Service Projects

Dr. Gropler’s group has developed a new PET radiotracer for the monocyte chemoattractant protein-1/C-C chemokine receptor type 2 (MCP-1/CCR2) axis. They are using this to image the inflammatory component of atherosclerosis. Push: This SP focuses on using chemokine imaging for inflammation. We will provide complementary, including clinical agents for inflammation, which they can benchmark against their CCR2 agent for human atherosclerosis. They can cross-reference our INDs. For example, PET atherosclerosis imaging at Washington University may benefit from our CSF1R imaging agents.

Senescent cells play a key role in the pathogenesis of rheumatoid and osteoarthritis and osteoarthritis. The Daldrup-Link group is developing new PET imaging biomarkers that are selectively taken up by senescent cells through cleavage by b-galactosidase, a senescent cell-specific enzyme in these cells. They are evaluating their novel 18F-PyGal PET radiotracer for imaging of inflammation in an antigen-induced mouse model of arthritis and a swine cartilage defect model, where MSCs are implanted to regenerate joint tissue. Developing new biomarkers that can detect local or systemic inflammation may aid in assessing the need for initiating immunosuppressive therapy and/or cell therapy regimens and be used for monitoring treatment outcome.

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.

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.

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.

While MRI is being used routinely in the clinic for the diagnosis of CNS diseases, conventional methods are not specific to MS pathology and hence have limited prognostic values. Another unmet need is the lack of sensitive MRI detection of the lesions in cortical gray matter, recently identified as a major site of MS pathology.

In his R01 project, Dr. Wang proposes to combine advanced diffusion MRI (dMRI) and Quantitative Susceptibility Mapping (QSM) technologies at high spatial resolution to afford robust and quantitative imaging-based biomarkers of MS by detecting the progression of iron dysregulation, demyelination, and axon damage through the whole brain. The quantitative diffusion MRI metrics can be used to distinguish different stages of demyelination and may serve as an imaging biomarker for demyelination. In particular, the neurite density index (NDI) derived from the neurite orientation dispersion and density imaging (NODDI) biophysical model has been able to distinguish the acute demyelination and the chronic demyelination stages. He also will perform quantitatively validation of MRI findings using the state-of-the-art whole-brain light sheet microscopy (LSM). Dr. Wang plans to use animal models such as the cuprizone mouse model and the experimental autoimmune encephalomyelitis (EAE) model to study the relationship between neuroinflammation and brain connectivity alterations.

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.

Hematopoietic stem cell (HSC) gene therapy is a promising treatment option for a variety of genetic diseases affecting the hematopoietic system, e.g., sickle cell disease (SCD), HIV/AIDS, and certain malignancies. Current ex vivo HSC gene therapy is inefficient, expensive, and limited in availability. Dr. Kiem is a pioneer in stem-cell and gene therapy. His focus has been 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. These nanotechnology tools would be useful for next generation ex vivo HSC engineering as well as in vivo HSC engineering.

The mission of the CMITT is to develop, validate and disseminate cutting-edge imaging technologies that leverage simultaneous PET/MR to improve accuracy of diagnosis, characterization and follow-up of disease in the very early stages. PET/MR enables novel radiochemistry, kinetic modeling, quantitative methods, image reconstruction and AI that exploit properties of PET and MR signals. Push: We will provide a number of our PET probes (or their precursors) for neuroinflammation, e.g., [11C]CPPC or a newer 18F-labeled analog, and cancer to validate the methods under development in the CMITT and learn if they can be enhanced by concurrent MR imaging. PET/MR of PSMA-targeted agents in the JHU NCBIB, e.g., a dual-targeting FAP-PSMA agent (TR&D3), would be of particular interest, as would agents developed for CEST (TR&D1). We will also be able to provide AI algorithms under development in the JHU NCBIB, e.g., for automated segmentation of PSMA PET.

As a major limitation in contrast enhanced MRI studies is that current MRI methods lack the combination of accuracy, precision, and temporal resolution to quantitatively measure contrast agents in vivo. Dr. Pagel and team have addressed that problem by developing dynamic Magnetic Resonance Fingerprinting (MRF) methods that can rapidly measure T1 or T2 relaxation times with outstanding accuracy and precision.