From chemistry to imaging: U of T professor advances PET imaging tools for brain research

“The brain is really like a black box,” says Chao Zheng.

Researchers can easily study the brain’s inputs and outputs — for example, sensory stimuli and movements or actions, respectively — but what happens within the organ to convert incoming signals into the appropriate outcomes has remained mysterious.

As a scientist at the Centre for Addiction and Mental Health and an assistant professor at the University of Toronto’s Temerty Faculty of Medicine, Zheng aims to develop new tools to make those hidden processes visible. His research brings together radiochemistry, molecular imaging and neuroscience to help researchers better detect, track, understand neurological disease and, ultimately, improve how it is treated.

His method of choice is positron emission tomography (PET), an imaging technique that uses radioactive compounds called radioligands to visualize specific biological processes in the body. While magnetic resonance imaging (MRI) and CT scans mainly show structural changes, PET imaging allows clinicians and researchers to see how specific proteins and pathways are functioning, making it a powerful tool to detect and monitor disease.

“A main focus of my lab is developing new radioligands for imaging the brain,” says Zheng, who holds appointments with Temerty Medicine’s departments of psychiatry and pharmacology and toxicology and U of T’s department of chemistry.

“We want to build tools that let us see what is happening inside the brain in a much more precise way.”

Prior to joining CAMH and U of T in 2023, Zheng was an associate research scientist at the Yale School of Medicine, where he designed and developed new radioligands to measure synaptic density in the brain. Synapses are the connections between neurons through which information is received, processed and transmitted. A loss of synapses, seen as a decrease in synaptic density, has been linked to cognitive decline and disease progression in neurodegenerative conditions and other illnesses.

One of the new radioligands Zheng developed tracks a synapse-associated protein called SV2A. By imaging SV2A in the living brain, researchers can assess synaptic loss non-invasively and gain insight into how disease develops over time.

In a study published in 2025 in the Journal of Nuclear Medicine, Zheng and his collaborators showed that they could use PET imaging of the new SV2A tracer to identify synapse loss in an animal model of spinal cord injury and determine which specific regions of the brain and spinal cord saw changes in synaptic density. While the findings need to be validated in humans, Zheng says they highlight the potential of SV2A PET imaging as a non-invasive tool to evaluate spinal cord injuries and monitor recovery and treatment response.

Currently, his lab is using this approach to other neurological disorders, including Alzheimer’s disease and multiple sclerosis (MS).

In a study published recently in PNAS, Zheng and his collaborators used their SV2A radioligand to map synaptic density loss across the brain and spinal cord in a mouse model of MS. In parallel, they also performed PET imaging in patients with MS using a different clinically available SV2A radiotracer. Their findings demonstrate that SV2A PET imaging is a sensitive and measurable biomarker of synaptic loss in MS, where it has been associated with disease progression, disability and long-term neurological deficits.

Beyond developing new radioligands for brain imaging, Zheng and his team are also advancing new chemistry methods for labelling compounds with fluorine-18, the most commonly used radioisotope for PET imaging. By adding a radioactive fluorine-18 tag to a drug or molecule, researchers can target a specific protein or pathway of interest so that it becomes visible on a PET scan.

One of the biggest challenges in PET imaging is that many potentially useful tracers are hard to make using existing methods — especially when fluorine-18 is involved. Because fluorine-18 begins to decay almost immediately, chemists have only a short window to build a tracer, test it and use it for imaging.

Zheng’s lab is working on ways to turn simple chemical building blocks into valuable fluorinated molecules in fewer steps and under milder conditions. The goal is not only to make the process faster, but also to open access to compounds that have been difficult to prepare using conventional methods.

“Our goal was to develop a straightforward way to build useful fluorinated molecules from simple starting materials in a single step,” says Zheng.

In a Nature Communications study published in December 2025, Zheng and his collaborators described a new one-step reaction that makes a class of fluorinated molecules that had been particularly challenging to access for radiochemistry.

He notes that while the radioactive labeling step itself must be fast, accessing certain fluorine-18-labeled molecules often requires lengthy, multi-step synthetic routes and specially prepared precursors. By contrast, the new method simplifies the process to a one-step reaction that takes just 10 to 20 minutes.

“With our research, we can quickly synthesize a library of useful compounds and then we have the chance to test if they work or not,” says Zheng.

He hopes the new method will expand the chemical toolbox for PET radiopharmaceutical discovery by making previously hard-to-fluorinate molecules more accessible. The work is part of a broader effort in his lab to develop new chemistry that can accelerate tracer development and translation.

“When we develop a radioligand or methodology that can be translated to clinical production and used in hospitals to help patients, that makes me really happy,” says Zheng.