Radiochemistry & Pharmacokinetics
Our research at the Chemistry Section of the Yale Biomedical Imaging Institute centers on the synthesis, preclinical evaluation, and clinical translation of radiopharmaceuticals (radiotracers). These radiopharmaceuticals are then used to investigate biochemical processes and biological targets implicated in diseases, as well as mechanisms of action and target engagement by therapeutic drugs. We focus on the development of PET imaging radiopharmaceuticals important for understanding the role and significance of various neurotransmitter systems in neuropsychiatric diseases and neurodegenerative disorders.
In addition, our studies extend to oncology and cardiology. Our team has developed many unique radiotracers targeting several biological processes, proteins, receptors and transporters as below.
- Synaptic vesicle proteins (SV2A)
- Opioid receptors
- Muscarinic acetylcholine receptors
- Serotonin receptors and transporters
- Sigma-1 and sigma-2 receptors
- ROCK2
- PARP1
- PD-L1
- Chemokine receptors
One particular strength of our program is our extensive collaboration with academic laboratories and industrial partners to develop useful radiopharmaceuticals for research in psychiatry, neurology, neuroscience, immunology, pharmacology, gene therapy, and cancer therapy. We have partnered with many pharmaceutical companies to conduct receptor occupancy studies to support clinical trials of new drugs, and to use PET imaging with novel radiotracers for disease diagnosis, patient selection, and monitoring of treatment outcomes in clinical trials of novel therapeutic agents.
Brain Imaging probes
One primary objective at Yale BioImaging is to develop PET tracers to measure synapse loss in neurodegenerative diseases. We have translated clinically two SV2A PET imaging probes that are now extensively employed by leading laboratories worldwide. SV2A is being used to quantify synaptic density, an indicator closely linked to cognitive decline, in Alzheimer’s disease (AD), Parkinson’s disease (PD), and other brain diseases and disorders.
Investigator: Jason Cai
Scheme of translational research of SV2A PET imaging from rodent studies to nonhuman primate imaging study and first-in-human PET imaging studies.
We are developing PET ligands, such as [11C]PyBic, targeting enzymes like PARP1 to study their roles in neurological diseases, memory, and cognition. We pioneered brain-penetrant PARP1 PET ligands, providing a noninvasive method to quantify PARP1 expression in the brain. These tracers are expected to revolutionize brain tumor management with valuable diagnostic and prognostic insights and enable precise imaging of parthanatos in neurodegenerative diseases.
Investigator: Jason Cai
The PET image of [11C]PyBic in a tumor model of glioma; the [11C]PyBic autoradiography image, PARP1 immunohistochemistry, H&E image, and PARP1 immunofluorescent image of brain sections support the in vivo PET images.
The PET image of [11C]PyBic in a tumor model of glioma; the [11C]PyBic autoradiography image, PARP1 immunohistochemistry, H&E image, and PARP1 immunofluorescent image of brain sections support the in vivo PET images.
Investigators: Richard Carson, Henry Huang, David Matuskey
PET imaging of PD-L1
One of the primary mechanisms for tumor cells to evade immunosurveillance is through the protein-protein interaction between programmed death-1 (PD-1) and its natural ligand, PD-L1. PET imaging of PD-L1can be used for patient stratification for PD-L1 immunotherapies and provide prognosis information to physicians regarding the rational use of these treatments in patients. We are working on the synthesis and radiolabeling of a library of small molecule PD-L1 ligands as potential PET imaging probes, aiming to find one probe that could penetrate the blood-brain barrier (BBB) and allow for the quantification of PD-L1 in brain tumor or metastasis.
Investigator: Jason Cai
Kinetic modeling (Pharmacokinetics)
After the administration of a positron-emitting radiopharmaceutical (tracer), PET permits measurement of the radioactivity profile in a 3D object over time. This 4D imaging method allows the estimation of physiological parameters like blood flow, metabolism, and receptor concentration, useful for assessing different states (with or without stimulus), comparing patient groups, or evaluating drug efficacy. The goal of PET tracer kinetic modeling is to create a biologically validated, quantitatively reliable, and practical method for human studies. This process starts with animal studies, followed by complex human trials that simplify over time. The mathematical methods involve differential equations, statistical estimation, avoiding arterial blood measurements, and novel rapid computational algorithms.
Neurotransmitter Measurements with PET Tracers
Plots of PET activity over time and the resulting parametric images showing the volume of distribution for two different synaptic density radiotracers.
PET neuroreceptor studies have focused on determining changes in receptor concentration as a function of disease or measurement of receptor occupancy by drugs. A more recent approach provides an estimate of changes in synaptic neurotransmitter concentration. This method determines the change in tracer binding levels after administering behavioral or pharmacological stimuli that affect neurotransmitter levels. With careful experimental design and appropriate mathematical modeling techniques, the change in radiotracer binding can be attributed to changes in the level of synaptic neurotransmitter that competes with the radiotracer for receptor binding. Such changes have been successfully demonstrated in the dopaminergic, muscarinic, and serotonergic systems.