The Past, Present and Future of Molecular Imaging @ Martinos

Gary Boas

Over the past several months, the MGH Martinos Center has been both celebrating the past and looking toward the future of its molecular imaging effort – with a symposium held last fall and now a series of initiatives designed to bolster the molecular imaging community.

While there has always been a molecular imaging effort at the Center, the effort kicked into high gear a little over a decade ago: in 2008, when the Center expanded into Building 75 in the Charlestown Navy Yard – across the street from its original home in Building 149. Following the work of Peter Caravan, whom the Center had hired the year before to help establish a molecular imaging program, the new space offered a large chemistry and biology wet lab footprint, and thus opened the door for researchers to pursue a wide array of molecular imaging studies.

New lab space was just one part of the equation, though. Plans for the new program also included a significant investment in new technologies and other facilities. Ciprian Catana, a pioneer in simultaneous PET-MRI, was recruited at approximately the same time as Caravan and, also in 2008, oversaw installation of a Siemens BrainPET scanner: the first commercial simultaneous PET-MRI scanner in the US. This was followed, in 2010, by the siting of a Siemens mMR whole-body simultaneous PET-MRI scanner. Jacob Hooker joined the Center a few years after Caravan and Catana and was instrumental in setting up a state-of-the-art PET radiotracer effort, including a cyclotron and radiochemistry production facility enabling the researchers to prepare PET radiotracers for human research studies.

The program continued to grow and today there are some 25 faculty at the Martinos Center who identify in some way with molecular imaging, working with some of the most advanced technology in the field to address a host of biomedical questions.

The Martinos Center’s molecular imaging researchers have a wildly productive decade

Molecular imaging groups in the Center have made significant strides over the past ten years, on a number of fronts. The Caravan Lab, for example, has successfully developed MRI and PET probes for the imaging of fibrosis, and reported a non-gadolinium MRI contrast agent to sidestep the possibility of safety issues with gadolinium-based probes. The Hooker Lab, meanwhile, discovered and introduced a PET tracer called Martinostat that enables, for the first time, imaging of epigenetic changes in the body. The tracer is now widely used by research groups around the world for clinical studies of diseases including cancer, schizophrenia and Alzheimer’s disease.

Zdravka Medarova and colleagues have explored use of nanoparticles as a “theranostics” platform for a range of cancer models, demonstrating that delivery of the nanoparticles can shrink primary tumors and prevent metastasis. Also, Chongzhao Ran’s group has successfully introduced a number of near-infrared fluorescence (NIRF) imaging probes for in vivo detection of amyloid beta in models of Alzheimer’s disease. More recently, they have shown that they can detect amyloid beta species in the eyes, pointing up the possibility of fast, inexpensive screening of Alzheimer’s patients in the future.

Several cutting-edge optical technologies have helped to advance molecular imaging investigations in the Center. Anand Kumar’s group has been developing new tools for in vivo optical molecular imaging: enabling imaging of a host of disease models using time-domain technology and exploiting fluorescence lifetime contrast to track multiple disease components simultaneously. Further, Sava Sakadžić and Abbas Yaseen have pioneered microscopy-based technologies to explore brain function and energy metabolism at the microscopic scale in living brains of preclinical disease models while Maria Angela Franceschini, Bin Deng and Stefan Carp have spearheaded the development of novel translatable technologies for measuring blood flow and oxygenation in clinical studies.

The availability of combined PET-MRI in the Center has sparked a number of innovations in molecular imaging. Christin Sander and colleagues have used combined functional imaging to demonstrate neurovascular coupling to receptor occupancy, for instance, and furthermore shown that combined dynamic evaluation of PET and fMRI signals can lead to discovery of new biomarkers – for example, for measurement of receptor internalization. Other studies by Martinos investigators have used novel PET radiotracers to study molecular pathways or targets of clinical disease. Not least of these are studies of pain by Marco Loggia and of alchohol use disorder by Changning Wang.

Just down the hall, Larry Wald and his group are developing magnetic particle imaging (MPI) for neuroimaging applications. MPI is similar to MRI – it uses many of the same principles and shares many of the same technologies – but instead of measuring secondary effects of magnetic resonance relaxation times it directly detects the magnetization of nanoparticles injected into the body, providing vastly improved sensitivity over the latter technique. Perhaps a dozen other groups around the world are developing MPI technologies but Wald was the first to recognize the potential of the technique for applications in the brain.

Ongoing studies define the state of the art in molecular imaging

In October of 2018, the Center celebrated its longstanding molecular imaging program with a symposium highlighting the research its investigators are currently pursuing. For Caravan, the symposium drove home how much the molecular imaging effort had grown since he’d joined the Center some eleven years before.

“What really stood out was the breadth of work in molecular imaging at Martinos,” he says. The 15 presentations covered optical, PET, MR, magnetic particle and molecular imaging, as well as image-guided therapy, and the range of application areas was similarly diverse. “We heard talks about the use of molecular imaging in immunotherapy and other cancer applications, in Alzheimer’s and other neurodegenerative diseases, in neuropathic pain, in fundamental neuroscience, in cardiovascular disease, in chronic liver disease, and in idiopathic pulmonary fibrosis.”

The presentations also emphasized the many innovations in radiochemistry – in molecular probe development, in hardware, and in image analysis and data modeling techniques – to have come out of the Center over the past decade. “Did you know that four novel PET tracers have been invented and had first-in-human studies performed at the Martinos Center?” Caravan continues. “I expect there will be three more by the end of 2019.”

Also in 2019, Martinos Center investigators continue to guide the field of molecular imaging through a variety of leadership positions. Sander is the Program Committee Co-Chair of this year’s World Molecular Imaging Congress, for example, while Caravan was recently elected to the Board of the World Molecular Imaging Society.

New initiatives bring together the Center’s molecular imaging community

In the past year, Caravan and a committee including researchers Christin Sander, Abbas Yaseen, David Izquierdo and Chongzhao Ran have been developing ways to consolidate and strengthen the molecular imaging community in the Center – while also emphasizing to the external research community that the Center has a core strength in molecular imaging, with a broad and diverse set of modalities and applications.

The committee has been especially busy in recent months. February saw the launch of the “Innovations in Molecular Imaging” seminar series, with invited speakers whose work spans a wide range of imaging modalities and imaging probes, with applications from basic science to clinical applications. In March, the researchers introduced a regular “Molecular Lunches” open lab meeting: a platform for internal research presentations and discussion and a forum for Martinos faculty and trainees to meet and socialize.

Facilitating such interactions between the researchers will help in establishing more of a sense of community among them. “The Martinos Center has always had a large community in molecular imaging,” Sander says. “But partly because the molecular imaging space is so diverse – including many imaging modalities, probe design and a variety of applications – we don’t always all cross paths naturally, even though there are a lot of common approaches and interests. We hope that bringing together all innovators in molecular imaging at the Martinos will help enable collaborations, share resources and instrumentation, and exchange knowledge and ideas that broaden everyone’s research area – especially for young investigators and trainees.”