The association between grey matter microstructural MRI biomarkers, mid‐life blood pressure, and late‐life Alzheimer’s disease pathology.

Background: With an aging population, it is essential to identify subtle features of brain pathology – both neurodegenerative and vascular – at an early stage, which may predict risk of future decline. We used diffusion MRI (dMRI) to assess grey matter cortical microstructure and investigate associations with 1) Alzheimer’s disease (AD) pathology and 2) mid/late‐life vascular risk (as measured by blood pressure (BP)).

Method: 151 asymptomatic individuals from the British 1946 birth cohort underwent combined PET/MR with [18F]florbetapir Aβ‐PET at ∼73yrs, and [18F]MK‐6240 tau‐PET at ∼76yrs.

Estimating the time between Aβ positivity and elevated regional tau in preclinical AD.

Background: Understanding when Aβ positive cognitively normal individuals develop tau pathology has important implications for treatment with anti‐Aβ therapies. We employed a changepoint regression approach to estimate time from Aβ‐PET positivity to regionally elevated tau‐PET in a population‐based cohort of primarily cognitively unimpaired individuals.

Method: Participants from Insight 46 (1946 British birth cohort) underwent two [F]florbetapir Aβ‐PET scans and a sub‐sample enriched for Aβ were also scanned with [F]MK‐6240 tau‐PET, characteristics are presented in Table 1.

Estimating the time between Aβ positivity and elevated regional tau in preclinical AD.

Background: Understanding when Aß positive cognitively normal individuals develop tau pathology has important implications for treatment with anti‐Aß therapies. We employed a changepoint regression approach to estimate time from Aß‐PET positivity to regionally elevated tau‐PET in a population‐based cohort of primarily cognitively unimpaired individuals.

Method: Participants from Insight 46 (1946 British birth cohort) underwent two [18F]florbetapir Aß‐PET scans and a sub‐sample enriched for Aß were also scanned with [18F]MK‐6240 tau‐PET, characteristics are presented in Table 1.

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

Background: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease.

Oxidation-Cyclisation of Biphenyl Thioethers to Dibenzothiophenium Salts for Ultrarapid F-Labelling of PET Tracers.

F-labelled radiotracers are in high demand and play an important role for diagnostic imaging with positron emission tomography (PET). Challenges associated with the synthesis of the labelling precursors and the incorporation of [F]fluoride with practical activity yields at batch scale are the main limitations for the development of new F-PET tracers. Herein, we report a high-yielding and robust synthetic method to access naked dibenzothiophenium salt precursors of complex PET tracers and their labelling with [F]fluoride.

Drug delivery, biodistribution and anti-EGFR activity: theragnostic nanoparticles for simultaneous delivery of tyrosine kinase inhibitors and kinase activity biosensors.

delivery of small molecule therapeutics to cancer cells, assessment of the selectivity of administration, and measuring the efficacity of the drug in question at the molecule level, are important ongoing challenges in developing new classes of cancer chemotherapeutics. One approach that has the potential to provide targeted delivery, tracking of biodistribution and readout of efficacy, is to use multimodal theragnostic nanoparticles to deliver the small molecule therapeutic. In this paper, we report the development of targeted theragnostic lipid/peptide/DNA lipopolyplexes.

Development of [F]AldoView as the First Highly Selective Aldosterone Synthase PET Tracer for Imaging of Primary Hyperaldosteronism.

The purpose of this study was to synthesize a fluorine-18 labeled, highly selective aldosterone synthase (CYP11B2) inhibitor, [F]AldoView, and to assess its potential for the detection of aldosterone-producing adenomas (APAs) with positron emission tomography in patients with primary hyperaldosteronism (PHA). Using dibenzothiophene sulfonium salt chemistry, [F]AldoView was obtained in high radiochemical yield in one step from [F]fluoride. In mice, the tracer showed a favorable pharmacokinetic profile, including rapid distribution and clearance.

Resolving the cellular specificity of TSPO imaging in a rat model of peripherally-induced neuroinflammation.

The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET). TSPO PET imaging of the central nervous system (CNS) has been widely undertaken, but to date no clear consensus has been reached about its utility in brain disorders. One reason for this could be because the interpretation of TSPO PET signal remains challenging, given the cellular heterogeneity and ubiquity of TSPO in the brain.

Validation of a combined image derived input function and venous sampling approach for the quantification of [F]GE-179 PET binding in the brain.

Blood-based kinetic analysis of PET data relies on an accurate estimate of the arterial plasma input function (PIF). An alternative to invasive measurements from arterial sampling is an image-derived input function (IDIF). However, an IDIF provides the whole blood radioactivity concentration, rather than the required free tracer radioactivity concentration in plasma.

Discriminatory ability of next-generation tau PET tracers for Alzheimer's disease.

A next generation of tau PET tracers for the imaging of Alzheimer's disease and other dementias has recently been developed. Whilst the new compounds have now entered clinical studies, there is limited information available to assess their suitability for clinical applications. Head-to-head comparisons are urgently needed to understand differences in the radiotracer binding profiles.

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.

Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers.

Objective: Identification of patients at risk of developing epilepsy before the first spontaneous seizure may promote the development of preventive treatment providing opportunity to stop or slow down the disease.

Methods: As development of novel radiotracers and on-site setup of existing radiotracers is highly time-consuming and expensive, we used dual-centre in vitro autoradiography as an approach to characterize the potential of innovative radiotracers in the context of epilepsy development. Using brain slices from the same group of rats, we aimed to characterise the evolution of neuroinflammation and expression of inhibitory and excitatory neuroreceptors during epileptogenesis using translational positron emission tomography (PET) tracers; F-flumazenil ( F-FMZ; GABA receptor), F-FPEB (metabotropic glutamate receptor 5; mGluR5), F-flutriciclamide (translocator protein; TSPO, microglia activation) and F-deprenyl (monoamine oxidase B, astroglia activation).

Hyperpolarised C MRI: a new horizon for non-invasive diagnosis of aggressive breast cancer.

Hyperpolarised C MRI (HP-MRI) is a novel imaging technique that allows real-time analysis of metabolic pathways . The technology to conduct HP-MRI in humans has recently become available and is starting to be clinically applied. As knowledge of molecular biology advances, it is increasingly apparent that cancer cell metabolism is related to disease outcomes, with lactate attracting specific attention.

First-in-human non-invasive assessment of intra-tumoral metabolic heterogeneity in renal cell carcinoma.

Intratumoral genetic heterogeneity and the role of metabolic reprogramming in renal cell carcinoma (RCC) have been extensively documented. However, the distribution of these metabolic changes within the tissue has not been explored. We report on the first-in-human non-invasive metabolic interrogation of RCC using hyperpolarized carbon-13 (C) magnetic resonance imaging (HP-MRI) and describe the validation of lactate metabolic heterogeneity against multi-regional mass spectrometry.

Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography.

Purpose: Drug resistance is a major obstacle for the effective treatment of patients with high-grade serous ovarian cancer (HGSOC). Currently, there is no satisfactory way to identify patients with HGSOC that are refractive to the standard of care. Here, we propose the system x radiotracer (4)-4-(3-[F]fluoropropyl)-l-glutamate ([F]FSPG) as a non-invasive method to measure upregulated antioxidant pathways present in drug-resistant HGSOC.

Mapping Aldehyde Dehydrogenase 1A1 Activity using an [ F]Substrate-Based Approach.

Aldehyde dehydrogenases (ALDHs) catalyze the oxidation of aldehydes to carboxylic acids. Elevated ALDH expression in human cancers is linked to metastases and poor overall survival. Despite ALDH being a poor prognostic factor, the non-invasive assessment of ALDH activity in vivo has not been possible due to a lack of sensitive and translational imaging agents.

Assessment of Tumor Redox Status through ()-4-(3-[F]fluoropropyl)-L-Glutamic Acid PET Imaging of System x Activity.

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system x maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis.

Comment on " In Vivo [F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates".

Schoenberger and colleagues ( Schoenberger et al. ( 2018 ) ACS Chem. Neurosci.

Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic F-Fluorination.

Herein, we report a novel intramolecular ring-closing reaction of biaryl thioethers that give access to highly functionalized dibenzothiophene sulfonium salts under mild conditions. The resulting precursors react regioselectively with [F]fluoride to give [F]fluoroarenes in predictable radiochemical yields. The strategy expands the available radiochemical space and provides superior labeling efficiency for clinically relevant PET tracers.

Large inter- and intra-case variability of first generation tau PET ligand binding in neurodegenerative dementias.

Imaging of pathological tau with positron emission tomography (PET) has the potential to allow early diagnosis of the dementias and monitoring of disease progression, including assessment of therapeutic interventions, in vivo. The first generation of tau PET tracers, including the carbazole flortaucipir and the 2-arylquinolines of the THK series, are now used in clinical research; however, concerns have been raised about off-target binding and low sensitivity.With the aim to determine the nature of tau pathology depicted by structurally distinct tau ligands we carried out a microscopic neuropathological evaluation in post-mortem human brain tissue of cases with primary and secondary tauopathies.

Functional imaging in microfluidic chambers reveals sensory neuron sensitivity is differentially regulated between neuronal regions.

Primary afferent sensory neurons are incredibly long cells, often traversing distances of over 1 m in humans. Cutaneous sensory stimuli are transduced in the periphery by specialised end organs or free nerve endings, which code the stimulus into electrical action potentials that propagate towards the central nervous system. Despite significant advances in our knowledge of sensory neuron physiology and ion channel expression, many commonly used techniques fail to accurately model the primary afferent neuron in its entirety.

A Dual Reporter Iodinated Labeling Reagent for Cancer Positron Emission Tomography Imaging and Fluorescence-Guided Surgery.

The combination of early diagnosis and complete surgical resection offers the greatest prospect of curative cancer treatment. An iodine-124/fluorescein-based dual-modality labeling reagent, I-Green, constitutes a generic tool for one-step installation of a positron emission tomography (PET) and a fluorescent reporter to any cancer-specific antibody. The resulting antibody conjugate would allow both cancer PET imaging and intraoperative fluorescence-guided surgery.