Chemistry, Probes & Molecular Therapy (CPMT)

The Chemistry, Probes and Molecular Therapy (CPMT) research group in the Department of Radiology and Biomedical Imaging at UCSF focuses on the development of new molecular imaging tools. This research group will complement our existing research and infrastructure groups to bring targeted therapies to the clinic, for both for the diagnosis and therapy of human disease.

About Chemistry, Probes & Molecular Therapy (CPMT)

CPMT conference schedule

Meetings related to the activities of the Chemistry, Probes and Molecular Therapy (CPMT) group will be held on Tuesday afternoons, at China Basin Landing in room 342, unless otherwise noted. The goal is 4-5PM with the exception of longer faculty meetings. These include:

  1. CPMT faculty meetings. These are held quarterly and include AIT SRG faculty members.
  2. Clinical research in progress (CRIP). These are designed for clinical researchers to discuss projects.
  3. Nuclear imaging research. Postdoctoral fellows in the Wilson, VanBrocklin, Flavell, and Evans labs will be presenting biweekly (Dr. Dave Korenchan and Barbara Green organizing). Researchers at all levels from Mission Bay groups are invited to join.
  4. Visiting speakers. Invited speakers will present on Tuesday afternoons. We welcome suggestions from all CPMT members.

Barbara Green ([email protected]) will be our contact administrator for the CPMT and related research meetings.

2020-2021 Scheduled meetings (updated weekly):

Jul 7, 2020

Yangjie Huang (Evans group)
Mike Evans, PhD presenting on behalf of his postdoctoral fellow - Yangjie Huang, PhD.

Jul 14, 2020 SNMMI meeting
Jul 21, 2020 Sinan Wang (Flavell group)
Jul 28, 2020 Jianbo Liu (Wilson group)
Aug 4, 2020 SRG meeting
Aug 11, 2020 Joe Blecha (VanBrocklin group)
Aug 18, 2020 Jaehoon Shin (Wilson group)
Aug 25, 2020 Ilona Polvoy (Wilson group)
Sep 1, 2020 Changhua Mu (Flavell group)
Sep 8, 2020 Zhuo Chen (Evans group)
Sep 15, 2020 Denis Beckford (VanBrocklin group)
Sep 22, 2020 Dongdong Liang (Wilson group)
Sep 29, 2020 Niranjan Meher (Flavell group)
Oct 6, 2020 Ning Zhao (Evans group)
Oct 13, 2020 Matt Parker (Wilson group)
Oct 20, 2020 Shalini Chopra (Flavell group)

2019-2020 Past Schedule

Aug 20, 2019 Dongdong Liang
Sept 24, 2019 CPMT faculty meeting
Sept 17, 2019 Joe Blecha
Title:  Real Time Arterial Sampling During MicroPET Imaging; Challenges and Findings
Abstract:  MicroPET imaging affords researchers valuable data while interrogating various disease states. Often the quantitative data is derived from the images assuming the tracer is intact over the imaging time period. However, when using metabolically instable PET imaging agents or prodrugs, the imaging findings need to be supported with arterial sampling from the small animal that is being imaged. Processing of the arterial samples is done in a tracer by tracer basis and needs to be thoroughly proven as accurate so that the radioactive species are separable at any given time point. This presentation will highlight a couple of the compounds that have been analyzed in our lab and talk about the challenges of arterial sampling as well as the findings. 
Oct 1, 2019 Junnian Wei
Title:  Profiling the surfaceome identifies therapeutic targets for cells with hyperactive mTORC1 signaling.
Abstract:  Aberrantly high mTORC1 signaling is a known driver of many cancers and human disorders, yet pharmacological inhibition of mTORC1 rarely confers durable clinical responses. To explore alternative therapeutic strategies, herein we conducted a proteomics survey to identify cell surface proteins upregulated by mTORC1. A comparison of the surfaceome from Tsc1-/- versus Tsc1+/+ mouse embryonic fibroblasts revealed 59 proteins predicted to be significantly overexpressed in Tsc1-/- cells. Further validation of the data in multiple mouse and human cell lines showed that mTORC1 signaling most dramatically induced the expression of the proteases neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). Functional studies showed that constitutive mTORC1 signaling sensitized cells to genetic ablation of NEP and APN, as well as the biochemical inhibition of APN.  In summary, these data show that mTORC1 signaling plays a significant role in the constitution of the surfaceome, which in turn may present novel therapeutic strategies.
Oct 8, 2019

Clinical Research in Progress (CRIP) group meeting
Presenter:  Dr. Tom Hope, MD will discuss research review

Oct 15, 2019 Dongdong Liang
Talk title: Developing positron emission tomography sensors of IDHm for detecting low-grade glioma.
Abstract: Isocitrate dehydrogenase IDH1 and IDH2 are metabolic enzymes that catalyze the conversion of isocitrate to alfa-ketoglutarate (α-KG) in cells. Genes encoding for IDH1 and IDH2 are mutated in >80% of grade II and III gliomas and secondary glioblastomas. Mutant IDH1/2 lose their normal catalytic activity but gain the ability to convert α-KG to 2-hydroxyglutarate (2-HG). 2-HG has a structure similar to α-KG and competitively inhibits several of the α-KG-dependent dioxygenases in cells, thereby, playing a role in tumor initiation. IDH mutations are the earliest genetic changes in the formation of low-grade gliomas. On the other hand, glioma patients with IDH1/2 mutations are found to have significantly longer survival compared to those with normal IDH1 tumors, suggesting the use of these mutations as prognostic biomarkers. IDH mutations are analyzed by ex vivo procedures and currently, there is no clinically applicable method available for noninvasive detection of these mutations in cancers. We aim to develop a positron emission tomography (PET) imaging method using radiolabeled probes to image IDH1 mutations, with the goal of addressing the critical need for an imaging biomarker to study these cancer-associated mutations.
Oct 29, 2019 Matt Parker
Talk title: PET imaging of bacterial infection by targeting peptidoglycan.
Abstract: A reliable imaging modality to probe live bacterial infection is still an unmet clinical need as the current methods of detection rely on indirect consequences of infection like morphologic changes or host immune response.  Our central hypothesis is that D-amino acids (DAA) could be used as a specific marker for live bacterial infections in vivo. Most bacteria produce and incorporate DAAs into the peptidoglycan cell wall, most specifically D-alanine. To this end, we have made use of D-[11C]methionine and D-[11C]alanine as PET imaging tracers for bacterial infection.  I will present our most recent findings from imaging studies of these and other supporting tracers in a variety of preclinical models as well as some progress toward next generation tracers.
Oct 31, 2019 Dr. Ming-Kai Chen, Yale University
Talk title: PET Imaging of Synaptic Density in Alzheimer's Disease
Nov 12, 2019 Jianbo Liu
Title: Direct Desulfurfluorination of Silver(I) difluoromethanethiolate with 18F− to Label Aryl-OCF3.
Summary: Positron emission tomography (PET) plays key roles in medical imaging, as well as drug discovery and development. However, there is a dearth of efficient and practical radiolabeling methods for 18F-Labeling of Aryl-OCF3, which limits advancements in PET radiotracer development. Here, we design a mild method for the fluorine-18(18F)–desulfurfluorination of Silver(I) difluoromethanethiolate by an [18F]F salt. This strategy may be applied to the synthesis of a wide range of 18F-labeled Aryl-OCF3, including pharmaceutical compounds. The labelling Aryl-OCF3 can be isolated efficiently apart from the pure salt mixture with this strategy, which provides chemists with a new platform to develop the synthesis and discovery of radiotracers and radioligands currently not within research.
Nov 26, 2019
Thomas Hayes
Title: Development of 18F and 11C PET Traces for Diagnostic Imaging and Therapy Evaluation.
Location: 4pm in the large conference room
Abstract:  During my time here at UCSF, I have had to work on a large number of projects involving 11C and 18F imaging agents.  These projects have been using a combination of automated, and hand chemistry, especially loop synthesis of labeled molecules for tracer production.  In this meeting I will talk about several of these projects, the capabilities of the ELIXYS system and 11C loop chemistry for the production of labeled tracers, as well as some of the results from those projects.
Dec 10, 2019 Ning Zhao
Dec 17, 2019

Brian Miller
Title:  Development & Applications of the iQID Camera: A Quantitative, Single-Particle Imaging Detector for small-animal SPECT and Targeted Radionuclide Therapy.

Jan 7, 2020
Mausam will be presenting "Radiotracers for Imaging Gram-Positive Bacterial Teichoic Acid".
Abstract: Gram-positive bacteria such as Staphylococcous aureus, Enterococcous spp., and Listeria monocytogenes and their multi-drug resistant forms represent a marked public health problem. Developing radiotracers for selective imaging of infection caused by gram-positive bacteria will significantly alleviate this problem. The cell walls of gram- positive bacteria consist of two types of teichoic acids- a) wall teichoic acids (WTAs) anchored to the peptidoglycans, and b) lipoteichoic acids (LTAs) attached to the cell wall glycolipids,.Teichoic acids are anionic glycopolymers with phosphodiester linked poly- glycerol or poly-D-ribitol.). We hypothesize that positron emission tomography (PET) tracers based on glycerol and ribitol will incorporate in the cell walls of gram-positive bacteria. In this study, we have synthesized 2-18F-glycerol, D-2- and D-3-18F-ribitols and the cold standard to test this hypothesis. Surprisingly, only D-3-18F-ribitol showed incorporation into L. monocytogenes. The imaging potential of this tracer is under investigation.

Jan 21, 2020

Ella Jones
Title:  “MRI and PET Imaging Markers For Prediction of Treatment Response in Breast Cancer Patients” 

Jan 28, 2020 Javier Villanueva-Meyer, MD hosts Dr. Sandip Biswal
Title:  "Pinpointing the site of pain generation using PET/MRI"
Feb 4, 2020
Michael Evans lab updates/group meeting
Feb 11, 2020

Robert Flavell, MD, PhD hosts Dr. Ka-Ngo Leung
Title:  "New Compact Neutron Generator for Multiple Medical Applications" 

Feb 18, 2020 Yangjie Huang
Mar 10, 2020 Ning Zhao
Title:  "Exploiting the Labile Fe(II) Pool to Image Gliomas with PET"
Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. High grade gliomas (HGG) are known or thought to require Fe(II) for survival, as numerous cancers and human disorders. Our recent work showed that the reaction-based probe 18F-TRX can be used for in-vivo imaging of several glioma models. Also, our results showed an enhanced efficacy of TRX-based prodrug for inhibiting the tumor progression in the glioma model. 
 
Mar 31, 2020

Sinan will be presenting "Development of CD46-targeted radiotracer for metastatic castration resistant prostate cancer imaging" at 4pm.

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer with an unmet need for improved mechanisms to select patients for appropriate treatment and novel therapies. CD46 is a novel therapeutic and imaging target, which is highly specific to prostate cancer, with intense cell surface expression in mCRPC and near absent expression in normal tissues. Positron emission tomography (PET) imaging of CD46 could provide fundamental information about its expression which cannot be obtained through other means, and enable selection of patients for appropriate treatment. A zirconium-89 (89Zr) radiolabeled anti-CD46 monoclonal antibody ([89Zr]DFO-YS5) was prepared in high (>95%) yield. This probe showed excellent binding affinity to CD46, with affinity of 6.0 nM against purified CD46 protein, and 6.7 nM against DU145 CD46 expressing cell line. μPET/CT imaging of [89Zr]DFO-YS5 was performed in mouse model. The radiotracer showed high and specific uptake at tumor as detected via micro PET/CT and biodistribution analysis, with uptake of  greater than 10%.  Taken together, these data suggest that [89Zr]DFO-YS5 is a promising theranostic agent for detecting CD46 expressing prostate cancer, potentially enabling therapies directed against this target.

Apr 7, 2020
Jaehoon Shin will have 2 parts presentation
Part I: "A Novel Strategy for Early Detection and Treatment of Malignancy Using Engineered T cells"
Most cancer deaths are due to the spread of the disease to other parts of the body and its consequence on impairing the vital organs such as the brain, kidneys or lungs. 75% of metastatic cancer patients were initially diagnosed as localized stage I-III, who later progressed to metastatic disease, often more than 5-10 years after the complete surgical resection of primary tumors. This is likely due to missing extremely early metastatic disease, below the detection limit of current imaging technologies. Once metastases become large enough to be detected by current imaging techniques such as CT, MRI or PET, there is no effective treatment for the disease. Using cutting-edge synthetic biology tools, we propose a simple but entirely novel approach to diagnose extremely early cancer metastases in unprecedented sensitivity via multiple rounds of signal amplification. In addition, using the same technology, we propose a novel way of treating numerous metastatic lesions simultaneously by using engineered T cells as carriers of therapeutic radiopharmaceuticals. Our approach is readily applicable in the clinic and would significantly improve both early and advanced cancer patients' lives by providing more sensitive diagnoses for early metastasis and treatment for multiple metastatic lesions.

Part II: "Local delivery of biopharmaceuticals and therapeutic radioisotopes using engineered T cells and intra-tumoral microbeads"
Using minimally invasive, image-guided techniques, interventional radiologists can deliver therapeutic agents directly into virtually any lesion in the body. However, current applications are limited to the intra-arterial administration of chemotherapeutic agents, either directly or loaded on beads, or therapeutic radioisotopes with short half-lives. Despite recent advances in protein-based biopharmaceuticals, such as monoclonal antibodies and immune checkpoint inhibitors, locoregional delivery of such agents is not possible, because of an inability to load them into beads and achieve controlled release. We herein propose a novel cell-based strategy to deliver biopharmaceuticals and therapeutic radioisotopes. Our overall project goal is to design T cells (“synNotch” method) that are engineered to either secrete biopharmaceuticals or accumulate radioisotopes upon encountering beads injected via image-guided interventions.  In this proposal, we will focus on building the groundwork for this novel technology.  First, we will demonstrate the designed secretion of proteins from T cells upon their binding to beads in vitro. Second, we will show the localization of radioisotopes to T cells upon their binding to beads in vitro. Third, using a mouse model, we will demonstrate the activation of T cells at bead injection sites in vivo, using the bioluminescence-producing protein luciferase or radioisotope as a readout.  We expect that the results of this project will demonstrate the feasibility of this novel cell-based approach and provide a foundation to translate these tools into cancer patients.

Apr 14, 2020
Dave Korenchan will be presenting "Denoising of Hyperpolarized Image Data via Tucker Decomposition".
Abstract:  Hyperpolarized 13C metabolic imaging often suffers from low signal-to-noise ratio, which can compromise the accuracy and robustness of quantification of imaging parameters. In this light, image denoising becomes a promising approach to improve quantification; however, if not careful denoising can also lead to parameter bias. This presentation will focus on a promising published method of image denoising, Tucker decomposition, and assess its application to datasets of hyperpolarized pH imaging.
Apr 21, 2020
Journal Club presenter - Ilona Polvoy, M.D. Postdoctoral researcher in Wilson Lab will be presenting "Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions".
Apr 28, 2020

Niranjan Meher, Ph.D. is presenting "Development of Carborane-Polymer Nanoparticle Based PSMA Theranostic Agents for Prostate Cancer Using Boron Neutron Capture Therapy".
Abstract: Prostate cancer (PCa) is the most prevalent noncutaneous cancer in men, with an unmet need for improved therapies. Boron neutron capture therapy (BNCT) is an therapy based on the nuclear fission reaction in boron to produce alpha particles. BNCT has strong potential to control the growth of tumors by initiating the cell apoptosis. Prostate-specific membrane antigen (PSMA) is a cell surface enzyme highly expressed on prostate cancer cells. Urea-based small molecule inhibitor agents targeting the enzymatic domain of PSMA have been developed for both imaging and therapy of prostate cancer. Recently we have described a series of boron labelled urea-based inhibitor agents targeting PMSA, which may enable BNCT targeted against prostate cancer. Selective delivery (>5-fold) of sufficient amounts of boron (>20 μg/g tissue) to tumor cells compared to surrounding healthy tissues is an essential criterion for effective BNCT. Herein, we have proposed to develop carborane encapsulated polymer nanoparticles conjugated with urea-based PSMA-inhibitor for optimal delivery of boron content for the effective treatment of prostate cancer using BNCT. We will conjugate the 89Zr-labeled deferoxamine (DFO) diagnostic agent to the polymer nanoparticles for simultaneous imaging of cancer cells using positron-emission tomography (PET). Specific aims of this project are (1) synthesis of PSMA binding ligand and DFO conjugated PLGA-b-PEG polymer, (2) formulation of targeted and carborane loaded polymer nanoparticle, and (3) in vitro and in vivo evaluation of the nanoparticles.

May 12, 2020
Changhua Mu, PhD
Talk title: "Optimization of Hyperpolarized Carbon-13 pH Image Probe Preparation for Clinical Translation of Prostate Cancer Staging"
Abstract: Extracellular acidification accompanies a pathologic progression of disease, notably for aggressive malignancies. Magnetic resonance imaging (MRI) based interstitial pH measurement represents an advanced non-invasive technology. Particularly, we can use a dynamic nuclear polarization technique to increase the sensitivity of carbon-13 labeled probe compounds by 10,000-fold or more in MR spectroscopy. Thus, the measurable signals of hyperpolarized (HP) 13CO2 and 13C-HCO3-, which liberate from a hyperpolarized precursor compound and equilibrate in tissues after injection, would allow us to image the interstitial pH using the Henderson-Hasselbalch equation (pH = pKa + log ([13C-HCO3-]/[13CO2]) to potentially distinguish early stage from late state prostate cancer. We have applied a preclinical polarizer (the HyperSense) to demonstrate the efficiency of HP imaging technique with mice models. Now we are optimizing the technique using a commercially available clinical polarizer (the SPINlab) towards the clinical translation. First, we use 1H NMR in both dynamic and kinetic manners to investigate the reaction mechanisms of 13C-HCO3- and 13CO2 liberating from our current 13C probes. We then synthesize and characterize new analogs of carbon-13 pH image probes for better efficiency. Furthermore, we will perform in vitro and in vivo evaluation, and eventually establish an entire mechanical system for the translation to human clinical application.
May 19, 2020
Dr. Dongdong Liang in Wilson lab will talk about ACE2 imaging entitled “Towards positron emission tomography imaging of ACE2 receptor depletion" 
May 26, 2020
Matthew Parker, PhD
Talk Title: "Future Directions for Infection Imaging"
Abstract:  With the D-alanine milestone firmly in the books and the rise of CoVid-19 pandemic, I will present my organizational effort of future directions for infection imaging.  This will include some attention to imaging ACE-2, the cell surface metallo-enzyme responsible for the initial binding and internalization of the Sars-cov-2 virus.  This approach is complimentary to the small molecule approaches outline at last week's seminar.  The major focus will be on future directions for bacterial infection imaging, both using our current arsenal of imaging tracers (D-Ala, D-Met, PABA) as well as continued development of new imaging tracers targeting peptidoglycan as well as other mechanisms.  Eight projects will be discussed which range from well established next steps to new concepts that were developed over this quarantine period.
Zoom: https://ucsf.zoom.us/j/93758372445?pwd=WHVERE1lenFTQlE4ZnV0aE5rdmg3UT09
Jun 2, 2020 Canceled
Jun 9, 2020
Denis Beckford Vera, PhD is an Assistant Researcher in VanBrocklin group.
Title: "A mismatch between radioisotope half-life and biomolecule pharmacokinetics that works"
Summary: Upregulation of tumor necrosis factor alpha (TNFα) in joints affected by rheumatoid arthritis (RA) drives inflammation and bone degradation. Varied response in RA patients to anti-TNFα biologics highlights the need to quantify TNFα in joints. We recently developed a 89Zr-labelled anti-TNFα certolizumab pegol (89Zr-CZP) that successfully assessed human TNFα expression in paws of transgenic mice (Beckford Vera at al. 2019). Dosimetric estimation of 89Zr-CZP revealed high potential human radiation exposure due to slow CZP clearance matched with the long half-life of 89Zr. However, observation that TNFα was visualized as early as 4h post-injection with 89Zr-CZP suggested that 89Zr could be substituted with a shorter-lived isotope such as 18F. This mismatch would significantly decrease radiation exposure while still providing suitable detection of TNFα. 18F is widely available and used in clinical practice. Hence, 18F-CZP could be easily adopted in regular clinical practice. Herein, we described the preparation of [18F]-fluorobenzoyl-CZP (18F-CZP) and its evaluation as a potential PET tracer for molecular imaging of TNFα in vivo. Moreover, I will share a summary of the multi-center R01 proposal to perform total-body PET (EXPLORER) in RA patients using 89Zr-CZP and 18F-CZP.
Zoom:https://ucsf.zoom.us/j/93758372445?pwd=WHVERE1lenFTQlE4ZnV0aE5rdmg3UT09
Meeting ID: 937 5837 2445 . Password: 492845
Jun 16, 2020 Canceled
Jun 23, 2020 Virtual farewell celebration
Jun 30, 2020 Canceled

Who we serve

The CPMT’s research will translate to healthier futures for:

  • Personalized medicine
  • Individual patient care according to unique metabolic, genetic, and biochemical profiles

Conditions we address

The clinical application of our research includes special focus on:

  • Cancer
  • Infection
  • Neurodegenerative disease

Who we partner with

We look forward to building relationships a wide range of partners:

  • Patients and their families
  • Researchers from our own and other institutions
  • Visionaries who seek to serve the populations we do
  • Donors committed to improving the lives of others

Who we are

The CPMT is made up of:

  • Clinical and research faculty
  • Radiochemists, physicists, spectroscopists, and nuclear medicine physicians
  • Postdoctoral fellows
  • Research staff
  • Medical and graduate students