[Zr]ZrCl for direct radiolabeling of DOTA-based precursors.

Introduction: Zirconium-89 (Zr) is a positron emitter with several advantages over other shorter-lived positron emission tomography (PET) compatible radiometals such as gallium-68 or copper-64. These include practically unlimited availability, extremely low cost, greatly facilitated distribution logistics, positron energy fit for medical PET imaging, and sufficiently long physical half-life to enable PET imaging at later time points for patient-specific dosimetry estimations. Despite these apparent benefits, the reception of Zr in the nuclear medicine community has been tepid.

Noninvasive Diagnostic Method to Objectively Measure Olfaction and Diagnose Smell Disorders by a Molecularly Targeted Fluorescence Imaging Agent.

Despite the recent advances in understanding the mechanisms of olfaction, no tools are currently available to noninvasively identify loss of smell. Because of the substantial increase in patients presenting with coronavirus disease 2019-related loss of smell, the pandemic has highlighted the urgent need to develop quantitative methods. Our group investigated the use of a novel fluorescent probe named Tsp1a-IR800 as a tool to diagnose loss of smell.

Na1.7 targeted fluorescence imaging agents for nerve identification during intraoperative procedures.

Surgeries and trauma result in traumatic and iatrogenic nerve damage that can result in a debilitating condition that approximately affects 189 million individuals worldwide. The risk of nerve injury during oncologic surgery is increased due to tumors displacing normal nerve location, blood turbidity, and past surgical procedures, which complicate even an experienced surgeon's ability to precisely locate vital nerves. Unfortunately, there is a glaring absence of contrast agents to assist surgeons in safeguarding vital nerves.

Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action.

Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism.

Simultaneous quantitative imaging of two PET radiotracers via the detection of positron-electron annihilation and prompt gamma emissions.

In conventional positron emission tomography (PET), only one radiotracer can be imaged at a time, because all PET isotopes produce the same two 511 keV annihilation photons. Here we describe an image reconstruction method for the simultaneous in vivo imaging of two PET tracers and thereby the independent quantification of two molecular signals. This method of multiplexed PET imaging leverages the 350-700 keV range to maximize the capture of 511 keV annihilation photons and prompt γ-ray emission in the same energy window, hence eliminating the need for energy discrimination during reconstruction or for signal separation beforehand.

Targeting Carbohydrate Mimetics of Tetrahydrofuran-Containing Acetogenins to Prostate Cancer.

The high potency of the tetrahydrofuran-containing acetogenins (THF-ACGs) against a broad range of human cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-ACG mimetics in which the THF and butenolide moieties of a mono-THF-ACG were replaced with carbohydrate and thiophene residues, respectively. In the present study, towards the targeting of these carbohydrate analogues to prostate cancer (PCa), we synthesized prodrugs in which a parent thiophene or butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA), a highly specific ligand for prostate-specific membrane antigen (PSMA), which is overexpressed on prostate tumors.

Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer.

Tumor expression of prostate-specific membrane antigen (PSMA) is lost in 15-20% of men with castration-resistant prostate cancer (CRPC), yet the underlying mechanisms remain poorly defined. In androgen receptor (AR)-positive CRPC, we observed lower PSMA expression in liver lesions versus other sites, suggesting a role of the microenvironment in modulating PSMA. PSMA suppression was associated with promoter histone 3 lysine 27 methylation and higher levels of neutral amino acid transporters, correlating with F-fluciclovine uptake on positron emission tomography imaging.

Non-invasive diagnostic method to objectively measure olfaction and diagnose smell disorders by molecularly targeted fluorescent imaging agent.

The sense of smell (olfaction) is one of the most important senses for animals including humans. Despite significant advances in the understanding mechanism of olfaction, currently, there are no objective non-invasive methods that can identify loss of smell. Covid-19-related loss of smell has highlighted the need to develop methods that can identify loss of olfaction.

Synthesis of carbohydrate analogues of the THF-acetogenin 4-deoxyannomontacin and their cytotoxicity against human prostate cancer cell lines.

The THF containing acetogenin 4-deoxyannonmontacin (4-DAN) has attracted interest for its potent cytotoxicity against a broad range of human tumor cell lines, and relatively simple structure. Herein is described the synthesis and cytotoxicity of C-10 epimers of 4-DAN and analogues thereof comprising carbohydrate and thiophene substitutes for the THF and butenolide moieties respectively. The key synthetic ploy was the union of THF and butenolide segments or their substitutes, via an alkene cross metathesis.

Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer with limited meaningful treatment options. NEPC lesions uniquely express delta-like ligand 3 (DLL3) on their cell surface. Taking advantage of DLL3 overexpression, we developed and evaluated lutetium-177 (Lu)-labeled DLL3-targeting antibody SC16 (Lu-DTPA-SC16) as a treatment for NEPC.

Synthesis of I-labeled epichaperome probes and assessment in visualizing pathologic protein-protein interaction networks in tumor bearing mice.

Epichaperomes are disease-associated pathologic scaffolds composed of tightly bound chaperones and co-chaperones. They provide opportunities for precision medicine where aberrant protein-protein interaction networks, rather than a single protein, are detected and targeted. This protocol describes the synthesis and characterization of two I-labeled epichaperome probes, [I]-PU-H71 and [I]-PU-AD, both which have translated to clinical studies.

Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor.

Previously published digital autoradiography of H-labeled capecitabine reveals a near-uniform distribution of activity throughout a murine pancreatic model. This is in contrast both to C-labeled gemcitabine, and established expectations, as the dense stroma of pancreatic cancer is understood to inhibit drug penetration. Capecitabine is a pro-drug for 5 FU.

Noninvasive Imaging of CD4+ T Cells in Humanized Mice.

Antibody-based PET (immunoPET) with radiotracers that recognize specific cells of the immune system provides an opportunity to monitor immune cell trafficking at the organismal scale. We previously reported the visualization of human CD8+ T cells, including CD8+ tumor-infiltrating lymphocytes (TIL), in mice using a humanized CD8-targeted minibody. Given the important role of CD4+ T cells in adaptive immune responses of health and disease including infections, tumors, and autoimmunity, we explored immunoPET using an anti-human-CD4 minibody.

Molecular Imaging of Neuroendocrine Prostate Cancer by Targeting Delta-Like Ligand 3.

Treatment-induced neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer. Using the Zr-labeled delta-like ligand 3 (DLL3) targeting antibody SC16 (Zr-desferrioxamine [DFO]-SC16), we have developed a PET agent to noninvasively identify the presence of DLL3-positive NEPC lesions. Quantitative polymerase chain reaction and immunohistochemistry were used to compare relative levels of androgen receptor (AR)-regulated markers and the NEPC marker DLL3 in a panel of prostate cancer cell lines.

Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer Exhibits Antitumor Efficacy with Low Toxicity.

Purpose: Small cell lung cancer (SCLC) is an exceptionally lethal form of lung cancer with limited treatment options. Delta-like ligand 3 (DLL3) is an attractive therapeutic target as surface expression is almost exclusive to tumor cells.

Experimental Design: We radiolabeled the anti-DLL3 mAb SC16 with the therapeutic radioisotope, Lutetium-177.

Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer.

Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours.

ERK Inhibition Improves Anti-PD-L1 Immune Checkpoint Blockade in Preclinical Pancreatic Ductal Adenocarcinoma.

Patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint blockade (ICB) along the PD-1/PD-L1 axis. Variable PD-L1 expression in PDAC indicates a potential access issue of PD-L1-targeted therapy. To monitor target engagement of PD-L1-targeted therapy, we generated a PD-L1-targeted PET tracer labeled with zirconium-89 (Zr).

Measuring Tumor Epichaperome Expression Using [I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer.

Purpose: Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target.

The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology.

Translational development of radiolabeled analogues or isotopologues of small molecule therapeutic drugs as clinical imaging biomarkers for optimizing patient outcomes in targeted cancer therapy aims to address an urgent and recurring clinical need in therapeutic cancer drug development: drug- and target-specific biomarker assays that can optimize patient selection, dosing strategy, and response assessment. Imaging the in vivo tumor pharmacokinetics and biomolecular pharmacodynamics of small molecule cancer drugs offers patient- and tumor-specific data which are not available from other pharmacometric modalities. This review article examines clinical research with a growing pharmacopoeia of investigational small molecule cancer drug tracers.

Oncology-Inspired Treatment Options for COVID-19.

CR3022 is a human antibody that binds to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we explore the use of CR3022 as a molecularly targeted radiotherapeutic. CR3022 was labeled with I and purified, yielding I-CR3022.

Predicting Gemcitabine Delivery by F-FAC PET in Murine Models of Pancreatic Cancer.

F-FAC (2'-deoxy-2'-F-fluoro-β-d-arabinofuranosylcytosine) has close structural similarity to gemcitabine and thus offers the potential to image drug delivery to tumors. We compared tumor F-FAC PET images with C-gemcitabine levels, established ex vivo, in 3 mouse models of pancreatic cancer. We further modified tumor gemcitabine levels with injectable PEGylated recombinant human hyaluronidase (PEGPH20) to test whether changes in gemcitabine would be tracked by F-FAC.

Improved radiosynthesis of I-MAPi, an auger theranostic agent.

Purpose: I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials.

Synthesis of the PET Tracer I-Trametinib for MAPK/ERK Kinase Distribution and Resistance Monitoring.

Trametinib is an extremely potent allosteric inhibitor of mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) (MEK) 1/2, which has been approved for treatment of metastatic melanoma and anaplastic thyroid cancer in patients with confirmed BRAF/K mutations. Though trametinib is highly efficacious, adverse side effects, including skin, gastrointestinal, and hepatic toxicity, are dose-limiting and can lead to treatment termination. Development of a noninvasive tool to visualize and quantify the delivery and distribution of trametinib (either as a single agent or in combination with other therapeutics) to tumors and organs would be helpful in assessing therapeutic index, personalizing individual dose, and potentially predicting resistance to therapy.