Imaging at the Molecular Level

In the fall of 2018, the Martinos Center celebrated ten years of growth that saw its molecular imaging effort emerge as one of the premier molecular imaging programs in the world.

While there had always been a molecular imaging effort of some kind at the Center, it kicked into high gear 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. Also in 2008, he 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 with molecular imaging, working with some of the most advanced technology in the field to address a host of biomedical questions.

A Consequential First Decade

Molecular imaging groups in the Center have made significant strides in the years since the program got its start, 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 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 alcohol 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.

Defining the State of the Art

In October 2018, the Center celebrated its longstanding molecular imaging program with a symposium highlighting its investigators’ multifaceted research. For Caravan, the symposium drove home how much the molecular imaging effort had grown since he had 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 previous decade. “Did you know that four novel PET tracers have been invented and had first-in-human studies performed at the Martinos Center?” Caravan says. “And the innovations in molecular imaging, and their many contributions to the advancement of care, just keep coming.”