Browse by Medical Category
Research at Mass General
Our diverse group of scientists from backgrounds including chemistry, biochemistry and medical physics (among others), develops and applies tools to image molecules within the living human brain using Positron Emission Tomography (PET).
While Magnetic Resonance (MR) images reveal the anatomical/structural data about the body, PET employs radiolabeled chemical ligands to visualize the density and localization of specific molecules within the body. PET neuroimaging provides insight into the neurochemistry of the healthy brain, enables investigation of when and where molecules are dysregulated in brain diseases, and can be used to develop therapeutic treatments.
In collaboration with other groups at the Martinos Center, clinicians from Massachusetts General Hospital (e.g. neurology and psychiatry) and academic centers worldwide, we examine molecular changes in the living brain throughout the course of disease so that we can better understand underlying disease mechanisms and develop novel therapeutic approaches. We are currently running several clinical studies to investigate the role of neuroinflammation and epigenetic enzymes in both neurodegenerative and psychiatric diseases.
Additional projects are focused on developing new methods and tools to enable imaging of novel molecular targets that will advance our ability to translate basic research towards the treatment of human illness.
Jacob Hooker, PhDAssociate ProfessorPhyllis and Jerome Lyle Rappaport MGH Research Scholar
Michael Placzek, PhDInstructor
Neuroinflammation is implicated in the pathology of many neurological disorders. Using the latest technology in simultaneous PET-MR imaging, our team is characterizing the relationship between neuroinflammation (measured by PET) and brain function/structure (measured by MR) in amytrophic lateral sclerosis (ALS), multiple sclerosis (MS), autism spectrum disorder (ASD) and Huntington's disease, among others.
a.) TSPO: One of the major PET imaging targets under investigation by our group is Translocator Protein (TSPO), which is imaged with the radioligand [11C]PBR28. TSPO is over-expressed in reactive astrocytes and microglia, the major immune cells of the central nervous system, and is widely considered a biomarker for “neuroinflammation”. In collaboration with other MGH researchers we are currently using[11C]PBR28 PET imaging to investigate reactive glia in the following clinical studies:
•Dr. Nazem Atassi (Mass General): simultaneous PET-MR to investigate TSPO expression as well as cortical thickness and white matter integrity in ALS. Thus far, we have observed increased TSPO in individuals with ALS in motor regions, which correlated with cortical thinning and decreased white matter integrity.
•Dr. Christopher McDougle (Lurie Center for Autism at Mass General): simultaneous PET-MR to investigate TSPO expression in individuals with ASD. Our goal is to better understand neuroinflammation in neurological illness to drive interventional treatment.
b.) Novel neuroinflammation targets: Our current clinical studies imaging TSPO have yielded data demonstrating unique brain expression patterns associated with neurodegenerative and psychiatric diseases, however, these results do not provide insight into what causes the inflammation or indicate the cell type that is dysregulated.
We are currently working to identify novel PET tracer targets that will enable specific characterization of microglial phenotypes to visualize dysfunction early in disease, before irreparable damage occurs.
Thus far, we have identified two novel targets for visualizing both microglial homeostasis and activation. In addition, we have designed and synthesized lead molecules for these targets and are working to optimize radiolabeling and preclinical evaluation with PET. Our hope is that these new radiotracers will enable mechanistic exploration of microglial activation as it progresses in the living brain during various stages of disease.
Each cell in our body contains the same sequence of DNA, but gene expression can be turned on and off to allow each cell to appear and function uniquely. Histone deacetylases (HDAC)s are a family of gene regulatory proteins, aka. epigenetic enzymes, that control if and when a gene is expressed. Abnormal HDAC activity is associated with multiple pathologies including cancer, cardiovascular disease, as well as neurodegenerative and psychiatric disorders.
To better understand the role HDACs play in health and disease, our lab developed the first PET radioligand for imaging HDAC density in living humans, [11C]Martinostat. We are currently applying [11C]Martinostat PET to investigate the role of HDACs in aging, Alzheimer’s disease, and schizophrenia.
Our main goal is to impact understanding and treatment of human health. Considering this pursuit, in collaboration with scientists from both academia and industry, we are actively investigating potential useful PET targets to help drive therapeutic development. Using our medicinal chemistry expertise and innovative 11C- and 18F-labeling technologies - many of them developed by our group - we can assess PET-tracer properties of molecular candidates in model systems and when promising, can set the stage for human applications.
Our most recent development is a novel histone deacetylase 6 (HDAC6) PET-radiotracer, [18F]Bavarostat. HDAC6 is an epigenetic enzyme implicated in a variety of neurological illnesses, which has attracted abundant interest from the clinical community. [18F]Bavarostat has shown great promise in pre-clinical evaluation for future human imaging studies, wherein we hope to soon investigate HDAC6 dysregulation in neurological disease.
The development of novel radiotracers for PET imaging often presents considerable obstacles, including challenges in radiochemical labeling. Radiolabeling methods need to be reliable, efficient and practical. Our lab has pushed boundaries in 18F and 11C radiolabeling methodology with respect to fundamentally new, but also practical, translatable methodology. Key examples of novel methodology we have developed with collaborators, are as follows:
•Tobias Ritter (Harvard Chemistry)- A general ruthenium-mediated deoxyfluorination. The practicality of this method allows the rapid development of new tracers, and enhances translation to human imaging through the fluorination of challenging molecules.
•Stephen Buchwald (MIT)- An expedited method for the preparation of [11C]aryl nitriles from aryl halides and/or triflates and a method for the direct [11C]CN-labeling of peptides via palladium-mediated sequential cross-coupling reactions. The latter serves as an ideal tool to access peptide radiotracers.
See Dr. Hooker's Harvard Catalyst Profile for a list of publications
Back to Top