2025 MIPS Molecular Imaging Seminar Series

For several PET decades, PET studies with novel radiopharmaceuticals have made major contributions to understanding normal physiology and pharmacology of the brain as well as mechanisms and treatment studies of neuropsychiatric disorders. This presentation will cover three aspects of recent developments in PET neuroimaging. 1) We developed PET radiopharmaceuticals which bind selectively to a synaptic vesicle protein, SV2A, and thus provides an imaging paradigm to measure synaptic density in humans. This presentation will include recent work in development and human applications of these ligands. 2) Specific radiopharmaceuticals for NMDA receptors are now under development and preclinical results will be shown. 3) The presentation will include human imaging results from a next-generation dedicated brain PET system, the NeuroEXPLORER, which provides exceptional spatial resolution and sensitivity.

Richard E. Carson, Ph.D., is Professor of Biomedical Engineering and of Radiology and Biomedical Imaging at Yale University and Emeritus Director of the Yale PET Center. His research focus includes development of mathematical models for PET radiopharmaceuticals, applications of PET in clinical populations and preclinical models of disease, and development of state-of-the-art brain PET systems. Dr. Carson has published over 400 papers, given over 200 invited lectures and has received numerous awards including the Kuhl-Lassen Award and the Edward J. Hoffman Award from the Society of Nuclear Medicine, the Distinguished Investigator Award from the Academy of Radiology Research, and the Edward J. Hoffman Award for Medical Imaging from the IEEE. He was named an IEEE Fellow in 2019, received the 2024 SNMMI Image-of-the-Year award, and the 2024 IEEE Marie Skłodowska-Curie Award sponsored by the IEEE Nuclear & Plasma Sciences Society.

Functional MRI (fMRI) is the most widely-used method for measuring neuronal activity noninvasively across the entire human brain. All fMRI techniques in use today measure brain function indirectly—by tracking the changes in blood flow, volume and oxygenation that accompany neuronal activity, and this has often been viewed as the fundamental limitation of the technique. However, recent evidence from microscopy studies has shown that the smallest blood vessels of the brain respond far more precisely, in space and in time, to neuronal activity than previously believed. This insight suggests that the “biological resolution” of fMRI is intrinsically high, and, with sufficiently high imaging resolution, it should fundamentally be possible to extract meaningful neuronally specific information from fMRI—provided that we understand how vascular anatomy and physiology shape the hemodynamics that generate the fMRI signals.

In this presentation I will review the physics and physiology of fMRI, then describe ongoing efforts to improve the neuronal specificity of fMRI and pose the question: How far can we go with fMRI? A key challenge is that the vascular architecture of the brain reflects its structure and function across spatial scales. Modern fMRI is also used to measure cerebrovascular physiology, which is impaired in many neurological disorders, and so a deeper understanding of the fMRI signals will improve our understanding of the brain in health and disease.

Jonathan R. Polimeni, Ph.D., is an Associate Professor of Radiology at Stanford University School of Medicine and Director of Ultra-High Field MRI Research at the Richard M. Lucas Center for Imaging at Stanford. His training is in electrical engineering, computational neuroscience, and functional MRI physics. He arrived at Stanford in January, 2025; previously he was faculty at Harvard Medical School and at the Massachusetts General Hospital (MGH), within the Athinoula A. Martinos Center for Biomedical Imaging, and affiliated faculty in the Program in Health Sciences and Technology (HST) at MIT. He leads the High-Resolution and Ultra-High-Field Functional Imaging Laboratory, which focuses on developing new technologies for high-resolution functional MRI (mainly at 7 Tesla) and on understanding how the brain’s vascular anatomy and physiology shape the fMRI signals in order to relate these measurements back to the underlying neuronal activity. Several MRI technologies he has developed are now incorporated into the Siemens MRI scanner platform and are used by researchers and clinicians worldwide. He also serves as Handling Editor of the new, open access, non-profit journal Imaging Neuroscience, handling submissions on fMRI physics, fMRI acquisition, and ultra-high field neuroimaging.

Coming soon!

Professor Michael Hofman is a nuclear medicine physician and physician-scientist with a broad interest in positron emission tomography (PET), molecular imaging applications in oncology and radionuclide therapy.

He previously completed a research fellowship at Guy's & St Thomas' in London. His research has pioneered the use of PET and theranostics (radionuclide therapy) in a variety of domains. He is an international leader on the novel use of nuclear medicine for improving outcomes in men with prostate cancer . Michael’s research has pioneered the use of PSMA PET/CT for imaging prostate cancer and also PSMA theranostics for treating prostate cancer.

Michael closely collaborates with surgical, medical oncology, radiation oncology, radiopharmacy and medical physics colleagues at both the Peter MacCallum Cancer Centre and leading national/international centres.

Mitochondria are critical regulators of cellular metabolism, immune cell activation, and stress responses across a range of diseases. [¹⁸F]F-AraG, a fluorine-18 labeled deoxyguanosine analog, offers a unique window into mitochondrial biology by selectively accumulating in cells undergoing active mitochondrial biogenesis.

Originally developed to image T cell activation, [¹⁸F]F-AraG is now being applied to assess mitochondrial function in other bioenergetically demanding cells including cardiomyocytes and metabolically active adipose tissue. This expanded utility has revealed previously unrecognized inter-organ communication, offering a new perspective on disease mechanisms once hidden from view.

This presentation highlights emerging applications of [¹⁸F]F-AraG PET in three areas: immuno-oncology, cardiology, and neuroinflammation. By targeting mitochondrial activity central to both immune and metabolic regulation, [¹⁸F]F-AraG emerges as a powerful tool to visualize coordinated responses across organs, with the potential to transform our understanding of immune-mediated diseases and guide therapeutic strategies across disciplines.

Dr. Jelena Levi is a molecular imaging scientist with a background in organic chemistry. She began her training in molecular imaging at Stanford University under the mentorship of Dr. Sanjiv Sam Gambhir. Under his guidance, she contributed to the development of agents for optical and photoacoustic imaging designed for early cancer detection and tracking biological processes occurring in the tumor microenvironment.

In 2017, Dr. Levi joined CellSight Technologies, a company cofounded by Dr. Gambhir and later run by his wife Aruna, to whose memory this seminar is dedicated. As Chief Scientific Officer at CellSight, she now leads the development of [18F]F-AraG, a PET agent originally designed to assess immune responses in the context of immunotherapy.

Dr. Levi received her Ph.D. in Organic Chemistry from the City University of New York and her B.Sc. in Chemistry from the University of Belgrade, Yugoslavia. Her work continues to focus on translating molecular imaging tools into clinical applications that enhance our understanding of disease and improve patient care and outcomes.

In February 1972 the Brookhaven Linac Isotope Producer (BLIP) came online to accept protons from the 200 MeV Linac that synergistically supports multiple programs including the isotope production program, the Nasa Space Radiation Laboratory (RHIC) as well as the Relativistic Hadron Ion Collider (RHIC).  In addition to the BLIP the isotope program operates the Radionuclide Research and Production Laboratory (RRPL) which contains laboratories and hot cells for processing targets irradiated at the BLIP for external customers as well as internal research.  New hot cells have been brought online to aid in the processing of Ac-225. The BLIP allows the production of isotopes from 200 MeV and down in energies using stacked target arrays that allows for multiple isotope production. High energy accelerators play a critical role in supplying radionuclides such as Sr-82 used in Sr-82/Rb-82 generators for cardiac imaging.  They continue to be upgraded to further production yields by installing beam rastering systems that have allowed higher intensities and thus higher production yields.  Demand for isotopes that can be produced by these systems have also increased.  Linear accelerators such as the one at Brookhaven National Laboratory when operating at maximum proton energy of 200 MeV can have simultaneous production of several medically relevant isotopes. Among those are Ac-225 (T1/2=10.0 d), Cu-67 (T1/2=64.83 h), Se-72/As-72 (T1/2=26 h), Sr-82/Rb-82 (T1/2=1.26 min) and Ti-44/Sc-44 (T1/2=3.97 h).  Discussion of recent facility enhancements and future upgrades and production of novel radionuclides will be presented.

Magnetic Particle Imaging (MPI) is an emerging noninvasive tracer imaging modality that shows great promise to become a non-radioactive complement to many Nuclear Medicine studies. The MPI signal is the unique nonlinear signature of superparamagnetic iron oxide tracers (25-nm SPIOs). MPI has very high molar sensitivity because the SPIO magnetization is 51 million times stronger than the nuclear magnetization imaged in a 3.0T MRI. Indeed, MPI can even detect 1 micromolar SPIO concentrations in seconds with quantitative, linear, and positive contrast. Human tissues produce zero MPI signal and are magnetically transparent and hence MPI offers ideal “positive contrast” at any depth.

MPI’s Niche MPI competes with tracer imaging modalities like SPECT and Scintigraphy, rather than with CT or MRI. MPI offers a zero-radiation option for: tracking CAR-T immunotherapies [2,3]; Pulmonary Embolism detection akin to Tc99m V/Q studies [4]; Capillary-level noninvasive CBV & CBF for stroke or traumatic brain injury [5]; diagnosing GI bleeds akin to RBC-Tc99m scintigraphy [6] and Cancer MPI [7]. MPI magnetic reporters persist for months [2,3]. This means tracers can be pre-targeted in the factory and injected immediately from the refrigerator. This is ideal for emergency diagnoses, with no need for 1-hour ``hot chemistry’’ common in Nuclear Medicine. Four recent applications developed in my lab at Cal will be presented:

•      Immuno Ab-MPI: We showed that Antibody (Ly6g) labeled SPIOs tag circulating neutrophils and macrophages. The now-labeled WBCs home to inflammation, infection, bone marrow, much like an In- 111 WBC scan [8]. Immuno Ab-MPI could allow for infection and cancer imaging.

•      Immunotherapy Monitoring: Pre-labeled cells can be tracked with MPI in the body for up to 3 months [3]. Radiosensitive T and NK cell therapies often fail to survive the radiotoxicity of In-111-WBC. Zeroradiation Immuno-MPI could soon guide CAR-T personalized therapies.

•      Superferromagnetic MPI Tracers: We developed a breakthrough tracer that boosts SNR and spatial resolution by up to 28-fold in all 3 dimensions Fig 1(a,b) [9]. No deconvolution algorithms were used.

•      Brownian MPI Molecular Imaging Tools: MPI has the unique ability to reversibly sense nanoparticle binding and viscosity changes [10,11]. Color MPI can highlight bound SPIO tracers from unbound, circulating tracers, thereby improving disease contrast and specificity.

References

[1] Gleich and Weizenecker Nature 435, 2005.

[2] B. Zheng et al., Nature Sci Reports 5, 2015.

[3] B. Zheng et al., Theranostics 2016.

[4] X. Zhou, et al., Phys. Med. Biology 62, 2017.

[5] R. Orendorff, et al., Phys. Med. Biology 62, 2017

[6] E. Yu et al. ACS Nano,11 (12), 2017

[7] E. Yu, et al Nano Lett.,17 (3), 2017

[8] P. Chandrasekharan, Nanotheranostics,2021.

[9] ZW Tay, Small Methods (2021)

[10] C. Saayujya, et al., Small 2024.

[11] Yao Lu et al, Int. J. Hyperth. 2020.  

Prof. Conolly received his Ph.D. in Electrical Engineering from Stanford University with Professor Albert Macovski. At Stanford, he specialized in optimizing the technology for Magnetic Resonance Imaging. Dr. Conolly has about 40 patents in various stages of approval, and more than half of these have been licensed by industry. His contributions in MRI include Optimal Control selective RF pulse design, Variable-rate Selective Excitation, several Adiabatic pulses, Positive Contrast SPIO detection pulse sequence, Pyrolytic Graphite Magnetic Susceptibility Matched Foam. He also dedicated 10 years at Stanford, along with colleague Dr. Greig Scott, to building three radically innovative and affordable Prepolarized MRI scanners, which cost only $65,000 but produced high-quality wrist and knee images (even near metal implants). In 2004, Prof. Conolly was a recipient of the prestigious Stanford's Outstanding Inventor award.

Prof. Conolly was elected Chair of the UC Berkeley-UCSF Joint Graduate Group in Bioengineering from 2006-2009 and he served as Vice Chair of Instruction for Berkeley Bioengineering for 9 years and Head Graduate Advisor for 9 years. He also served as the Berkeley PI on the joint UC Berkeley/UCSF Bioengineering NIH T32 Training grant. At UC Berkeley, he is the faculty director of the Berkeley Preclinical Imaging Core facility, which houses a 7.0 T MRI scanner, a micro-CT scanner, a Visualsonics Ultrasound scanner.

Dr. Conolly’s lab specializes in medical imaging hardware, with a focus on Magnetic Particle Imaging (MPI) and Magnetic Resonance Imaging. MPI shows extraordinary promise as a safe, noninvasive, and quantitative imaging method and could soon provide a noninvasive complement to imaging tests that rely on Nuclear Medicine today. Dr. Conolly has pioneered the hardware, image reconstruction methods, pulse sequences, preclinical applications, and high-resolution tracers of MPI. His lab conducted many first-in-animal preclinical applications include stem cell tracking, WBC imaging following, Ab-MPI, ventilation-perfusion imaging to detect pulmonary embolisms, Traumatic Brain Injuries and stroke, gut bleed detection, angiography and cancer imaging. Prof. Conolly has won research support from CIRM, NIH, TRDRP, UC Discovery, Bakar foundation, Siebel Foundation and the Keck Foundation. In 2016, he co-founded a startup company called Magnetic Insight, which is now the leading preclinical MPI company in the world.

Coming soon!

Matthias Herth obtained his PhD in 2009 from Johannes Gutenberg University in Mainz, Germany, under the supervision of Professor Frank Rösch. Following his graduation, he moved to Denmark, where he joined the group of Professor Gitte M. Knudsen as a postdoctoral researcher. In 2015, he was appointed Associate Professor at the University of Copenhagen, and since 2024, he has held a full professorship at the same institution.

His research focuses on the development of innovative radiolabeling techniques and theranostic strategies, including pretargeting approaches. A particular emphasis of his group is the advancement of radiohalogens for therapeutic applications, with particular emphasis on developing novel chemistry to enable the clinical translation of 211At-labeled radiopharmaceuticals and pretargeted imaging and therapy strategies.