Comparative evaluation of three F-fluorinated FAP ligands in rodent tumor models.

Fibroblast activation protein (FAP) is almost exclusively expressed on cancer-associated stromal cells, making it a promising target for tumor imaging by positron emission tomography (PET). While Ga- or Al[F]F-labeled FAP inhibitors (FAPIs) have been characterized in detail, the potential advantages of FAPIs containing a covalently bound F-label remain largely unknown. The aim of the present work was to address this gap by comparing two FAPIs with a covalently bound F-label and the chelator-based radioligand Al[F]F-FAPI-42.

"Fill States": PET-derived Markers of the Spatial Extent of Alzheimer Disease Pathology.

Background Alzheimer disease (AD) progression can be monitored by tracking intensity changes in PET standardized uptake value (SUV) ratios of amyloid, tau, and neurodegeneration. The spatial extent ("fill state") of these three hallmark pathologic abnormalities may serve as critical pathophysiologic information, pending further investigation. Purpose To examine the clinical utility and increase the accessibility of PET-derived fill states.

Fully Automated Production of ((()-1-Carboxy-5-(6-([F]fluoro)-2-methoxynicotinamido)pentyl)carbamoyl)-l-glutamic Acid ([F]JK-PSMA-7).

The radiotracer [F]JK-PSMA-7, a prostate cancer imaging agent for positron emission tomography (PET), was previously synthesized by indirect radiofluorination using an F-labeled active ester as a prosthetic group, which had to be isolated and purified before it could be linked to the pharmacologically active Lys-urea-Glu motif. Although this procedure could be automated on two-reactor modules like the GE TRACERLab FX2N (FXN) to afford the tracer in modest radiochemical yields (RCY) of 18-25%, it is unsuitable for cassette-based systems with a single reactor. To simplify implementation on an automated synthesis module, the radiosynthesis of [F]JK-PSMA-7 was devised as a one-pot, two-step reaction.

[F]R91150: Improved radiosynthesis and in vivo evaluation as imaging probe for 5-HT receptors.

Serotonergic 5-HT receptors in the cortex and other forebrain structures have been linked to cognitive, emotional and memory processes. In addition, dysfunction or altered expression of these receptors is associated with neuropsychiatric and neurodegenerative disorders. [F]R91150 is a candidate radiotracer for positron emission tomography (PET) imaging of 5-HT receptors, which showed promising properties in in vitro studies.

Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.

Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity.

Do you know your PSMA-tracer? Variability in the biodistribution of different PSMA ligands and its potential impact on defining PSMA-positivity prior to PSMA-targeted therapy.

Background: In clinical practice, several radiopharmaceuticals are used for PSMA-PET imaging, each with distinct biodistribution patterns. This may impact treatment decisions and outcomes, as eligibility for PSMA-directed radioligand therapy is usually assessed by comparing tumoral uptake to normal liver uptake as a reference. In this study, we aimed to compare tracer uptake intraindividually in various reference regions including liver, parotid gland and spleen as well as the respective tumor-to-background ratios (TBR) of different F-labeled PSMA ligands to today's standard radiopharmaceutical Ga-PSMA-11 in a series of patients with biochemical recurrence of prostate cancer who underwent a dual PSMA-PET examination as part of an individualized diagnostic approach.

Preparation and Preclinical Evaluation of F-Labeled Olutasidenib Derivatives for Non-Invasive Detection of Mutated Isocitrate Dehydrogenase 1 (mIDH1).

Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling and cannot be used for longitudinal studies. Positron emission tomography (PET) imaging with mIDH1-selective radioligands is a promising alternative approach that could enable non-invasive assessment of the IDH status. In the present work, we developed efficient protocols for the preparation of four F-labeled derivatives of the mIDH1-selective inhibitor olutasidenib.

Cerebellar Metabolic Connectivity during Treadmill Walking before and after Unilateral Dopamine Depletion in Rats.

Compensatory changes in brain connectivity keep motor symptoms mild in prodromal Parkinson's disease. Studying compensation in patients is hampered by the steady progression of the disease and a lack of individual baseline controls. Furthermore, combining fMRI with walking is intricate.

Excitation functions of Ge(p,xn)As reactions from threshold up to 45 MeV for production of the non-standard positron emitter As.

Nuclear reaction cross sections for the formation of As and As in proton-induced reactions on enriched Ge targets were measured up to 45 MeV utilizing three different cyclotrons at the Forschungszentrum Jülich. The stacked-thin sample activation technique in combination with high-resolution γ-ray spectrometry was used. The major γ-ray peaks of As and As formed via the Ge(p,n)As and Ge(p,2n)As reactions, respectively, were analyzed.

Progressive Supranuclear Palsy: Subcortical Tau Depositions Are Associated with Cortical Perfusion in Frontal and Limbic Regions.

In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex.

Radiosynthesis and Preclinical Evaluation of -[F]FET and [F]FET-OMe as Novel [F]FET Analogs for Brain Tumor Imaging.

-([F]Fluoroethyl)-l-tyrosine ([F]FET) is actively transported into the brain and cancer cells by LAT1 and possibly other amino acid transporters, which enables brain tumor imaging by positron emission tomography (PET). However, tumor delivery of this probe in the presence of competing amino acids may be limited by a relatively low affinity for LAT1. The aim of the present work was to evaluate the -substituted [F]FET analog -[F]FET and the methyl ester [F]FET-OMe, which were designed to improve tumor delivery by altering the physicochemical, pharmacokinetic, and/or transport properties.

Early Blood-Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice.

Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice.

Multiparametric Characterization of the DSL-6A/C1 Pancreatic Cancer Model in Rats.

The DSL-6A/C1 murine pancreatic ductal adenocarcinoma (PDAC) tumor model was established in Lewis rats and characterized through a comprehensive multiparametric analysis to compare it to other preclinical tumor models and explore potential diagnostic and therapeutical targets. DSL-6A/C1 tumors were histologically analyzed to elucidate PDAC features. The tumor microenvironment was studied for immune cell prevalence.

8-Bicycloalkyl-CPFPX derivatives as potent and selective tools for in vivo imaging of the A adenosine receptor.

Imaging of the A adenosine receptor (AR) by positron emission tomography (PET) with 8-cyclopentyl-3-(3-[F]fluoropropyl)-1-propyl-xanthine ([F]CPFPX) has been widely used in preclinical and clinical studies. However, this radioligand suffers from rapid peripheral metabolism and subsequent accumulation of radiometabolites in the vascular compartment. In the present work, we prepared four derivatives of CPFPX by replacement of the cyclopentyl group with norbornane moieties.

Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [F]PI-2620.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e.

Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons.

Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading to mitochondrial dysfunction, are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations.

Radiosynthesis and In Vitro Evaluation of [C]tozadenant as Adenosine A Receptor Radioligand.

Tozadenant (4-hydroxy--(4-methoxy-7-morpholinobenzo[]thiazol-2-yl)-4-methylpiperidine-1-carboxamide) is a highly selective adenosine A receptor (AR) antagonist and a promising lead structure for the development of AR-selective positron emission tomography (PET) probes. Although several F-labelled tozadenant derivatives showed favorable in vitro properties, recent in vivo PET studies observed poor brain penetration and lower specific binding than anticipated from the in vitro data. While these findings might be attributable to the structural modification associated with F-labelling, they could also reflect inherent properties of the parent compound.

Desmethyl SuFEx-IT: SOF-Free Synthesis and Evaluation as a Fluorosulfurylating Agent.

Access to SuFExable compounds was remarkably simplified by introduction of the solid FOS-donor SuFEx-IT. However, the published process for preparation of this reagent relies on the use of sulfuryl fluoride (SOF), which is difficult to obtain and highly toxic. Herein, we disclose a simple protocol for SOF-free, hectogram-scale preparation of the analogous desmethyl SuFEx-IT from inexpensive starting materials.

Fragmentation of functional resting state brain networks in a transgenic mouse model of tau pathology: A metabolic connectivity study using [F]FDG-PET.

In a previous study, regional reductions in cerebral glucose metabolism have been demonstrated in the tauopathy mouse model rTg4510 (Endepols et al., 2022). Notably, glucose hypometabolism was present in some brain regions without co-localized synaptic degeneration measured with [F]UCB-H.

Preparation of -Methyl-6-[F]fluoro- and 5-Hydroxy-7-[F]fluorotryptophans as Candidate PET-Tracers for Pathway-Specific Visualization of Tryptophan Metabolism.

Tryptophan (Trp) is an essential proteinogenic amino acid and metabolic precursor for several signaling molecules that has been implicated in many physiological and pathological processes. Since the two main branches of Trp metabolism-serotonin biosynthesis and kynurenine pathway-are differently affected by a variety of neurological and neoplastic diseases, selective visualization of these pathways is of high clinical relevance. However, while positron emission tomography (PET) with existing probes can be used for non-invasive assessment of total Trp metabolism, optimal imaging agents for pathway-specific PET imaging are still lacking.

In Vivo Measurement of Tau Depositions in Anti-IgLON5 Disease Using [18F]PI-2620 PET.

Objectives: Anti-IgLON5 disease is a recently discovered neurologic disorder combining autoimmunity and neurodegeneration. Core manifestations include sleep disorders, bulbar symptoms, gait abnormalities, and cognitive dysfunction, but other presentations have been reported. Hallmarks are autoantibodies targeting the neuronal surface protein IgLON5, a strong human leukocyte antigen system Class II association, and brainstem and hypothalamus-dominant tau deposits.

TgF344-AD Rat Model of Alzheimer's Disease: Spatial Disorientation and Asymmetry in Hemispheric Neurodegeneration.

Background: The TgF344-AD ratline represents a transgenic animal model of Alzheimer's disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation.

Assessment of Brain Tumour Perfusion Using Early-Phase F-FET PET: Comparison with Perfusion-Weighted MRI.

Purpose: Morphological imaging using MRI is essential for brain tumour diagnostics. Dynamic susceptibility contrast (DSC) perfusion-weighted MRI (PWI), as well as amino acid PET, may provide additional information in ambiguous cases. Since PWI is often unavailable in patients referred for amino acid PET, we explored whether maps of relative cerebral blood volume (rCBV) in brain tumours can be extracted from the early phase of PET using O-(2-F-fluoroethyl)-L-tyrosine (F-FET).

Validation of analytical HPLC with post-column injection as a method for rapid and precise quantification of radiochemical yields.

Accurate assessment of isolated radiochemical yields (RCYs) is a prerequisite for efficient and reliable optimization of labeling reactions. In practice, radiochemical conversions (RCCs) determined by HPLC analysis of crude reaction mixtures are often used to estimate RCYs. However, incomplete recovery of radioactivity from the stationary phase can lead to significant inaccuracies if RCCs are calculated based on the activity eluted from the column (i.

7-[F]Fluoro-8-azaisatoic Anhydrides: Versatile Prosthetic Groups for the Preparation of PET Tracers.

F-Fluorination of sensitive molecules is often challenging, but can be accomplished under suitably mild conditions using radiofluorinated prosthetic groups (PGs). Herein, 1-alkylamino-7-[F]fluoro-8-azaisatoic anhydrides ([F]AFAs) are introduced as versatile F-labeled building blocks that can be used as amine-reactive or "click chemistry" PGs. [F]AFAs were efficiently prepared within 15 min by "on cartridge" radiolabeling of readily accessible trimethylammonium precursors.