Richard E. Carson - US grants

DESCRIPTION (provided by applicant): Positron Emission Tomography (PET) has played a unique role in brain research over the past 25 years. PET imaging has had wide applications in neuropsychiatric research due to 1) the use of specific radiotracers to produce a highly targeted molecular signal, 2) PET scanners that produce quantitative radioactivity images, and 3) tracer kinetic modeling techniques that allow production of images of physiological parameters (flow, metabolism, receptor number) from dynamic (4-D) data and measurements of the arterial input function. However, widespread application of these quantitative techniques has been limited primarily to research studies in a small number of academic centers due to their overall complexity and expense. Thus, the development of robust algorithms for analysis of PET data could lead to a dramatic expansion in the applicability of this technology in clinical and research studies. In addition, PET has been limited, compared to MRI, due to its lower spatial resolution. Recently, the High Resolution Research Tomograph (HRRT), a new scanner designed for human brain studies, has become available. The HRRT provides high sensitivity, list mode acquisition, a large axial field-of-view, and resolution better than 3 mm. Although there is a large potential improvement in the quality of physiological information from the HRRT, there are many scientific and practical challenges accompanying this new technology. In other words, the complexity of quantitative brain PET studies has increased even further with a scanner like the HRRT. To address these challenges and to work towards the ultimate goal of facilitating widespread use of quantitative brain PET methods, the following aims are proposed: Aim 1: Extend and validate our cluster-based listmode reconstruction algorithm to improve resolution and quantitative accuracy and to reduce noise. Aim 2: Correct for head motion during scanning without loss of resolution by incorporation of direct motion measurements into the image reconstruction process. Aim 3: Develop and validate methods to extract the arterial input function using image-based measurements of the carotid arteries and suitable brain reference regions. Aim 4: Extend the reconstruction algorithm to incorporate spatial information from MR-based anatomical images and temporal information from tracer kinetic models. Aim 5: Demonstrate the practical effect of these reconstruction, physics modeling, and kinetic modeling innovations on human PET data.

DESCRIPTION (provided by applicant): The goal of this shared instrumentation proposal is to expand the capabilities of the Yale Positron Emission Tomography (PET) Center by the acquisition of a state-of-the-art PET/CT scanner for human research studies. PET imaging provides a non-invasive method to detect and examine biochemical processes and physiological functions in the living body. Through the use of specific radiolabeled molecules, state-of-the-art scanning equipment, and the techniques of tracer kinetic modeling, quantitative measurements of a wide range of physiological functions can be assessed in clinical and pre-clinical populations. PET has broad applications in the areas of oncology, cardiology, neurosciences, metabolic disorders, inflammation, and others. The goal of this proposal is to leverage the Yale PET Center's expertise in radiochemistry and quantitative PET imaging from our existing PET-only scanners and to expand the use of PET/CT in human research studies involving cardiovascular disease, diabetes, and oncology. Therefore, we have chosen the proposed PET/CT system with time-of-flight capabilities, high sensitivity and resolution, and excellent performance in terms of quantitative accuracy and count rate performance. When these PET instrumentation characteristics are combined with a CT scanner with excellent axial sampling and high speed, the system can provide ideal characteristics for PET/CT research studies of Yale investigators. The need for a combined PET/CT is self-evident for oncology research which requires simultaneous anatomical localization of tumor uptake. Work in diabetes requires combined PET/CT for pancreas measurements of 2 cell function and cardiovascular studies require combined PET/CT to correlate CT-based anatomical and functional measures with the physiological measurements from PET. The need for combined PET/CT will be of even greater importance in research studies using novel radiopharmaceuticals. The interpretation of the spatial localization of a new tracer, where normal uptake patterns are unknown, cannot be performed without high resolution anatomical data. In addition, the proposed high-end PET/CT will be of even greater utility when sophisticated multimodality image analysis techniques are employed, including image-based measurement of tracer input function and corrections for cardiac and respiratory motion artifacts. The proposed system will support NIH-funded investigators in the Departments of Cardiology, Diagnostic Radiology, Internal Medicine, Medical Oncology, Obstetrics and Gynecology, and Therapeutic Radiology. Enhanced utilization of novel radiopharmaceuticals and PET/CT imaging will lead to a better understanding of biochemical processes involved in cardiac disease, cancer, metabolic disorders, and others, which in turn will lead to the development of new, or improved treatment for these diseases. Together, these applications hold tremendous potential in improving the health of the general public. PUBLIC HEALTH RELEVANCE: This research project aims to provide state-of-the art imaging equipment for combined Positron Emission Tomography (PET) and CT research studies. PET/CT imaging is used to investigate and understand the biochemical and pathophysiological processes involved in cancers, metabolic diseases such as diabetes, and cardiovascular disease. Addition of a new PET/CT system will allow us to leverage the Yale PET Center's expertise in radiochemistry and quantitative PET imaging to support a wide range of clinical imaging research projects, which in turn will lead to the development of new disease treatments and new approaches for monitoring of disease progressions and treatment outcomes.

The main goal of this PET imaging section of the P20 proposal (Project 2) is to better understand the neural mechanisms associated with the two major types of impulsive behavior (impulsive choice and impulsive response) as related to drug abuse, by assessing the neurochemical and behavioral differences in cocaine dependent (CD) subjects as compared to healthy control (HC) subjects. We propose to compare the binding potential of [11C]PHN0, a potent dopamine D2/D3 PET agonist ligand, in ventral and dorsal striatum of HC and CD (Specific Aim 1), and then correlate the binding potential with the event-related BOLD activity measured by fMRI (Project 1) during a task assessing impulsive choice and during a task assessing impulsive response (Specific Aim 2). We further propose to conduct PET imaging in rats and non-human primates before and after cocaine exposure and correlate the results on the dopamine D2/D3 availability with impulsivity measures using the same cognitive/behavior tasks. This is the first study specifically designed to characterize impulsivity across all three species, both behaviorally and neurochemically, and to investigate the relationship of impulsivity to cocaine addiction. The proposed translafional research will provide synergisfic informafion by linking the clinical and preclinical findings to address a major gap in our understanding of the factors that influence addiction liability or vulnerability to the effects of drugs, the neurobiological alterations that may lead to abuse and addicfion, and how drugs of abuse may affect brain systems and processes that change over time after exposure to drugs. By employing neuroimaging technology (Project 2) paired with sophisficated functional and behavioral measurement paradigms (Project 1 &3), and by integrating viral-mediated gene expression study (Project 4), we can begin to better understand the alterafion induced by cocaine at mulfiple levels, including the molecular genefic, neural and behavioral levels. Thus, the proposed study has significant potenfial to yield results that can be inform treatment development for cocaine addiction in humans.

DESCRIPTION (provided by applicant): State-of-the-Art Small Animal PET/CT Instrumentation Yale University PET Center The goal of this shared instrumentation proposal is to expand the capabilities of the Yale Positron Emission Tomography (PET) Center by the acquisition of a state-of-the-art small animal PET/CT scanner for rodent research studies. PET imaging provides a non-invasive method to detect and examine biochemical processes and physiological functions in the living body. Through the use of specific radiolabeled molecules, state-of-the- art scanning equipment, and the techniques of tracer kinetic modeling, quantitative measurements of a wide range of physiological functions can be assessed in clinical and pre-clinical populations. PET has broad applications in the areas of oncology, cardiology, neurosciences, metabolic disorders, inflammation, drug delivery, and others. The goal of this proposal is to leverage the Yale PET Center's expertise in radiochemistry and quantitative PET imaging from our existing PET-only scanners and to expand the use of PET/CT in rodent research studies, as part of a translational arm to human PET/CT studies. We have chosen the proposed PET/CT system with large axial field-of-view, high sensitivity and resolution, and including measurement of photon depth of interaction. When these PET instrumentation characteristics are combined with a CT scanner, the system can provide ideal characteristics for rodent research studies of Yale investigators. The need for a combined PET/CT is self-evident for most small animal oncology research, which requires simultaneous anatomical localization of tumor uptake. Work in diabetes requires combined PET/CT for pancreas measurements of beta cell function, and cardiovascular studies require combined PET/CT to correlate CT- based anatomical and functional measures with PET physiological measurements. The need for combined PET/CT is of even greater importance in research studies using novel radiopharmaceuticals, where the interpretation of the spatial localization of a new tracer cannot be performed without high-resolution anatomical data. The proposed system will support NIH-funded investigators in the Departments of Biomedical Engineering, Cardiology, Diagnostic Radiology, Internal Medicine, Medical Oncology, Obstetrics and Gynecology, Neurology, Psychiatry, and Therapeutic Radiology. Enhanced utilization of novel radiopharmaceuticals and PET/CT imaging will lead to a better understanding of biochemical processes involved in cardiac disease, cancer, metabolic disorders, neuropsychiatric disorders, and others, which in turn will lead to the development of new or improved treatment for these diseases. Together, these applications hold tremendous potential to improve the health of the general public.

DESCRIPTION (provided by applicant): A clinically viable means to measure pancreatic beta-cell mass (BCM) is essential for evaluating the physiological basis of therapeutic approaches to restore deficient insulin secretory capacity. Major advances in imaging BCM have been made by taking advantage of receptor-specific imaging probes that have been successfully used for neuroimaging. Neurons and ?-cells are functionally similar in being able to respond to cell-specific extracellular stimuli with the secretion of the contents of intracellular vesicles. Hence, Positron Emission Tomography (PET) imaging ligands that were originally developed to specifically bind to neurons may prove useful for imaging BCM. The Yale PET Center has been at the forefront of imaging both brain receptors and BCM and proposes to evaluate its extensive library of human neuroimaging agents as in vivo probes to quantitatively determine BCM. To maximize the value of these studies, pancreatic imaging in humans will be obtained together with validation studies in healthy and type 1 and 2 diabetes mellitus pancreas. Imaging probes that show suitable in vivo specific uptake in pancreas and appropriate imaging properties in humans, and can distinguish between healthy and diabetic pancreas in vitro will then be tested in a limited clinical PET-imaging trial to assess whether there is a measurable decrease in radiotracer binding in the pancreas of T1DM patients. In Specific Aim 1, we will evaluate whether the approved radiotracers currently in use at the Yale PET center for human neuroimaging can be used for imaging BCM in healthy individuals. We plan to either piggyback onto ongoing imaging studies to evaluate the suitability for pancreas imaging of at least 10 radioligands currently in use for neuroimaging. In Specific Aim 2, we will validate ?-cell specificity of the radioligands in vitro in healthy, T1DM, and T2DM human pancreas tissue obtained from the network for Pancreatic Organ Donors with Diabetes (nPOD), and in human islets. Those radioligands that may be useful for measuring insulin secreting beta-cells will have higher specific binding to healthy human islets and to pancreas from healthy donors compared to pancreas from patients with T1DM or T2DM. In Specific Aim 3, we will perform a clinical evaluation in healthy and T1DM volunteers of those agents that meet the criteria of 1) promising pancreas imaging characteristics determined in Aim 1 and 2) favorable ?-cell specificity as determined in Aim 2. A limited clinical evaluation is necessary to establish whether the radioligand can quantitatively measure changes in BCM that are physiologically relevant to diabetes progression.

? DESCRIPTION (provided by applicant): Vesicles in presynaptic neuron terminals secrete neurotransmitters by fusing with the presynaptic membrane. One essential vesicle membrane protein is the synaptic vesicle glycoprotein 2 (SV2), with one of its isoforms, SV2A, ubiquitously expressed in virtually all synapses. Clinical and experimental data have suggested that SV2A is involved in epilepsy with decreased SV2A receptor density found in the epileptogenic zone. Animal models of epilepsy suggest that loss of SV2A could contribute to epileptogenesis and pharmacoresistance. Furthermore, SV2A has been found to be the site of action of the anticonvulsant Levetiracetam (LEV). We recently developed 11C-UCB-J as a promising radioligand for quantitative measurement of SV2A with positron emission tomography (PET). In our pilot first-in-human SV2A PET studies in healthy subjects, we found that 11C-UCB-J has the potential to be an excellent PET tracer for quantitative imaging of SV2A in the human brain. In addition, this tracer has the potential to be a general-purpose tool for measuring synaptic vesicle density. We propose to fully develop and validate 11C-UCB-J for human use and perform an initial clinical study in epilepsy. In the first aim, we will quantify SV2A using bolus/infusion delivery on the High Resolution Research Tomography (HRRT) and perform paired test/retest scans in one day in young healthy controls. In a separate cohort, we will determine the magnitude of specific binding in young healthy controls by paired studies at baseline and following IV administration of LEV. Data from these experiments will define the optimal scanning protocol and the most appropriate quantitative method. In the second aim, we will assess age effects on SV2A by assessing specific and nonspecific binding of 11C-UCB-J. MR-based partial volume correction will be performed to eliminate any artifactual effects of cortical atrophy. Such results will be important to interpret any disease-related changes, e.g., due to neurodegeneration, as a function of age. The third aim is to assess SV2A density in epilepsy patients with medically refractory focal epilepsies who are candidates for surgical resection. We will compare 11C-UCB-J binding in these patients to age- and sex-matched healthy controls and assess whether SV2A density is decreased at the site of origin of seizures. We will validate these results with measurements of SV2A expression in surgically removed tissue samples. 11C-UCB-J binding will also be compared to that of 18F-FDG in the same patients, to evaluate if 11C-UCB-J is more diagnostically useful than FDG for seizure focus determination.

Project Summary/Abstract Alzheimer's disease (AD) afflicts 6 million people in the USA, and the number of AD patients will double by 2050 if no cure is identified. The clinical dementia of AD is coupled to a distinct pathology, with ?-amyloid plaques, neurofibrillary tangles, and synaptic loss. Synapses are essential for cognitive function, and their loss is well established as the major structural correlate of cognitive impairment in AD. An early event in AD pathogenesis, synaptic failure is detectable in individuals with the prodromal stage of MCI. Positron Emission Tomography (PET) imaging is increasingly employed in studies of AD, using tracers for glucose metabolism, ?- amyloid, and neurofibrillary tangles. However, currently, there are no PET radioligands that directly image synaptic density in vivo, which would be of high utility in studies of AD as well as in monitoring potential therapies. One suitable molecular target for a synaptic density imaging agent is the synaptic vesicle glycoprotein 2 (SV2), an essential vesicle membrane protein, with one of its isoforms, SV2A, ubiquitously expressed in virtually all synapses. We recently developed 11C-UCB-J as a promising radioligand for quantitative measurement of SV2A with PET. In our pilot first-in-human SV2A PET studies in healthy subjects, we found that 11C-UCB-J has the potential to be an excellent PET tracer for quantitative imaging of SV2A in the human brain, and can act as a general-purpose tool for measuring synaptic vesicle density. We propose to apply 11C-UCB-J with human imaging studies in AD. In Aim 1, we will quantify SV2A using bolus/infusion delivery on the High Resolution Research Tomography (HRRT) and examine SV2A density in AD compared to healthy controls (HC). We hypothesize that 11C-UCB-J will reveal decreased SV2A binding in the AD brain with a pattern that may differ from the cortical regions previously validated for 18F-FDG. All subjects will also be evaluated for amyloid status and the effect of overall amyloid status on SV2A binding will be determined. In Aim 2, we will compare group and individual differences in SV2A density to differences in glucose metabolism measured with 18F-FDG. Regional patterns of deficits will be compared to HC for the 2 tracers. We hypothesize that the magnitude of reduction in specific binding of 11C-UCB-J in AD compared to HC will be greater than that found with 18F-FDG. Further, we will correlate the magnitude of reduction in synaptic density and glucose metabolism with neuropsychological test performance. Aim 3 compares the group and individual differences in amyloid distribution from 11C-PIB to SV2A-PET as well as FDG-PET, with the expectation that patterns of synaptic loss produced by 11C-UCB-J will differ from that of amyloid PET, particularly in the earlier phases of the AD spectrum. In summary, this project will take the first critical steps to validating a novel imaging biomarker of synaptic density for studies in AD and other neuropsychiatric disorders.

? DESCRIPTION (provided by applicant): The purpose of this proposal is to develop a radioligand development program to discover, test and apply innovative PET radioligands to probe high priority molecular targets implicated in mental illness. This program will build on Molecular Neuroimaging's existing radioligand development laboratory and clinical program to create a robust process to effectively select and test radioligands. We propose to utilize a tiered radioligand development and application strategy with Tier 1 - Chemistry development and in vitro testing, Tier 2 - In vivo assessment in non-human primates, Tier 3-IND acquisition and human proof of concept and validation studies, and Tier 4 - Application to test mechanisms of action, assess brain penetrance, and target occupancy of drug candidates. Depending on the existing data, radioligands may enter the development scheme at any tier if there is sufficient rationale that advancing the radioligand will inform relevant mental health disease mechanisms. The goal is to simultaneously develop multiple radioligands at different tiers as funding allows. We will implement a priori go/no-go decision rules for each development tier recognizing that the risk of failure for any radioligand is greatest at Tier 1 and likelihood of success increases a the ligand progresses from Tier 1 to Tier 4. The program Steering Committee consisting of NIH leadership, MNI scientists, and industry and academic subject-matter experts will nominate radioligand targets, review ongoing data, and manage resource allocation to optimize the program radioligand pipeline. In specific aims 1-3, we propose to develop radiotracers targeting the D1 dopamine receptor, GABA transporter, and PDE2a in collaboration with pharmaceutical colleagues both as examples of key targets for radioligand development for mental health disorders and as a proof of concept for the strategy for a collaborative program for innovative PET radioligand development. The protocols, INDs and data acquired through the proposed PET imaging program will be made available through the MNI website and an existing online resource (SNIDD). PET imaging provides the opportunity to determine the brain distribution of the molecular target, to examine and distinguish target subtypes, to investigate the expression of the target in mental health disorders, and to demonstrate the target occupancy to determine an optimal therapeutic dose of potential therapeutic compounds. The comprehensive radioligand development program is designed to work collaboratively with the pharmaceutical industry, biotech and academics to identify and efficiently assess molecular targets relevant to ultimately accelerate therapeutic development for mental health diseases. Developing tools to demonstrate target engagement is a crucial step in assessing compounds that may probe the pathobiology and/or provide novel therapies for mental health disorders.

Project summary Quantitative PET has become increasingly important in clinical management and research, in particular for predicting and assessing response to therapy for cancer patients. Current PET protocols involve injection of PET tracers that typically result in ~6-7 mSv radiation dose to patients. For patients who require multiple repeated PET scans to monitor the response to therapy, and for patients who need PET scans with two or more tracers (e.g., FDG + FLT) to optimally predict response to therapy, it is critical to reduce the radiation dose from the PET tracer injection, while still maintaining the quantitative accuracy and image quality for cancer management. When reducing injection dose, the PET images will have higher noise due to fewer detected counts, which will subsequently introduce errors in quantitative measurements. For moving organs and tumors such as those in the lung and abdomen, respiratory motion can substantially degrade quantitative accuracy, so motion correction is required. Conventional motion correction uses a gating strategy that rebins the PET data, resulting in substantially higher noise in each gate. More advanced methods incorporate motion vector estimation in the image domain for post-registration or motion compensated image reconstruction using all detected events without increasing noise. The motion vectors need to be derived from gated PET, which are even noisier when using a reduced tracer injection in low-dose studies, imposing substantial challenges for accurate and reliable voxel-by-voxel motion vector estimation. In dynamic PET studies with clinical cardiac tracers and other novel oncology and neurology tracers, quantification is even more challenging for low-dose PET as each dynamic frame only contains a small fraction of detected events so the high image noise will affect the determination of image-derived input functions and can lead to bias and high noise in parametric images. In this project, to reduce image noise and maintain quantitative accuracy in PET, we propose to develop, optimize, and evaluate multiple innovative imaging methods for low-dose PET data to achieve comparable quantitative accuracy as full-dose PET. While the imaging developments are generally applicable to all PET tracers in oncology, neurology, and cardiology, since cancer is the primary clinical application of PET, we will focus our investigation and optimization in this project on three lung cancer imaging tracers at different clinical adoption stages as examples: 1) 18F-FDG as a routine clinical tracer, 2) 18F-FMISO for hypoxia studies as a tracer for human research, and 3) 18F-PD-L1 that specifically binds to human PD-L1 in tumors and other organs as a recent first-in-human tracer. For each tracer, we will investigate 1) static PET, 2) gated and respiratory motion corrected PET, and 3) dynamic PET.

IMAGING CORE The Penn PET Addiction Center of Excellence (PACE) Imaging Core will support the design, implementation, execution, and analysis of the PET imaging components of the Center's pilot projects. The Imaging Core will function as a resource for expertise and guidance for investigators and will also serve as a functioning platform to provide services for P30 investigators that include imaging study design, imaging study execution including imaging-related patient coordination, image analysis, PET image data archiving, and regulatory support. As such, the Imaging Core will work closely with the other Cores and the PIs of the P30 Core Center's pilot projects to support the Center's mission in drug addiction research and to expand the scope of PET imaging for research on opiate use disorders at Penn and Yale University. Specific aims of the Imaging Core include: 1) to design the PET components of the Penn PACE pilot core projects; 2) to coordinate and execute PET imaging studies proposed in the Pilot Core at Penn and at Yale; 3) to guide and execute PET image analyses, including kinetic analysis and novel image analysis approaches; and (4) to guide and support regulatory submissions and provide oversight of imaging studies by working closely with the other Cores on data and safety monitoring for the PET imaging component of Pilot Core projects. The Imaging Core is co-led by Dr. David Mankoff of Penn and Dr. Richard Carson of the Yale University PET Center. The Imaging Core takes advantage of a highly developed infrastructure for human PET imaging research at both the Penn and the Yale University PET Centers. The core also benefits from synergistic expertise at Penn (multi-center clinical trials, protocol development, regulatory infrastructure) and Yale (molecular brain imaging methodology, tracer kinetic analysis). The Core has a unusual depth of combined depth of expertise in PET instrumentation physics, image generation, and data analysis ? along with dedicated unique scanner resources- to support the scientific mission of this P30 Center.

Research applications of brain Positron Emission Tomography (PET) have been in place for over 40 years. The combination of quantitative PET systems with novel radiotracers has led to a numerous imaging para- digms to understand normal brain physiology including neurotransmitter dynamics and receptor pharmacology at rest and during activation. Brain-dedicated PET systems offer important advantages over currently available PET systems in terms of sensitivity and resolution. However, the state-of-the-art for brain PET has not progressed beyond the 20-year-old HRRT. Therefore, there is a compelling need to build the next generation of brain PET systems for human studies. This proposal brings together a highly experienced collaborative team from Yale, UC Davis, and United Imaging Healthcare America (UIHA). to develop the next generation NeuroEXPLORER (NX) PET system with the following Aims. Specific Aim 1: Design and Build the NeuroEXPLORER: In 2 years, we will complete the design and build the NX system. The design includes high performance LYSO-SiPM blocks with small detectors, 4-mm depth-of-interaction, 250 ps time-of-flight resolution, and axial length of ~50 cm, paired with CT for attenuation correction. This design will produce a factor of 10 greater effective sensitivity than the HRRT and practical resolution of 1.5-2 mm in the human brain. The system will include built-in real-time state-of-art motion tracking cameras and will be tested using novel phantom experiments to assess the full-range of operation to validate the dramatic improvement in small- region precision and accuracy. Specific Aim 2: Algorithm Development for Fully-Quantitative Brain PET. We will develop the novel algorithms for this system. Using EXPLORER experience. we will implement reconstruction algorithms to produce dynamic images with uniform ultra-high resolution in space and time, Extending Yale?s HRRT motion correction experience, we will develop camera-based motion detection and correction algorithms to deliver ultra-high resolution human brain images. Using the carotid artery shape and geometry, we will develop methods to accurately measure blood activity to be compared to human arterial data with the goal to permit kinetic modeling without arterial sampling. We will develop noise reduction methods with machine learning to reduce dose for studying health brains and to eliminate the need for the CT scan for attenuation correction. Specific Aim 3: Human Paradigm Demonstration. With human subjects, we will evaluate specific imaging paradigms to demonstrate the effectiveness of the NX system: 1) demonstration of the dramatic sensitivity increase (with a direct comparison to the HRRT) and its impact on detection of pharmacologic effects, 2) leveraging high sensitivity to reliably measure uptake in small nuclei; and 3) opening new frontiers of imaging neurotransmitter dynamics, including dopamine and opioid release. The ultimate goal is a fully functioning and characterized system that dramatically expands the scope of brain PET protocols and applications.