Many probes, one box

To facilitate a paradigm shift in the enablement of novel PET probes for the research and clinical community, a fundamental change in their routine synthesis methods is required. Standardizing the synthesis and purification through automation serves to reduce barriers to reliable, robust, safe synthesis, as well enable the ability to rapidly disseminate protocols across multiple sites. Professor Michael van Dam has devoted the last decade of his multi-disciplinary career inventing technologies that can advance and accelerate research in cancer and other diseases. By bringing together physics, engineering, chemistry, computer science, and biotechnology, Dr. van Dam enables clinical research. Specifically, he focuses on creating tools for in vivo molecular imaging, including platforms to increase the diversity and availability of new positron emission tomography (PET) imaging probes, and platforms for molecular imaging of cells. They are also interested in advancing the technologies (e.g. microfluidics) frequently used in the lab.

One example of Dr. van Dam’s vision for PET can be seen in the ELIXYS Flex/Chem, originally invented and developed in his lab. We wanted to know more about this experience, so we met up with Dr. van Dam to discuss ELIXYS, the SOFIE Probe Network, and what is on the horizon for his research.

Melissa Moore: Tell us about the van Dam lab at UCLA’s Crump Institute of Molecular Imaging, and how the automation of radiosynthesis plays a part in your day-to-day research.

Mike van Dam: Our day-to-day research is automation of radiochemistry! We recognize the enormous value of PET in fundamental research, drug development, and medicine, and we see this value increasing as the number of different PET probes grows and enables monitoring of greater diversity of important biological processes. We also recognize the critical role that PET will play in transforming healthcare via precision medicine. To accelerate these developments, we want to put PET into the hands of more investigators. An important focus of our lab to develop novel technologies that can drive down the costs of producing PET tracers.

We also collaborate with several groups that are developing new PET probes or new basic chemistry methodologies, and automated technologies, including ELIXYS, have helped these investigators reduce radiation exposure and increase productivity.

As Director of the Crump Institute Cyclotron and Radiochemistry Technology Center, you also act as a service provider for the production of PET probes to pharma, biotech, and academia. What are some key challenges that you face in this role and how does ELIXYS help in these efforts?

One challenge we have faced is the diversity of PET probes requested by our customers. A lot of these requests have been for “established” probes that we did not have previous experience making, and thus we needed rapid and low-cost ways to establish the capability for reliably making these probes at UCLA. The ELIXYS has helped in a number of ways to streamline this process. The high degree of flexibility (3 reactors, wide temperature and pressure range) means we can typically use the reaction conditions as reported in literature, without ever running into limitations of the synthesizer that would require changes to be made. The R&D features allow us to monitor initial runs in detail to ensure that each step performs as expected in the system, and then instantly transition to routine production once adequate performance is achieved. These features have also been extremely helpful in projects to develop entirely novel tracers.

Another challenge we face is limited resources in the center. The Crump Institute radiochemistry facility is currently shared among 4 faculty research labs in addition to the probe production service, and contains only 4 hot cells and several mini cells. The ability of ELIXYS to make different tracers without any hardware reconfiguration has allowed our radiochemist to meet the diverse demands for probe production with only a single dedicated ELIXYS system (and single hot cell).

MM: You’re one of the first labs in the world to develop and produce as many probes as you have on a single radiosynthesizer in a single hot cell. Tell us about that journey.

MVD: The journey has only been possible because of the efforts of many talented students, postdocs, our radiochemist, and the contributions of colleagues at UCLA and other institutions.

It started during the development of the ELIXYS system itself. From the ground up, the ELIXYS system was designed to be extremely flexible so that it could synthesize nearly any probe. To convince the research community that we had achieved this design goal, we started by demonstrating that it was capable of synthesizing not only [18F]FDG (a straightforward probe often used to benchmark new technologies), but also probes like [18F]FAC (which required 3 reaction vessels as well as unusually high temperatures and pressures). We then developed protocols for a handful of additional well-known tracers (e.g. [18F]FLT, [18F]SFB, [18F]Fallypride) and several additional nucleoside analogs to demonstrate that tracers of varying complexity could be made without any need for system reconfiguration. At that point we were up to about 8 tracers.

Since then our efforts have been driven by our probe production service to meet the needs of various investigators. In the last year and half, we have added another 12 tracers to our list of “routine” probes, and we expect this to continue to grow. We have learned a few tricks for adapting probes onto ELIXYS, and this has helped speed our efforts when faced with the challenging of brining a new probe online.

It has really been a lot of fun for us to see how flexible the system actually is, and I’m really proud of the team that has worked so hard to get to this point!

MM: How do you see the SOFIE Probe Network enhancing your novel PET probe development?

MVD: Even though the ELIXYS synthesizer makes it very easy to adapt new synthesis protocols from the literature, it still takes effort to do this. At the very least, the newly developed ELIXYS program needs to be run a few times to assess the repeatability; in other cases, more significant optimization or changes may be needed before it is ready for routine production. It would certainly be much easier to directly download an ELIXYS program that has already been tested and optimized.

With a significant number of ELIXYS systems in use, the chances are increasing for any given probe that someone has already performed all of this work. The Sofie Probe Network will provide a very rapid and efficient tool for communicating these types of activities. We hope this is something the community will really get behind. For example, we plan to make available programs for all of the probes we have made so far so that others instantly have the capability to make all of these probes. We hope that others will do the same. We also anticipate the network will be used to share improvements and optimizations so the quality/repeatability of the protocols will be improving over time.

MM: As an inventor of ELIXYS, you have a clear understanding of its features. As a user, do you or your team have a favorite?

MVD: It’s hard to pick just one! The straightforward, drag-and-drop programming is very popular. This feature reduces the learning curve, making it easy for new lab members or collaborators to get started using the ELIXYS system for their research projects. For new probe development, the programming interface is a major time-saver, allowing us to create a bug-free program in a very short time and to be confident that it will perform the intended steps.

We also really like the features that support probe development and optimization. The ability to easily add pauses (i.e. “Prompt” unit operations) and access the contents of the reaction vessel is very beneficial when first starting to work with a new probe, or for optimization. We can remove the vial for accurate quantitation of radioactivity and sample the contents for radio-TLC or radio-HPLC analysis, providing detailed insight into each step of the synthesis. We’ll often take intermediate measurements at all stages so we can rank which steps to optimize first in terms of greatest potential for improving overall performance.

MM: What’s next for the van Dam lab?

MVD: In terms of the probe production service, we plan to continue ramping up our efforts to increase the diversity of available probes, and to increase our production throughput to serve more investigators.

In terms of our own research, we are focused on miniaturization and other strategies to further reduce the cost of PET probe synthesis. Considerable progress has been made toward an ultra-compact microfluidic synthesizer, and this technology is currently being commercialized by Sofie Biosciences. We are also exploring novel technologies, such as microscale purification and microscale quality control (QC) testing, to address remaining bottlenecks in the PET probe production process. As was the case with ELIXYS, we anticipate integrating these technologies into our probe production service to lower the cost of PET probes.

In addition, we are working with several collaborators for whom the ability to perform radiochemistry in small volumes provides fundamental advantages for advancing their research.