Service Project #1: The PET Radiotracer Translation and Resource Center (PET-RTRC)
Gropler et al. have established the PET Radiotracer Translation and Resource Center (PET-RTRC) by leveraging the expertise at Washington University and the Mallinckrodt Institute of Radiology in PET radiotracer design, development, training and use with that of research groups throughout the country who are studying molecular and cellular processes of interest to facilitate the development and
dissemination of novel PET radiotracers. They will benefit from exchange of PET radiotracers and other molecular imaging agents from the Johns Hopkins NCBIB, further enhancing dissemination from each site. The PET-RTRC has projects that are complementary to those of the Johns Hopkins NCBIB, and are dedicated to vascular imaging, e.g., mapping matrix metalloproteases and the chemokine receptor monocyte chemoattractant protein-1/C-C chemokine receptor type 2 (MCP-1/CCR2) axis. Both projects have elements of imaging in
inflammation – in the periphery. We have recently designed an imaging agent for targeting cells of the monocytic lineage in the periphery to complement our more advanced program of imaging CSF1R in the periphery. Our new compound, [11C]JNJ-28312141, has proved capable of clear and specific imaging of monocytes in the periphery, for identifying infectious foci, particularly tuberculosis. Lesions due to TB are replete with monocytes.
Service Project #2: Molecular Magnetic Resonance Imaging of Inflammation
Imaging extracellular reactive oxygen species (ROS) represents a potential biomarker to noninvasively diagnose and quantify liver inflammation disease activity. ROS are tightly regulated in normal liver tissue but are present in high concentrations in inflamed liver
due to myeloid cell respiratory burst. The Gale lab recently developed a small molecule Fe-based MRI contrast agent (Fe-PyC3A) that
undergoes a 10-fold increase in relaxivity in the presence of ROS, resulting in an instantaneous, MR signal ‘turn on’ effect. The goal of their R01 project is to develop imaging to differentiate patients with non-progressive non-alcoholic fatty liver (NAFL) disease from patients with inflammatory progressive nonalcoholic steatohepatitis NASH). Fig SP2.1.B demonstrates differential signal enhancement in liver tissue of a nutritional mouse model of steatohepatitis compared to normal liver.
Service Project #3: Molecular Imaging of Transient and Remote Activation of Brain Microglia in Vivo
The Michaelides lab at NIDA has made fundamental discoveries with respect to chemogenetics, in part in collaboration with the NCBIB during the first funding period. They have a particular interest in designer receptors exclusively activated by designer drugs (DREADD)
technology. They also study chemical mechanisms of drugs of abuse. The NCBIB will continue to provide them suitably radiolabeled PET reporter molecules, e.g, [18F]JHU37107, [11C]clozapine and [18F]ASEM, and assist with their validation.
Service Project #4: Imaging B Cells in the Brain and Beyond: Developing an Immuno-PET Toolbox to Improve Understanding and Treatment of Multiple Sclerosis
To date, only one PET tracer for CD20+ B cells has undergone preliminary evaluation in MS, and no PET tracers have been developed for imaging CD19, expressed on a broader range of B cells (including suspected pathogenic antibody-secreting plasmablasts and circulating plasma cells). James et al. propose to develop novel immuno-PET tracers based on clinically approved CD19 and CD20 monoclonal
antibody therapeutics for translation. As precision medicine enables subtyping of individuals with MS, who may benefit from a variety of new treatments coming online, imaging – for prognosis and therapeutic monitoring – becomes more important than ever. Imaging agents in the NCBIB are complementary to the B cell agents under way in Dr. James’ group.
Service Project #5: Arginine Metabolism Regulates Myeloid Immune Suppression in Glioblastoma
Tumor-associated myeloid cells (TAMCs), which consist of tumor associated macrophages and myeloid- derived suppressor cells, comprise a majority of cellular infiltrates in glioma. TAMCs are potently immunosuppressive, and represent a major barrier to successful immunotherapy. The overall goal of the grant associated with SP5 is to determine how arginine is catabolized into polyamines by TAMCs, and to determine if inhibition of this metabolic pathway can enhance immunotherapy for glioma. Dr. Lesniak does not have a cell-specific way to study TAMCs non-invasively or clinically.
Service Project #6: Application of Hyperpolarized 13C Magnetic Resonance Imaging to Detect Target Inhibition of NF-kB Activation and Response in Primary CNS Lymphoma
NF-kB is a key pro-survival transcriptional regulator that drives resistance in a variety of malignancies, one of which is primary CNS lymphoma (PCNSL) a highly refractory form of activated B-cell (ABC)-type large cell lymphoma, an important cause of cancer-related mortality worldwide. Although targeted agents that block NF-kB activation have shown activity in PCNSL and systemic ABC-type lymphoma, the responses last only a few months, suggesting that alternative pathways of NF-kB activation are adaptively induced to mediate resistance. Dr. Chaumeil is implementing an innovative metabolic imaging approach, hyperpolarized (HP)13C MRI, to dissect
the pathogenesis of NF-kB in primary CNS lymphoma: to identify novel and more effective combinations of NF-kB targeting agents and to identify novel biomarkers that may predict resistance to immunotherapy. An example of HP 13C imaging of the conversion of [2-13C]pyrvuate to [5-13C]glutamate using a specialized 13C 32-channel head coil.
Service Project #7: Validation of Retinal Abeta as a Potential Biomarker of Alzheimer's Disease
This project aims to image retinal beta-amyloid plaques as an early biomarker of Alzheimer’s disease (AD) in a mouse model using aerosolized formulations derived from the fluorescent curcumin analogs developed in his laboratory. Early detection of Abeta in the eyes at ophthalmology centers, widely available in every health community setting, is a promising approach in terms of practicality, feasibility,
safety, and cost. The innovation of this work is the integration of intranasal aerosol delivery technology with the use of targeted imaging of retinal Abeta for the early detection of AD using optical imaging. The fluorescence signal depicted from Thioflavin S corroborates with the signal of anti-Abeta 6E10 antibodies. This work has direct clinical relevance, as it has recently been shown that stem cells and stem-cell derived EVs can be delivered intranasally for delivery to the brain, and several clinical trials on the use of MSC-EVs are in progress.
Service Project #8: Cell Manipulation Tools
Dr. Kiem is a pioneer in stem-cell and gene therapy. His focus has been on the development of improved treatment and curative approaches for patients with genetic and infectious diseases or cancer. While historically focused on viral approaches, he and his lab are also very interested in non-viral technologies to facilitate gene therapy and gene editing as enabling tools.
Service Project #9: Imaging Acidosis and Immune Therapy in PDAC
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal of all cancers and is largely resistant to all therapies, including immune therapies (IT). Despite that resistance, there are no fewer than 12 open clinical trials investigating treatment of PDAC with checkpoint blockade IT. Gillies et al. have shown that neutralization of tumor acidosis with oral NaHCO3 in murine models of PDAC can lead to dramatic improvements in response to checkpoint blockade. Because phase I and IIa clinical trials using that strategy have failed to dose-escalate, other ways are sought to neutralize tumor acidity, e.g., by using a CEACAM-6-targeted urease. Current strategies in the grant associated with SP9 include imaging pharmacokinetics of such tumor-alkalinizing agents through chemical exchange saturation transfer (CEST) MR imaging of pH. Carbonic anhydrase 9 is a hypoxia-responsive protein (CAIX) that may be used to report on the tumor microenvironment. Antibody-based clinical molecular imaging of CAIX has been accomplished. The NCBIB has developed and refined the first small-molecule CAIX imaging agents for SPECT and PET.
Service Project #10: Development and Dissemination of Clinical CEST MRI Acquisition and Analysis Methods for Cancer Imaging Applications
The Pagel lab has made fundamental discoveries with respect to CEST imaging of cancer and has a particular interest in tumor microenvironment (TME) and pHe imaging. Located at the world's largest cancer center, the MD Anderson Cancer Center, this lab is able to leverage their unique research environment and expertise and perform studies of CEST MRI methods to image models of brain, breast, lung, and head & neck cancer and also test these methods in patients. The NCBIB will provide them CEST MRI probes for collagen and