Hidden in Plain Sight: Clinical Imaging of the Tumor Microenvironment with PET.

PET imaging enables the spatiotemporal assessment of tumor biomarkers. In this issue, Kong and colleagues describe the clinical PET imaging of tumor-associated fibroblasts, which improved the diagnostic accuracy and management of a subset of patients with medullary thyroid carcinoma. See related article by Kong et al.

Compact and cGMP-compliant automated synthesis of [F]FSPG on the Trasis AllinOne™.

Background: (S)-4-(3-F-Fluoropropyl)-ʟ-glutamic acid ([F]FSPG) is a positron emission tomography radiotracer used to image system x, an antiporter that is upregulated in several cancers. Not only does imaging system x with [F]FSPG identify tumours, but it can also provide an early readout of response and resistance to therapy. Unfortunately, the clinical production of [F]FSPG has been hampered by a lack of robust, cGMP-compliant methods.

Molecular Imaging of Cancer Stem Cells and Their Role in Therapy Resistance.

Despite recent therapeutic breakthroughs, cancer patients continue to face high recurrence and mortality rates due to treatment resistance. Cancer stem cells (CSCs), a subpopulation with self-renewal capabilities, are key drivers of refractive disease. This review explores the application of molecular imaging techniques, such as PET and SPECT, for the noninvasive detection of CSCs.

Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system x radiotracer, [F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC.

Is there a role for [F]-FMISO PET to guide dose adaptive radiotherapy in head and neck cancer? A review of the literature.

Purpose: Hypoxia is a major cause of radioresistance in head and neck cancer (HNC), resulting in treatment failure and disease recurrence. F-fluoromisonidazole [F]FMISO PET has been proposed as a means of localising intratumoural hypoxia in HNC so that radiotherapy can be specifically escalated in hypoxic regions. This concept may not be deliverable in routine clinical practice, however, given that [F]FMISO PET is costly, time consuming and difficult to access.

[F]FSPG-PET provides an early marker of radiotherapy response in head and neck squamous cell cancer.

The ability to image early treatment response to radiotherapy in head and neck squamous cell carcinoma (HNSCC) will enable the identification of radioresistant tumor volumes suitable for treatment intensification. Here, we propose the system x radiotracer (4)-4-(3-[F]fluoropropyl)-L-glutamate ([F]FSPG) as a non-invasive method to monitor radiation response in HNSCC. We assessed temporal changes in cell death, antioxidant status, and [F]FSPG retention following a single dose of 10 Gy irradiation in FaDU HNSCC cells.

(SiFA)SeFe: A Hydrophilic Silicon-Based Fluoride Acceptor Enabling Versatile Peptidic Radiohybrid Tracers.

The radiohybrid (rh) concept to design targeted (and chemically identical) radiotracers for imaging or radionuclide therapy of tumors has gained momentum. For this strategy, a new bifunctional Silicon-based Fluoride Acceptor (SiFA) moiety was synthesized, endowed with improved hydrophilicity and high versatility of integration into rh-compounds. Preliminary radiolabeling and stability studies under different conditions were conducted using model bioconjugate peptides.

The chicken chorioallantoic membrane as a low-cost, high-throughput model for cancer imaging.

Mouse models are invaluable tools for radiotracer development and validation. They are, however, expensive, low throughput, and are constrained by animal welfare considerations. Here, we assessed the chicken chorioallantoic membrane (CAM) as an alternative to mice for preclinical cancer imaging studies.

Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system x, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by ()-4-(3-F-fluoropropyl)-l-glutamate ([F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC.

Imaging the Tumor Antioxidant Response with [F]FSPG PET.

(4S)-4-(3-[F]Fluoropropyl)-L-glutamic acid ([F]FSPG) is a flourine-18 labeled glutamate analog that enables the noninvasive in vivo imaging of cellular redox status. [F]FSPG is transported across the cell membrane by the cystine/glutamate antiporter, system x, whose expression is upregulated in multiple cancer types. The requirement of cystine for the biosynthesis of glutathione, a major antioxidant, connects [F]FSPG tissue retention to the intracellular redox response via system x activity.

A prodrug strategy for the imaging of aldehyde dehydrogenase activity.

Therapy resistance is one of the biggest challenges facing clinical oncology. Despite a revolution in new anti-cancer drugs targeting multiple components of the tumour microenvironment, acquired or innate resistance frequently blunts the efficacy of these treatments. Non-invasive identification of drug-resistant tumours will enable modification of the patient treatment pathway through the selection of appropriate second-line treatments.

Radiotracer stereochemistry affects substrate affinity and kinetics for improved imaging of system x in tumors.

Amino acid utilization is perturbed in cancer cells, which rewire their metabolism to support cell survival and proliferation. This metabolic reprogramming can be exploited for diagnostic purposes through positron emission tomography imaging of fluorine-18 labeled amino acids. Despite its promise, little is known regarding transporter-recognition of non-natural amino acid stereoisomers or their utility for cancer imaging.

Latest Advances in Imaging Oxidative Stress in Cancer.

Oxidative stress is the imbalance of harmful reactive oxygen species (ROS) and the action of neutralizing antioxidant mechanisms. If left unchecked, the deleterious effects of oxidative stress result in damage to DNA, proteins, and membranes, ultimately leading to cell death. Tumors are highly proliferative and consequently generate high levels of mitochondrial ROS.

Robust and Facile Automated Radiosynthesis of [F]FSPG on the GE FASTlab.

Purpose: (S)-4-(3-F-Fluoropropyl)-ʟ-Glutamic Acid ([F]FSPG) is a radiolabeled non-natural amino acid that is used for positron emission tomography (PET) imaging of the glutamate/cystine antiporter, system x, whose expression is upregulated in many cancer types. To increase the clinical adoption of this radiotracer, reliable and facile automated procedures for [F]FSPG production are required. Here, we report a cassette-based method to produce [F]FSPG at high radioactivity concentrations from low amounts of starting activity.

The chemical tool-kit for molecular imaging with radionuclides in the age of targeted and immune therapy.

Nuclear medicine has evolved over the last half-century from a functional imaging modality using a handful of radiopharmaceuticals, many of unknown structure and mechanism of action, into a modern speciality that can properly be described as molecular imaging, with a very large number of specific radioactive probes of known structure that image specific molecular processes. The advances of cancer treatment in recent decades towards targeted and immune therapies, combined with recognition of heterogeneity of cancer cell phenotype among patients, within patients and even within tumours, has created a growing need for personalised molecular imaging to support treatment decision. This article describes the evolution of the present vast range of radioactive probes - radiopharmaceuticals - leveraging a wide variety of chemical disciplines, over the last half century.

Correction: Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by 18F-ICMT-11-Positron Emission Tomography.

[This corrects the article DOI: 10.1371/journal.pone.

Iron(II)/Persulfate Mediated Newman-Kwart Rearrangement.

Herein, we report that iron(II)/ammonium persulfate in aqueous acetonitrile mediates the Newman-Kwart rearrangement of -aryl carbamothioates. Electron-rich substrates react rapidly under moderate heating to afford the rearranged products in excellent yields. The mild conditions, rapid reaction rates, and suitability for scale up offers immediate practical benefits to access functionalized thiophenols.

One-Pot Radiosynthesis and Biological Evaluation of a Caspase-3 Selective 5-[I]iodo-1,2,3-triazole derived Isatin SPECT Tracer.

Induction of apoptosis is often necessary for successful cancer therapy, and the non-invasive monitoring of apoptosis post-therapy could assist in clinical decision making. Isatins are a class of compounds that target activated caspase-3 during apoptosis. Here we report the synthesis of the 5-iodo-1,2,3-triazole (FITI) analog of the PET tracer [F]ICMT11 as a candidate tracer for imaging of apoptosis with SPECT, as well as PET.

Imaging of T-cells and their responses during anti-cancer immunotherapy.

Immunotherapy has proven to be an effective approach in a growing number of cancers. Despite durable clinical responses achieved with antibodies targeting immune checkpoint molecules, many patients do not respond. The common denominator for immunotherapies that have successfully been introduced in the clinic is their potential to induce or enhance infiltration of cytotoxic T-cells into the tumour.