We are interested if certain proteins (aggregates)/ receptors/enzymes are dysregulated in the brains of certain psychiatric and neurodegenerative disease populations. We create novel radiotracers to look within the living human brain and to treat specific conditions and develop novel compounds for disease treatment.

Human Epigenetic Research

Dysfunction of histone deacetylase (HDAC) enzymes have been associated with different disorders. We aim to explore the relation between HDAC inhibitors using PET probe [¹¹C]Martinostat and clinical populations, such as Alcohol Use Disorder, Parkinson’s Disease, and Dementia with Lewy Bodies. We will take advantage of a combined PET/MRI system to collect simultaneous PET and structural MRI to obtain high-resolution special maps.

Alcohol Use Disorder

Alcohol use disorder (AUD) is a devastating illness with a profound health impact. In the past decade, research on epigenetics has revealed that AUD may have a strong connection with dysfunction of chromatin-modifying enzymes, and among them, histone deacetylases (HDACs) are frequently implicated. HDACs hold a great potential as therapeutic targets and the investigation on HDAC expression changes in the development of AUD will directly advance understanding of the importance of epigenetic roles in the neurobiology of AUD. We are currently using the PET imaging probe [¹¹C]Martinostat to explore this.

In our pilot study,  we use a machine learning approach to identify and validate non-invasively in vivo human brain histone deacetylase (HDAC) PET neuroimaging biomarkers using [¹¹C]Martinostat radiotracer for differentiating case-control cases in the context of precision medicine.

Parkinson’s Disease

• Parkinson’s Disease (PD) is a devastating illness with a profound health impact. In the past decade, research on epigenetics has revealed that PD may have a strong connection with dysfunction of chromatin-modifying enzymes, and among them, histone deacetylases (HDACs) are frequently implicated. HDACs hold a great potential as therapeutic targets and the investigation on HDAC expression changes in the development of PD will directly advance understanding of the importance of epigenetic roles in the neurobiology of PD. We are currently using the PET imaging probe [¹¹C]Martinostat to explore this.

Dementia with Lewy Bodies

• Dementia with Lewy Bodies (DLB) is a devastating illness with a profound health impact. In the past decade, research on epigenetics has revealed that DLB may have a strong connection with dysfunction of chromatin-modifying enzymes, and among them, histone deacetylases (HDACs) are frequently implicated. HDACs hold a great potential as therapeutic targets and the investigation on HDAC expression changes in the development of DLB will directly advance understanding of the importance of epigenetic roles in the neurobiology of DLB. We are currently using the PET imaging probe [¹¹C]Martinostat to explore this.

Novel PET imaging probes

Protein aggregates

Protein misfolding and aggregation occur frequently within cells that have evolved a range of mechanisms to ensure proper folding and eliminate aggregated or otherwise damaged proteins. A common characteristic of many protein aggregation diseases, especially neurodegenerative diseases, is due to a failure of clearance of the misfolded proteins. These diseases include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), Parkinson’s disease (PD), multiple system atrophy (MSA), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). The same protein can be found in more than one disease; mixed proteinopathies are highly prevalent. Proteins within the aggregate possess altered physical properties that are responsible for their misfolding. It is more than a century since pathological protein aggregates were first identified in the brains of patients with neurodegenerative diseases. However, we still do not have effective therapies to treat or slow the progression of these devastating diseases or diagnostics for early detection and monitoring of disease progression.

To systematically address this challenge, we have assembled a unique program to develop and test molecular imaging probes of protein aggregates, including investigation in preclinical models and in patients with neurodegenerative diseases. Particularly, we have developed non-invasive molecular imaging methods, e.g., positron emission tomography (PET) radioligands, to visualize and analyze molecular targets in inaccessible tissues, e.g., the brain, thereby providing distinct advantages for clinical studies. The methods are in contrast with in vitro techniques that cannot provide molecular read-outs of intact organisms over time in natural environments. Notably, in vivo molecular PET imaging has been developed as an important tool to evaluate disease pathological processes and progression. The PET ligands for protein aggregates, including those for Aβ plaques and NFTs, are widely utilized and are becoming more routine in the clinical evaluation of AD and trials of potential drugs. These imaging results have generated “PET imaging-based phenotypic signatures”, enabling better definition of optimal patient groups as well as targets to engage in clinical trials.

In our recent study, we identified one novel small molecule-based PET probe ([¹¹C]SY08) targeting a-synuclein aggregates and we received the Study May Proceed letter for IND# 168964 from the FDA on Oct 2023 to start first-in-human imaging study (NCT06098612, Phase 0/1 trial) with this probe in late 2023 in PD, DLB, MSA patients as well as healthy controls.

γ-secretase

The pathogenesis of Alzheimer’s disease (AD) is primarily driven by brain accumulation of the amyloid-β-42 (Aβ42) peptide generated from the amyloid-β protein precursor (APP) via cleavages by β- and γ-secretase. γ-Secretase is a prime drug target for AD; however, its brain regional expression and distribution remain largely unknown. We utilized our recently developed γ-secretase modulators (GSMs) and synthesized our GSM-based imaging agent, [11C]GSM. We subsequently performed molecular imaging in rodents, including AD transgenic animals, and macaques which revealed that our probe displayed good brain uptake and selectivity, stable metabolism and appropriate kinetics and distribution for imaging γ-secretase in the brain. Interestingly, rodents and macaques shared certain brain areas with high γ-secretase expressions, suggesting a functional conservation of γ-secretase. Collectively, we have provided the first molecular brain imaging of γ-secretase, which may not only accelerate our drug discovery for AD, but also will advance the understanding of AD. The next step is to image human subjects with this PET probe.

Novel small molecule inhibitors

HDAC11 Inhibitors

Epigenetics is implicated in almost all aspects of biology – cellular differentiation, growth, development, and aging. The global epigenetic drug market size is USD 9.14 Billion in 2020 and expected to reach 36.52 billion in 2028. Over the past decade, scientists have found that key enzymes in epigenetic regulation – histone deacetylases (HDACs) – may be promising epigenetic targets for the development of new therapeutics. Altered HDAC expression in postmortem tissue has been linked to cancers and CNS diseases including pain, Alzheimer’s disease (AD), Parkinson’s disease (PD), bipolar disorder, schizophrenia, and major depressive disorder. Due to its broad application, we targeted some diseases, and one or more targets can be chosen for further evaluation.
Dementia (AD and PD): AD and PD are the primary causes of dementia in the elderly and account for between 50 and 75% of all cases. By 2030 it is estimated that more than 65 million people will be living with dementia, with projections almost doubling every 20 years. Currently, dementia is estimated to cost the US economy $290 Billion a year and $1Trillion globally, including the cost of health care and paid-for social care. Although decades of research in both industry and academia have improved the understanding of AD and PD, they have yet to yield effective therapy that can prevent, stop or reverse cognitive deficits associated with AD and PD. Existing treatments provide only temporary symptomatic relief.

Pain: More than 25 million Americans suffer from chronic pain, a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an overreliance on opioids for chronic pain despite their poor ability to improve function, which to some extent contributes to the significant and alarming epidemic of opioid overdose deaths and addictions. Other limitations for current treatments include substantial side effects, such as gastrointestinal and renal side effects, poor evidence supporting functional improvement. Therefore, there is an urgent need to identify new potential targets for pain and non-opioid therapeutics. Currently available pain therapies focus on the block of peripheral or central neurotransmission as well as altering factors underlying the maintenance of pain. Recent advances in pain research have expanded the horizon for treatment, including gene therapies, cellular therapies, and epigenetic therapies.