplified fluid path. The robotic mechanism has far fewer fluidic connections than most systems, reducing the risk of connection failures.
Disposable fluid path. No cleaning is required, simplifying the validation and production processes.
No need for reconfiguration. Numerous probes can be synthesized with zero custom modifications / reconfiguration of the system.
Intuitive software and programming. The unit operation programming paradigm results in vastly shorter programs, and much quicker programming times. More details of the software can be found on our Radiochemistry Software project page.
3 reactors. Other systems are limited to probes that can be made with 1 or 2 reactors.
High temperature and pressure capability. Pressures up to 200 psi can be sustained, enabling reactions in volatile solvents at much higher temperatures than in other systems. This simplifies the process of translating protocols from manual to automated processing, and enables MeCN to be used in place of DMSO in many cases.
Multiple runs per day. We have demonstrated that 3 probes can be made back-to-back on the system

Figure 2: (A) 3D rendering of the ELIXYS synthesizer showing the main components: three reactors, three disposable cassettes, and a reagent vial and gas-handling robot that serves all three reactors. (B) Annotated photographs of the top and bottom of the disposable cassettes. The top of the cassette contains locations for storage of sealed reagent vials as well as interface points to deliver gas pressure to drive fluids through the system. The bottom of the cassette contains a gasket against which the reaction vessel can be sealed in several positions, and also contains stopcock valves for manipulating the fluid pathway.

Current Status and Future Directions

Currently, several systems are being used at UCLA for production of PET tracers for preclinical and clinical imaging. In addition, they support research projects of several members of the Crump Institute for Molecular Imaging.

Current efforts are aimed at the development of reliable, automated protocols for additional tracers, exploring reactions at high temperatures, as well as increasing the flexibility and automation of purification and formulation. Ongoing collaboration with Sofie Biosciences has culminated in the development of a dedicated purification/formulation module (ELIXYS PURE/FORM). This module provides fully-automated purification and formulation functionality that is integrated into the main ELIXYS software.

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.
M. Lazari, J. Collins, B. Shen, M. Farhoud, D. Yeh, B. Maraglia, F. T. Chin, D. A. Nathanson, M. Moore, and R. M. van Dam, “Fully Automated Production of Diverse 18F-Labeled PET Tracers on the ELIXYS Multireactor Radiosynthesizer Without Hardware Modification,” J. Nucl. Med. Technol., vol. 42, no. 3, pp. 203–210, Sep. 2014.
Mark Lazari, Serge K. Lyashchenko, Eva M. Burnazi, Jason S. Lewis, R. Michael van Dam, Jennifer M. Murphy. Fully-automated synthesis of Fully-automated synthesis of 16β-18F-fluoro-5α-dihydrotestosterone (FDHT) on the ELIXYS radiosynthesizer. Applied Radiation and Isotopes 103: 9 – 14, 2015.

Team Members and Collaborators

Current:

Jeffrey Collins (staff radiochemist)

Former:

Alex Hsiao (Sofie, Inc.)
Eric Schopf (Sofie, Inc.)
Ruben Guzman (Sofie, Inc.)
Aaoron Funk (Sofie, Inc.)
Melissa Moore (Sofie, Inc.)
Brandon Maraglia (Sofie, Inc.)
Mark Lazari (graduate student)
Henry Herman (staff engineer)
Shane Claggett (postdoctoral scholar)
Kevin Quinn (staff researcher)
Mark Eddings (postdoctoral scholar)
Graciela Flores (collaborator from Kwang-Fu Shen Lab; later research staff)
Mingwei Wang (collaborator from Kwang-Fu Shen Lab)
Sebastian Olma (collaborator from Kwang-Fu Shen Lab)
Gaurav Shah (Sofie Biosciences, Inc.)
Dirk Williams (staff machinist)
Darin Williams (staff machinist)
Hui-Jiang Ding (staff researcher)
Prof. Satyamurthy Nagichettiar (collaborator)
Prof. Kwang-Fu Clifton Shen (collaborator)
Chiyun Xia (postdoctoral scholar)
Hong-Dun Lin (postdoctoral scholar)
Yuliang Deng (graduate exchange student)
Roland Hwang (high-school student)

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